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clinicalnlplab
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PLOS_1shot_test

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train · 26.1k rows

id stringlengths 5 9	query stringlengths 520 6.19k	answer stringlengths 115 4.83k
PLOS0	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Control of arbovirus transmission remains focused on vector control through application of insecticides directly to the environment. However, these insecticide applications are often reactive interventions that can be poorly-targeted, inadequate for localized control during outbreaks, and opposed due to environmental and toxicity concerns. In this study, we developed endectocide-treated feed as a systemic endectocide for birds to target blood feeding Culex tarsalis, the primary West Nile virus (WNV) bridge vector in the western United States, and conducted preliminary tests on the effects of deploying this feed in the field. In lab tests, ivermectin (IVM) was the most effective endectocide tested against Cx. tarsalis and WNV-infection did not influence mosquito mortality from IVM. Chickens and wild Eurasian collared doves exhibited no signs of toxicity when fed solely on bird feed treated with concentrations up to 200 mg IVM/kg of diet, and significantly more Cx. tarsalis that blood fed on these birds died (greater than 80% mortality) compared to controls (less than 25% mortality). Mosquito mortality following blood feeding correlated with IVM serum concentrations at the time of blood feeding, which dropped rapidly after the withdrawal of treated feed. Preliminary field testing over one WNV season in Fort Collins, Colorado demonstrated that nearly all birds captured around treated bird feeders had detectable levels of IVM in their blood. However, entomological data showed that WNV transmission was non-significantly reduced around treated bird feeders. With further development, deployment of ivermectin-treated bird feed might be an effective, localized WNV transmission control tool. Output:	West Nile virus (WNV) is a mosquito-borne virus that causes significant disease and death every year in humans, domesticated animals, and wildlife. Control of WNV transmission is focused on controlling the mosquito vector through applications of insecticides directly to the environment. In this study, we evaluate a novel control strategy for WNV transmission by targeting the main mosquito bridge vector in the Great Plains region, Culex tarsalis, through its blood feeding behavior. Because Culex tarsalis favor taking blood meals from particular bird species, our strategy aims to target these bird species with endectocide-treated bird feed that will result in lethal blood meals for Cx. tarsalis. In this study, we developed a safe and effective formulation of ivermectin-treated diet that resulted in increased mortality for Cx. tarsalis blood fed on birds consuming this treated diet as compared to mosquitoes feeding on control birds. We also conducted a pilot field trial in Fort Collins, Colorado to test this strategy in a natural transmission cycle, which demonstrated promising results.
PLOS1	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Ebola virus emerged in West Africa in December 2013. The high population mobility and poor public health infrastructure in this region led to the development of the largest Ebola virus disease (EVD) outbreak to date. On September 26, 2014, China dispatched a Mobile Biosafety Level-3 Laboratory (MBSL-3 Lab) and a well-trained diagnostic team to Sierra Leone to assist in EVD diagnosis using quantitative real-time PCR, which allowed the diagnosis of suspected EVD cases in less than 4 hours from the time of sample receiving. This laboratory was composed of three container vehicles equipped with advanced ventilation system, communication system, electricity and gas supply system. We strictly applied multiple safety precautions to reduce exposure risks. Personnel, materials, water and air flow management were the key elements of the biosafety measures in the MBSL-3 Lab. Air samples were regularly collected from the MBSL-3 Lab, but no evidence of Ebola virus infectious aerosols was detected. Potentially contaminated objects were also tested by collecting swabs. On one occasion, a pipette tested positive for EVD. A total of 1,635 suspected EVD cases (824 positive [50.4%]) were tested from September 28 to November 11, 2014, and no member of the diagnostic team was infected with Ebola virus or other pathogens, including Lassa fever. The specimens tested included blood (69.2%) and oral swabs (30.8%) with positivity rates of 54.2% and 41.9%, respectively. The China mobile laboratory was thus instrumental in the EVD outbreak response by providing timely and reliable diagnostics. The MBSL-3 Lab significantly contributed to establishing a suitable laboratory response capacity during the emergence of EVD in Sierra Leone. Output:	A Mobile Biosafety Level-3 Laboratory (MBSL-3 Lab) and a well-trained diagnostic team were dispatched to Sierra Leone to assist in Ebola virus disease (EVD) diagnosis when the largest outbreak of EVD to date emerged in West Africa in 2014. This setup allowed for the diagnosis of suspected EVD cases in less than 4 hours from the time of sample receiving. The laboratory was composed of three container vehicles and was equipped with advanced ventilation system, communication system, electricity and gas supply system. Multiple safety precautions were strictly applied to reduce exposure risks. A total of 1,635 suspected EVD cases were evaluated from September 28 to November 11, 2014, and none of the staff members was infected with Ebola virus or other pathogens. The China mobile laboratory was thus instrumental in the EVD outbreak response by providing timely and accurate diagnostics. Therefore, the MBSL-3 Lab played a significant role in establishing a suitable laboratory response capacity during the emergence of EVD in Sierra Leone.
PLOS2	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Infection with HIV-1 perturbs homeostasis of human T cell subsets, leading to accelerated immunologic deterioration. While studying changes in CD4+ memory and naïve T cells during HIV-1 infection, we found that a subset of CD4+ effector memory T cells that are CCR7−CD45RO−CD45RA+ (referred to as TEMRA cells), was significantly increased in some HIV-infected individuals. This T cell subset displayed a differentiated phenotype and skewed Th1-type cytokine production. Despite expressing high levels of CCR5, TEMRA cells were strikingly resistant to infection with CCR5 (R5)–tropic HIV-1, but remained highly susceptible to CXCR4 (X4)–tropic HIV-1. The resistance of TEMRA cells to R5-tropic viruses was determined to be post-entry of the virus and prior to early viral reverse transcription, suggesting a block at the uncoating stage. Remarkably, in a subset of the HIV-infected individuals, the relatively high proportion of TEMRA cells within effector T cells strongly correlated with higher CD4+ T cell numbers. These data provide compelling evidence for selection of an HIV-1–resistant CD4+ T cell population during the course of HIV-1 infection. Determining the host factors within TEMRA cells that restrict R5-tropic viruses and endow HIV-1–specific CD4+ T cells with this ability may result in novel therapeutic strategies against HIV-1 infection. Output:	HIV-1 infection profoundly perturbs the immune system and is characterized by depletion of CD4+ T cells and chronic immune activation, which lead to AIDS. Although HIV-1 targets CD4+ T cells, it also requires a second receptor in order to infect the target cells. The majority of HIV-1 strains that are transmitted use a cell surface molecule called CCR5, which is expressed on a portion of T cells. In this manuscript we identify a subset of human CD4+ T cells, which we termed TEMRA cells, that express CCR5 but still remain resistant to infection. We show that HIV-1 infection is blocked in TEMRA cells after entry of the virus, but before it has a chance to integrate into the cellular genome. TEMRA cells are present at low frequency in HIV-1 uninfected individuals but greatly increase in some HIV-infected individuals, which correlates with higher CD4+ T cell numbers. These findings provide the basis for future studies to understand the role of TEMRA cells during HIV-1 infection and identify the host factors that could restrict the virus. This knowledge may be used to endow susceptible T cells with the ability to resist infection and result in novel vaccine or therapeutic strategies against HIV-1 infection.
PLOS3	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The guanylate-binding proteins (GBPs) belong to the dynamin superfamily of GTPases and function in cell-autonomous defense against intracellular pathogens. IpaH9.8, an E3 ligase from the pathogenic bacterium Shigella flexneri, ubiquitinates a subset of GBPs and leads to their proteasomal degradation. Here we report the structure of a C-terminally truncated GBP1 in complex with the IpaH9.8 Leucine-rich repeat (LRR) domain. IpaH9.8LRR engages the GTPase domain of GBP1, and differences in the Switch II and α3 helix regions render some GBPs such as GBP3 and GBP7 resistant to IpaH9.8. Comparisons with other IpaH structures uncover interaction hot spots in their LRR domains. The C-terminal region of GBP1 undergoes a large rotation compared to previously determined structures. We further show that the C-terminal farnesylation modification also plays a role in regulating GBP1 conformation. Our results suggest a general mechanism by which the IpaH proteins target their cellular substrates and shed light on the structural dynamics of the GBPs. Output:	Shigella flexneri is a Gram-negative bacteria that causes diarrhea in humans and leads to a million deaths every year. Once inside the cell, S. flexneri injects the host cell cytoplasm with effector proteins to suppress host defense. The guanylate-binding proteins (GBPs) have potent antimicrobial functions against a number of pathogens including S. flexneri. For successful infection, S. flexneri relies on an effector protein known as IpaH9.8, a unique ubiquitin E3 ligase to target a subset of GBPs for proteasomal degradation. How these GBPs are specifically recognized by IpaH9.8 was unclear. Here, using a combination of structural and biochemical approaches, we reveal the molecular basis of GBP-IpaH9.8 interaction, and show that subtle differences in the seven human GBPs can significantly impact the targeting specificity of IpaH9.8. We also show that the GBPs have considerable structural flexibility, which is likely important for their function. Our results provide further insights into S. flexneri pathogenesis, and laid the groundwork for future biophysical and biochemical studies to investigate the functional mechanism of GBPs.
PLOS4	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Identification of cellular receptors and characterization of viral tropism in animal models have vastly improved our understanding of morbillivirus pathogenesis. However, specific aspects of viral entry, dissemination and transmission remain difficult to recapitulate in animal models. Here, we used three virologically identical but phenotypically distinct recombinant (r) canine distemper viruses (CDV) expressing different fluorescent reporter proteins for in vivo competition and airborne transmission studies in ferrets (Mustela putorius furo). Six donor ferrets simultaneously received three rCDVs expressing green, red or blue fluorescent proteins via conjunctival (ocular, Oc), intra-nasal (IN) or intra-tracheal (IT) inoculation. Two days post-inoculation sentinel ferrets were placed in physically separated adjacent cages to assess airborne transmission. All donor ferrets developed lymphopenia, fever and lethargy, showed progressively increasing systemic viral loads and were euthanized 14 to 16 days post-inoculation. Systemic replication of virus inoculated via the Oc, IN and IT routes was detected in 2/6, 5/6 and 6/6 ferrets, respectively. In five donor ferrets the IT delivered virus dominated, although replication of two or three different viruses was detected in 5/6 animals. Single lymphocytes expressing multiple fluorescent proteins were abundant in peripheral blood and lymphoid tissues, demonstrating the occurrence of double and triple virus infections. Transmission occurred efficiently and all recipient ferrets showed evidence of infection between 18 and 22 days post-inoculation of the donor ferrets. In all cases, airborne transmission resulted in replication of a single-colored virus, which was the dominant virus in the donor ferret. This study demonstrates that morbilliviruses can use multiple entry routes in parallel, and co-infection of cells during viral dissemination in the host is common. Airborne transmission was efficient, although transmission of viruses expressing a single color suggested a bottleneck event. The identity of the transmitted virus was not determined by the site of inoculation but by the viral dominance during dissemination. Output:	Canine distemper virus (CDV) infection of ferrets is a tractable animal model for measles. Ferrets are highly susceptible to CDV, and inoculation with a low dose leads to lethal disease. We performed in vivo competition experiments to study virus entry, dissemination and transmission. Ferrets were simultaneously inoculated with CDV via the conjunctival, intra-nasal and intra-tracheal routes. The viruses were identical except for the fluorescent reporter protein encoded by the viral genome. By detecting cells expressing the different fluorescent reporter proteins at various sites in the host, we determined that CDV can enter the host in parallel at multiple sites. Virus spread in the ferret occurred via infected lymphocytes, which often turned out to be double- or triple-infected. Sentinel ferrets, placed in physically separated adjacent cages, became infected by airborne transmission. Transmission of the dominant single color despite replication of multicolor viruses in the upper respiratory tract suggested a bottleneck event.
PLOS5	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Seminal fluid proteins affect fertility at multiple stages in reproduction. In many species, a male's ejaculate coagulates to form a copulatory plug. Although taxonomically widespread, the molecular details of plug formation remain poorly understood, limiting our ability to manipulate the structure and understand its role in reproduction. Here I show that male mice knockouts for transglutaminase IV (Tgm4) fail to form a copulatory plug, demonstrating that this gene is necessary for plug formation and lending a powerful new genetic tool to begin characterizing plug function. Tgm4 knockout males show normal sperm count, sperm motility, and reproductive morphology. However, very little of their ejaculate migrates into the female's reproductive tract, suggesting the plug prevents ejaculate leakage. Poor ejaculate migration leads to a reduction in the proportion of oocytes fertilized. However, Tgm4 knockout males fertilized between 3–11 oocytes, which should be adequate for a normal litter. Nevertheless, females mated to Tgm4 knockout males for approximately 14 days were significantly less likely to give birth to a litter compared to females mated to wild-type males. Therefore, it appears that the plug also affects post-fertilization events such as implantation and/or gestation. This study shows that a gene influencing the viscosity of seminal fluid has a major influence on male fertility. Output:	Male reproductive fitness is strongly affected by seminal fluid. In many animals, the male's ejaculate coagulates in the female's reproductive tract to form a structure known as the copulatory plug. Here, I show that male mice without a functional copy of the gene transglutaminase IV cannot form a plug and suffer severe fertility defects. In spite of normal reproductive morphology, less of the ejaculate migrates through the female's reproductive tract and Tgm4 knockout males sire significantly fewer litters than wild type. This study demonstrates that the copulatory plug and/or Tgm4 itself is necessary for normal fertility.
PLOS6	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual to different vaccines. We analyzed longitudinal data on antibody titers in 45 individuals to characterize the extent of this heterogeneity and used models to determine how it affected the longevity of protective immunity to measles, rubella, vaccinia, tetanus, and diphtheria. Our analysis showed that the magnitude of responses in different individuals varied between 12- and 200-fold (95% coverage) depending on the antigen. Heterogeneity in the magnitude and decay rate contribute comparably to variation in the longevity of protective immunity between different individuals. We found that some individuals have, on average, slightly longer-lasting memory than others—on average, they have higher antibody levels with slower decay rates. We identified different patterns for the loss of protective levels of antibodies to different vaccine and virus antigens. Specifically, we found that for the first 25 to 50 years, virtually all individuals have protective antibody titers against diphtheria and tetanus, respectively, but about 10% of the population subsequently lose protective immunity per decade. In contrast, at the outset, not all individuals had protective titers against measles, rubella, and vaccinia. However, these antibody titers wane much more slowly, with a loss of protective immunity in only 1% to 3% of the population per decade. Our results highlight the importance of long-term longitudinal studies for estimating the duration of protective immunity and suggest both how vaccines might be improved and how boosting schedules might be reevaluated. Output:	Immunological memory, mediated by antibodies, is a hallmark of immunity. A key problem for determining the longevity of protective immunity is heterogeneity in the responses of different individuals. We characterize the extent of this heterogeneity and determine how it affects the longevity of protection. We found that some individuals have higher antibody titers and these same individuals tend to have slower decay rates than others. We also found substantial heterogeneity in both the magnitude and decay rate of responses. Furthermore, differences in these two factors contribute comparably to the variation in antibody titers between different individuals over their lifetime. We then use statistical models to determine how variation in the magnitude and decay rate affect how protective immunity is lost at the population level to different virus and vaccine antigens. We identified different patterns for the loss of protective immunity elicited by protein immunization (tetanus and diphtheria) versus replicating viruses (measles, rubella, and vaccinia). While our results agree with the conventional view that antibodies elicited by protein immunization decay faster than those elicited by replicating viruses, we found that this is compensated for by the higher magnitude of responses (relative to the level for protection) for tetanus and diphtheria. Indeed, for the first 4 decades, a higher fraction of vaccinated individuals have protective immunity to tetanus and diphtheria than to measles, rubella, and vaccinia.
PLOS7	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The Down syndrome cell adhesion molecule, also known as Dscam, is a member of the immunoglobulin super family. Dscam plays an essential function in neuronal wiring and appears to be involved in innate immune reactions in insects. The deduced amino acid sequence of Dscam in the crustacean Pacifastacus leniusculus (PlDscam), encodes 9(Ig)-4(FNIII)-(Ig)-2(FNIII)-TM and it has variable regions in the N-terminal half of Ig2 and Ig3 and the complete Ig7 and in the transmembrane domain. The cytoplasmic tail can generate multiple isoforms. PlDscam can generate more than 22,000 different unique isoforms. Bacteria and LPS injection enhanced the expression of PlDscam, but no response in expression occurred after a white spot syndrome virus (WSSV) infection or injection with peptidoglycans. Furthermore, PlDscam silencing did not have any effect on the replication of the WSSV. Bacterial specific isoforms of PlDscam were shown to have a specific binding property to each tested bacteria, E. coli or S. aureus. The bacteria specific isoforms of PlDscam were shown to be associated with bacterial clearance and phagocytosis in crayfish. Output:	Invertebrate animals lack an adaptive immune system and have no antibodies. Vertebrate antibodies belong to the immunoglobulin super family of proteins, and one other member of this large family is the Down syndrome cell adhesion molecule or Dscam. Of specific interest is that Dscam proteins in invertebrates show a great diversity of isoforms, and its gene structure in Drosophila melanogaster and other insect species allow for more than 30,000 different isoforms. Dscam proteins are important for the interaction between neurons in insects, but recently a role for this hypervariable protein in immune defense has been shown. Here, we show that Dscam proteins with similar highly variable structures are present in a crustacean, the freshwater crayfish Pacifastacus leniusculus. We also found that specific isoforms could be induced in the animal after injection of different bacteria. The Dscam isoforms induced by Escherichia coli were found to cluster together in a phylogenetic analysis. Furthermore we produced recombinant proteins of the different isoforms that were induced by E. coli and Staphylococcus aureus and we could demonstrate that these proteins can bind specifically to their corresponding bacteria. The bacteria specific isoforms of Dscam were also shown to be associated with bacterial clearance and phagocytosis in crayfish. Our study therefore provides new insights into the function of invertebrate Dscams in immunity.
PLOS8	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection. Output:	When taken consistently, PrEP has been shown to reduce the risk of HIV infection by up to 92% in people who are at high risk. However, PrEP is much less effective if it is not taken consistently. To improve adherence to the drug regimen, several new drug delivery systems, that include novel gel formulations and long-acting delivery systems, are being evaluated. In this manuscript, we used BLT humanized mice, an in vivo model of vaginal HIV transmission, to evaluate two novel delivery systems for HIV prevention. In the first approach, we combined the highly efficient encapsulation of antiretroviral drugs into nanoparticles with a thermosensitive gel that remains liquid at room temperature and solidifies at body temperature. Our results showed that this delivery system provided significant protection from HIV vaginal infection. In a second approach, we evaluated a long-acting nanoparticle formulation for coitus-independent protection from HIV acquisition. Our results showed that a single injection of the long-acting antiviral drug also resulted in reduced HIV infection. However, protection was not complete and transmission was concealed by a significant delay in the onset of plasma viremia that could result in superinfection by two different viruses administered up to four weeks apart.
PLOS9	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The CsrRS (or CovRS) two component system controls expression of up to 15% of the genome of group A Streptococcus (GAS). While some studies have suggested that the sensor histidine kinase CsrS responds to membrane perturbations as a result of various environmental stresses, other data have implicated the human antimicrobial peptide LL-37 and extracellular Mg2+ as specific signals. We now report that Mg2+ and LL-37 have opposite effects on expression of multiple genes that are activated or repressed by the transcriptional regulator CsrR. Using a GAS isolate representative of the recently emerged and widely disseminated M1T1 clone implicated in severe invasive disease, we found marked up-regulation by CsrRS of multiple virulence factors including pyrogenic exotoxin A, DNase Sda1, streptolysin O, and the hyaluronic acid capsular polysaccharide, among others. Topology and surface protein labeling studies indicated that CsrS is associated with the bacterial cell membrane and has a surface-exposed extracellular domain accessible to environmental ligands. Replacement of a cluster of three acidic amino acids with uncharged residues in the extracellular domain of CsrS abrogated LL-37 signaling and conferred a hyporesponsive phenotype consistent with tonic activation of CsrS autokinase activity, an effect that could be overridden by mutation of the CsrS active site histidine. Both loss- and gain-of-function mutations of a conserved site in the receiver domain of CsrR established an essential role for lysine 102 in CsrS-to-CsrR signal transduction. These results provide strong evidence that Mg2+ and LL-37 are specific signals that function by altering CsrS autokinase activity and downstream phosphotransfer to CsrR to modulate its activity as a transcriptional regulator. The representation of multiple antiphagocytic and cytotoxic factors in the CsrRS regulon together with results of in vitro phagocytic killing assays support the hypothesis that CsrRS mediates conversion of GAS from a colonizing to an invasive phenotype in response to signaling by host LL-37. Output:	Group A Streptococcus (S. pyogenes or GAS) is exclusively a human pathogen that can inhabit the human throat as a harmless commensal, cause localized, self-limited infection in the form of pharyngitis or strep throat, or invade local tissues or the bloodstream to produce life-threatening disease states such as necrotizing fasciitis or streptococcal toxic shock. We present evidence that the GAS CsrRS (or CovRS) two component system governs the transition from a colonizing to an invasive phenotype by transducing a specific signal from the antimicrobial peptide LL-37 that is secreted as part of the human innate immune response to GAS infection. We show that LL-37 signaling requires specific domains of both the CsrS sensor kinase and the CsrR response regulator, and that signaling results in a coordinated and marked increase in expression of multiple bacterial factors that confer resistance to phagocytic killing, a hallmark of GAS virulence.
PLOS10	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: North East Europe harbors a high diversity of cultures and languages, suggesting a complex genetic history. Archaeological, anthropological, and genetic research has revealed a series of influences from Western and Eastern Eurasia in the past. While genetic data from modern-day populations is commonly used to make inferences about their origins and past migrations, ancient DNA provides a powerful test of such hypotheses by giving a snapshot of the past genetic diversity. In order to better understand the dynamics that have shaped the gene pool of North East Europeans, we generated and analyzed 34 mitochondrial genotypes from the skeletal remains of three archaeological sites in northwest Russia. These sites were dated to the Mesolithic and the Early Metal Age (7,500 and 3,500 uncalibrated years Before Present). We applied a suite of population genetic analyses (principal component analysis, genetic distance mapping, haplotype sharing analyses) and compared past demographic models through coalescent simulations using Bayesian Serial SimCoal and Approximate Bayesian Computation. Comparisons of genetic data from ancient and modern-day populations revealed significant changes in the mitochondrial makeup of North East Europeans through time. Mesolithic foragers showed high frequencies and diversity of haplogroups U (U2e, U4, U5a), a pattern observed previously in European hunter-gatherers from Iberia to Scandinavia. In contrast, the presence of mitochondrial DNA haplogroups C, D, and Z in Early Metal Age individuals suggested discontinuity with Mesolithic hunter-gatherers and genetic influx from central/eastern Siberia. We identified remarkable genetic dissimilarities between prehistoric and modern-day North East Europeans/Saami, which suggests an important role of post-Mesolithic migrations from Western Europe and subsequent population replacement/extinctions. This work demonstrates how ancient DNA can improve our understanding of human population movements across Eurasia. It contributes to the description of the spatio-temporal distribution of mitochondrial diversity and will be of significance for future reconstructions of the history of Europeans. Output:	The history of human populations can be retraced by studying the archaeological and anthropological record, but also by examining the current distribution of genetic markers, such as the maternally inherited mitochondrial DNA. Ancient DNA research allows the retrieval of DNA from ancient skeletal remains and contributes to the reconstruction of the human population history through the comparison of ancient and present-day genetic data. Here, we analysed the mitochondrial DNA of prehistoric remains from archaeological sites dated to 7,500 and 3,500 years Before Present. These sites are located in North East Europe, a region that displays a significant cultural and linguistic diversity today but for which no ancient human DNA was available before. We show that prehistoric hunter-gatherers of North East Europe were genetically similar to other European foragers. We also detected a prehistoric genetic input from Siberia, followed by migrations from Western Europe into North East Europe. Our research contributes to the understanding of the origins and past dynamics of human population in Europe.
PLOS11	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Output:	Highly pathogenic H5N1 influenza A viruses have caused more than 500 human infections with approximately 60% lethality in 15 countries and continue to pose a pandemic threat. The recent worldwide spread of pandemic H1N1 influenza A viruses raises the concern of reassortment between the H5N1 viruses and other influenza viruses. However, the molecular determinants for high virulence of the H5N1 viruses in mammals are not fully understood. We, therefore, investigated their virulence in a ferret model, which is a widely accepted animal model for assessing human influenza virus replication. We identified an amino acid in hemagglutinin and four amino acids in nonstructural proteins that are associated with high virulence of a human H5N1 virus, A/Vietnam/UT3062/04. We also found that the amino acid in hemagglutinin changes its receptor-binding property and the amino acids in nonstructural protein 1 affect its interferon antagonistic ability. These findings provide insight into the pathogenesis of H5N1 viruses in mammals.
PLOS12	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Plant microRNAs (miRNA) guide cleavage of target mRNAs by DICER-like proteins, thereby reducing mRNA abundance. Native precursor miRNAs can be redesigned to target RNAs of interest, and one application of such artificial microRNA (amiRNA) technology is to generate plants resistant to pathogenic viruses. Transgenic Arabidopsis plants expressing amiRNAs designed to target the genome of two unrelated viruses were resistant, in a highly specific manner, to the appropriate virus. Here, we pursued two different goals. First, we confirmed that the 21-nt target site of viral RNAs is both necessary and sufficient for resistance. Second, we studied the evolutionary stability of amiRNA-mediated resistance against a genetically plastic RNA virus, TuMV. To dissociate selective pressures acting upon protein function from those acting at the RNA level, we constructed a chimeric TuMV harboring a 21-nt, amiRNA target site in a non-essential region. In the first set of experiments designed to assess the likelihood of resistance breakdown, we explored the effect of single nucleotide mutation within the target 21-nt on the ability of mutant viruses to successfully infect amiRNA-expressing plants. We found non-equivalency of the target nucleotides, which can be divided into three categories depending on their impact in virus pathogenicity. In the second set of experiments, we investigated the evolution of the virus mutants in amiRNA-expressing plants. The most common outcome was the deletion of the target. However, when the 21-nt target was retained, viruses accumulated additional substitutions on it, further reducing the binding/cleavage ability of the amiRNA. The pattern of substitutions within the viral target was largely dominated by G to A and C to U transitions. Output:	RNA viruses are well-known for their tremendous capacity to evolve, a characteristic that threatens the development of effective antiviral strategies. A new antiviral strategy was recently proposed to control plant RNA viruses that relied on the expression in plants of artificial microRNAs (amiRNAs) targeting short sequences of 21-nt in the viral genome. Here, we have evaluated the likelihood that changes in the 21-nt target sequence would result in resistance breakdown. We found that changes at different sites in the target had different consequences on the ability of the virus to evade amiRNA surveillance. Then, we evolved viruses with a single substitution within the target under the selective pressure imposed by amiRNAs but without any selective pressure at the protein level. We found extra mutations accumulated in the target that further reduced base pairing with the amiRNA. These results showed that when allowed to replicate, RNA viruses would readily generate genetic variability that would facilitate evasion from the engineered miRNA-mediated virus resistance.
PLOS13	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Iron is essential for photosynthesis and is often a limiting nutrient for plant productivity. Plants respond to conditions of iron deficiency by increasing transcript abundance of key genes involved in iron homeostasis, but only a few regulators of these genes have been identified. Using genome-wide expression analysis, we searched for transcription factors that are induced within 24 hours after transferring plants to iron-deficient growth conditions. Out of nearly 100 transcription factors shown to be up-regulated, we identified MYB10 and MYB72 as the most highly induced transcription factors. Here, we show that MYB10 and MYB72 are functionally redundant and are required for plant survival in alkaline soil where iron availability is greatly restricted. myb10myb72 double mutants fail to induce transcript accumulation of the nicotianamine synthase gene NAS4. Both myb10myb72 mutants and nas4-1 mutants have reduced iron concentrations, chlorophyll levels, and shoot mass under iron-limiting conditions, indicating that these genes are essential for proper plant growth. The double myb10myb72 mutant also showed nickel and zinc sensitivity, similar to the nas4 mutant. Ectopic expression of NAS4 rescues myb10myb72 plants, suggesting that loss of NAS4 is the primary defect in these plants and emphasizes the importance of nicotianamine, an iron chelator, in iron homeostasis. Overall, our results provide evidence that MYB10 and MYB72 act early in the iron-deficiency regulatory cascade to drive gene expression of NAS4 and are essential for plant survival under iron deficiency. Output:	Iron deficiency is the most common human nutritional disorder, afflicting more than three billion people worldwide. Most of these people rely on plants for their dietary iron. Iron is also one of the three nutrients that most commonly limit plant growth. Despite progress in tracing how Fe moves throughout the plant, we still do not fully understand how plants sense and respond to Fe availability. Here, we report on two apparently redundant MYB transcription factors that are acting to control one gene that has a major impact on the ability of plants to grow in alkaline soil where iron availability is greatly restricted. In the absence of these transcription factors, plants are unable to survive on this soil. As 1/3 of the world's soils are alkaline, understanding how plants cope may enable the growth of crops on soils currently not suitable for agricultural production. These two transcription factors also extend the iron deficiency network and this work provides insight into the tight control plants exert over iron uptake and distribution.
PLOS14	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Chikungunya virus (CHIKV) is a re-emerging, pathogenic alphavirus that is transmitted to humans by Aedes spp. mosquitoes—causing fever and debilitating joint pain, with frequent long-term health implications and high morbidity. The CHIKV lifecycle is poorly understood and specific antiviral therapeutics or vaccines are lacking. In this study, we investigated the role of host-cell chloride (Cl-) channels on CHIKV replication.We demonstrate that specific pharmacological Cl- channel inhibitors significantly inhibit CHIKV replication in a dose-dependent manner, suggesting that Cl-channels are pro-viral factors in human cells. Further analysis of the effect of the inhibitors on CHIKV attachment, entry, viral protein expression and replicon replication demonstrated that Cl- channels are specifically required for efficient CHIKV genome replication. This was conserved in mosquito cells, where CHIKV replication and genome copy number was significantly reduced following Cl- channel inhibition. siRNA silencing identified chloride intracellular channels 1 and 4 (CLIC1 and CLIC4, respectively) as required for efficient CHIKV replication and protein affinity chromatography showed low levels of CLIC1 in complex with CHIKV nsP3, an essential component of the viral replication machinery. In summary, for the first time we demonstrate that efficient replication of the CHIKV genome depends on cellular Cl- channels, in both human and mosquito cells and identifies CLIC1 and CLIC4 as agonists of CHIKV replication in human cells. We observe a modest interaction, either direct or indirect, between CLIC1 and nsP3 and hypothesize that CLIC1 may play a role in the formation/maintenance of CHIKV replication complexes. These findings advance our molecular understanding of CHIKV replication and identify potential druggable targets for the treatment and prevention of CHIKV mediated disease. Output:	Chikungunya virus (CHIKV) is a mosquito-borne virus that infects humans and causes chikungunya fever—characterized by fever, rash and chronic arthralgia. Treatment of chikungunya fever is limited to the alleviation of the symptoms and no vaccine is available to prevent infection. Consequently, new anti-CHIKV therapies or targets are urgently required. Since its initial isolation in Tanzania in 1952, CHIKV has spread widely across tropical/sub-tropical and more temperate regions. It has been responsible for epidemics in >70 different regions of the world, resulting in high morbidity and financial burden. Despite this, the CHIKV lifecycle is poorly understood. Here, we demonstrate for the first time that CHIKV requires host-cell ion channels that mediate chloride ion (Cl-) flux through the membranes of infected cells, to complete its lifecycle. Specifically, using pharmacological compounds, we show that Cl- channels are required for efficient replication of the virus genome, identify two specific channels (CLIC1 and CLIC4) required for replication and demonstrate that CLIC1 may interact with viral non-structural protein 3 (nsP3)—an essential component of the CHIKV replicase complex. These findings advance our understanding of CHIKV replication and identify potential druggable targets for the treatment and prevention of CHIKV mediated disease.
PLOS15	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies. Output:	Few proteins carry out their tasks in isolation. Instead, proteins combine with each other in complicated ways that can be affected by either the natural genetic variation that occurs among people or by disease causing mutations such as those that occur in cancer or in genetic disorders. To understand how these mutations affect our health, it is necessary to understand how mutations can affect the strength of the interactions that bind proteins together. This is a difficult task to do in a laboratory on a large scale and scientists are increasingly turning to computational methods to predict these effects in advance. We show that by looking at the multiple alignments of similar protein-protein complex structures at the interface regions, new constraints based on the evolution of the three dimensional structures of proteins can be made to predict which mutations are compatible with two proteins interacting and which are not.
PLOS16	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise. Output:	Mitochondrial dysfunction is associated with a number of metabolic and neurological diseases such as Leigh syndrome and progressive blindness. Increased oxidative stress, which is often associated with mitochondrial dysfunction, is thought to be a common cause of disease progression. Here, we identified nuclear genes that encode mitochondrial proteins, whose loss causes the demise of photoreceptor neurons. Contrary to the common idea that this degeneration is triggered by elevated levels of oxidative stress, we find no change in the levels of oxidative stress. We show that activating photoreceptor neurons with light significantly increases energy production, and that this process is required to sustain their activity. Mitochondrial dysfunction impairs this capacity and leads to a premature termination of the light response. This in turn impairs the cycling of the light-sensitive receptor Rhodopsin in photoreceptors, and Rhodopsin accumulates in the cell inducing toxicity. This distinct mechanism of degeneration suggests that different mitochondrial diseases may follow different paths of disease progression and would hence respond differently to treatments.
PLOS17	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P<10−16). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes. Output:	Many genetic variants have been found associated with diseases. However, for many of these genetic variants, it remains unclear how they exert their effect on the eventual phenotype. We investigated genetic variants that are known to be associated with diseases and complex phenotypes and assessed whether these variants were also associated with gene expression levels in a set of 1,469 unrelated whole blood samples. For several diseases, such as type 1 diabetes and ulcerative colitis, we observed that genetic variants affect the expression of genes, not implicated before. For complex traits, such as mean platelet volume and mean corpuscular volume, we observed that independent genetic variants on different chromosomes influence the expression of exactly the same genes. For mean platelet volume, these genes include well-known blood coagulation genes but also genes with still unknown functions. These results indicate that, by systematically correlating genetic variation with gene expression levels, it is possible to identify downstream genes, which provide important avenues for further research.
PLOS18	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The splicing regulator Polypyrimidine Tract Binding Protein (PTBP1) has four RNA binding domains that each binds a short pyrimidine element, allowing recognition of diverse pyrimidine-rich sequences. This variation makes it difficult to evaluate PTBP1 binding to particular sites based on sequence alone and thus to identify target RNAs. Conversely, transcriptome-wide binding assays such as CLIP identify many in vivo targets, but do not provide a quantitative assessment of binding and are informative only for the cells where the analysis is performed. A general method of predicting PTBP1 binding and possible targets in any cell type is needed. We developed computational models that predict the binding and splicing targets of PTBP1. A Hidden Markov Model (HMM), trained on CLIP-seq data, was used to score probable PTBP1 binding sites. Scores from this model are highly correlated (ρ = −0.9) with experimentally determined dissociation constants. Notably, we find that the protein is not strictly pyrimidine specific, as interspersed Guanosine residues are well tolerated within PTBP1 binding sites. This model identifies many previously unrecognized PTBP1 binding sites, and can score PTBP1 binding across the transcriptome in the absence of CLIP data. Using this model to examine the placement of PTBP1 binding sites in controlling splicing, we trained a multinomial logistic model on sets of PTBP1 regulated and unregulated exons. Applying this model to rank exons across the mouse transcriptome identifies known PTBP1 targets and many new exons that were confirmed as PTBP1-repressed by RT-PCR and RNA-seq after PTBP1 depletion. We find that PTBP1 dependent exons are diverse in structure and do not all fit previous descriptions of the placement of PTBP1 binding sites. Our study uncovers new features of RNA recognition and splicing regulation by PTBP1. This approach can be applied to other multi-RRM domain proteins to assess binding site degeneracy and multifactorial splicing regulation. Output:	A key step in the regulation of mammalian genes is the splicing of the messenger RNA precursor to produce a mature mRNA that can be translated into a particular protein needed by the cell. Through the process of alternative splicing, mRNAs encoding different proteins can be derived from the same primary gene transcript. The regulation of this process plays essential roles in the development of differentiated tissues and is mediated by special pre-mRNA binding proteins. To understand how these proteins control gene expression, one must characterize what they recognize in RNA and identify these binding sites across the genome in order to predict their targets. Models that allow this prediction are essential to understanding developmental regulatory programs and their perturbation by disease causing mutations. In this study, we use statistical methods to build models of RNA recognition by the important splicing regulator PTBP1 and then apply these models to predict PTBP1 regulation of new gene transcripts. We show that PTBP1 has different specificity for RNA than was previously recognized and that its target exons are more diverse than was known before. There are many similar splicing regulators in mammalian cells, and these analyses provide a general framework for the computational analysis of their RNA binding and target identification.
PLOS19	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Phages play critical roles in the survival and pathogenicity of their hosts, via lysogenic conversion factors, and in nutrient redistribution, via cell lysis. Analyses of phage- and viral-encoded genes in environmental samples provide insights into the physiological impact of viruses on microbial communities and human health. However, phage ORFs are extremely diverse of which over 70% of them are dissimilar to any genes with annotated functions in GenBank. Better identification of viruses would also aid in better detection and diagnosis of disease, in vaccine development, and generally in better understanding the physiological potential of any environment. In contrast to enzymes, viral structural protein function can be much more challenging to detect from sequence data because of low sequence conservation, few known conserved catalytic sites or sequence domains, and relatively limited experimental data. We have designed a method of predicting phage structural protein sequences that uses Artificial Neural Networks (ANNs). First, we trained ANNs to classify viral structural proteins using amino acid frequency; these correctly classify a large fraction of test cases with a high degree of specificity and sensitivity. Subsequently, we added estimates of protein isoelectric points as a feature to ANNs that classify specialized families of proteins, namely major capsid and tail proteins. As expected, these more specialized ANNs are more accurate than the structural ANNs. To experimentally validate the ANN predictions, several ORFs with no significant similarities to known sequences that are ANN-predicted structural proteins were examined by transmission electron microscopy. Some of these self-assembled into structures strongly resembling virion structures. Thus, our ANNs are new tools for identifying phage and potential prophage structural proteins that are difficult or impossible to detect by other bioinformatic analysis. The networks will be valuable when sequence is available but in vitro propagation of the phage may not be practical or possible. Output:	Bacteriophages are extremely abundant and diverse biological entities. All phage particles are comprised of nucleic acids and structural proteins, with few other packaged proteins. Despite their simplicity and abundance, more than 70% of phage sequences in the viral Reference Sequence database encode proteins with unknown function based on FASTA annotations. As a result, the use of sequence similarity is often insufficient for detecting virus structural proteins among unknown viral sequences. Viral structural protein function is challenging to detect from sequence data because structural proteins possess few known conserved catalytic motifs and sequence domains. To address these issues we investigated the use of Artificial Neural Networks as an alternative means of predicting function. Here, we trained thousands of networks using the amino acid frequency of structural protein sequences and identified the optimal architectures with the highest accuracies. Some hypothetical protein sequences detected by our networks were expressed and visualized by TEM, and produced images that strongly resemble virion structures. Our results support the utility of our neural networks in predicting the functions of unknown viral sequences.
PLOS20	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: DNA looping mediated by transcription factors plays critical roles in prokaryotic gene regulation. The “genetic switch” of bacteriophage λ determines whether a prophage stays incorporated in the E. coli chromosome or enters the lytic cycle of phage propagation and cell lysis. Past studies have shown that long-range DNA interactions between the operator sequences OR and OL (separated by 2.3 kb), mediated by the λ repressor CI (accession number P03034), play key roles in regulating the λ switch. In vitro, it was demonstrated that DNA segments harboring the operator sequences formed loops in the presence of CI, but CI-mediated DNA looping has not been directly visualized in vivo, hindering a deep understanding of the corresponding dynamics in realistic cellular environments. We report a high-resolution, single-molecule imaging method to probe CI-mediated DNA looping in live E. coli cells. We labeled two DNA loci with differently colored fluorescent fusion proteins and tracked their separations in real time with ∼40 nm accuracy, enabling the first direct analysis of transcription-factor-mediated DNA looping in live cells. Combining looping measurements with measurements of CI expression levels in different operator mutants, we show quantitatively that DNA looping activates transcription and enhances repression. Further, we estimated the upper bound of the rate of conformational change from the unlooped to the looped state, and discuss how chromosome compaction may impact looping kinetics. Our results provide insights into transcription-factor-mediated DNA looping in a variety of operator and CI mutant backgrounds in vivo, and our methodology can be applied to a broad range of questions regarding chromosome conformations in prokaryotes and higher organisms. Output:	One mechanism cells use to regulate gene expression is DNA looping, whereby two distant DNA sites are brought together by regulatory proteins. The looping then either enhances interactions between other regulatory proteins bound at the separate sites or brings those regulatory proteins close to RNA polymerase at the promoter. Recent work in bacteriophage λ has suggested that DNA looping mediated by a transcription factor called λ repressor CI plays a critical role in regulating the expression of λ genes and consequently in determining the fate of the host E. coli bacterial cells. CI-mediated DNA looping has been directly demonstrated in vitro, but it has only been indirectly inferred in vivo. For the current study we developed a method to visualize CI-mediated DNA looping in individual live E. coli cells. We labeled two DNA sites—one each side of the proposed loop—with differently colored fluorescent fusion proteins, allowing us to measure their separation with an accuracy of a few tens of nanometers. Using this method, we directly analyzed CI-mediated DNA looping, providing insight into how transcription factor-mediated DNA looping influences gene regulation in live E. coli cells. Our methodology can be applied to a broad range of questions regarding chromosome conformation in prokaryotes and higher organisms.
PLOS21	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Rabies is a neglected zoonotic disease. Given the low incidence, apart from the existing reporting syst, there is a need to look for other means of case detection strategies for rabies. Contact tracing is one such method to efficiently capture information. To find out the rabid status of biting animal through contact tracing and to determine health seeking behavior of the bite victims. An exploratory study using contact tracing was conducted during the first quarter of 2017 in villages coming under three Public Health Centers. The households of the bite victims were visited and details of rabies exposure obtained from the bite victim/ adult responsible respondent using a standardized questionnaire. A total of 69 dog/cat bite cases were identified. 69.5% of bites were by stray dogs. 97.1% bite victims had Category III bites. Only 4.5% bite victims had taken PEP. 70.1% of animal bite cases were administered ARV. Only 7.2% bite victims had exposure to probable rabid animals. All dog bite victims were alive after 3 months of follow up. Contact tracing was successful in case detection of probable rabid animal exposures and suitable for a period of one year. Output:	In India, Rabies is a neglected zoonotic disease and the burden of rabies is usually not captured by the health system due to varied reasons. Hence, an exploratory study was attempted to find out the rabid status of the biting animal through contact tracing during the first quarter of 2017 in villages coming under three Public Health Centers. A total of 69 dog/cat bite cases were identified. Majority of bites were by stray dogs, Category-III, exposure to non cases and few received PEP. Percentage of bite victims who actually required PEP was calculated. These findings support the fact that contact tracing can be used as an additional tool by the health care provider for measurement of rabid animal bites, where resources are scarce, reporting systems are weak and priorities for disease vary. A rabies check list/score card to be made available at Public Health Centers, which shall ensure better utilization of limited but lifesaving Rabies Immunobiologicals.
PLOS22	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity. Output:	Genetic studies (e.g GWAS) revealed substantial heritability on birth weight (BW), childhood obesity (CO) and childhood body mass index (CBMI), however, the etiological mechanisms and relevant tissue(s) underlying these traits/conditions are not clear. We incorporated the data from largest GWASes to date and placenta expressional quantitative trait loci (eQTL) that have been newly published, and showed the variants associated with BW, CO and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs in 7 adult tissues such as adipose and liver, only eQTLs in the placenta were found to contribute significantly not only to anthropometry outcomes at birth (BW) but also to childhood phenotypes (CO/CBMI). Further, we employed COLOC and MetaXcan analyses and identified placenta transcripts potential mediate the genetic effect of BW/CO/CBMI GWAS loci. In summary, our study strongly supports a key role for the placenta in determining BW, CO and CMBI at the molecular level, and pinpointed genes whose expression levels in placenta potentially influences BW and CO risk.
PLOS23	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: As increasingly more genomes are sequenced, the vast majority of proteins may only be annotated computationally, given experimental investigation is extremely costly. This highlights the need for computational methods to determine protein functions quickly and reliably. We believe dividing a protein family into subtypes which share specific functions uncommon to the whole family reduces the function annotation problem’s complexity. Hence, this work’s purpose is to detect isofunctional subfamilies inside a family of unknown function, while identifying differentiating residues. Similarity between protein pairs according to various properties is interpreted as functional similarity evidence. Data are integrated using genetic programming and provided to a spectral clustering algorithm, which creates clusters of similar proteins. The proposed framework was applied to well-known protein families and to a family of unknown function, then compared to ASMC. Results showed our fully automated technique obtained better clusters than ASMC for two families, besides equivalent results for other two, including one whose clusters were manually defined. Clusters produced by our framework showed great correspondence with the known subfamilies, besides being more contrasting than those produced by ASMC. Additionally, for the families whose specificity determining positions are known, such residues were among those our technique considered most important to differentiate a given group. When run with the crotonase and enolase SFLD superfamilies, the results showed great agreement with this gold-standard. Best results consistently involved multiple data types, thus confirming our hypothesis that similarities according to different knowledge domains may be used as functional similarity evidence. Our main contributions are the proposed strategy for selecting and integrating data types, along with the ability to work with noisy and incomplete data; domain knowledge usage for detecting subfamilies in a family with different specificities, thus reducing the complexity of the experimental function characterization problem; and the identification of residues responsible for specificity. Output:	The knowledge of protein functions is central for understanding life at a molecular level and has huge biochemical and pharmaceutical implications. However, despite best research efforts, a substantial and ever-increasing number of proteins predicted by genome sequencing projects still lack functional annotations. Computational methods are required to determine protein functions quickly and reliably since experimental investigation is difficult and costly. Considering literature shows combining various types of information is crucial for functionally annotating proteins, such methods must be able to integrate data from different sources which may be scattered, non-standardized, incomplete, and noisy. Many protein families are composed of proteins with different folds and functions. In such cases, the division into subtypes which share specific functions uncommon to the family as a whole may lead to important information about the function and structure of a related protein of unknown function, as well as about the functional diversification acquired by the family during evolution. This work’s purpose is to automatically detect isofunctional subfamilies in a protein family of unknown function, as well as identify residues responsible for differentiation. We integrate data and then provide it to a clustering algorithm, which creates clusters of similar proteins we found correspond to same-specificity subfamilies.
PLOS24	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei. Output:	Fungal pathogen populations show patterns ranging from globally recombining to endemic and clonal. Among the most genetically and spatially restricted fungi is the highly clonal pathogen Penicillium marneffei, an endemic AIDS-associated pathogen in Southeast Asia. Previous studies have shown that P. marneffei has a pattern of extreme clonality despite the ability to disperse across wide distances and the presence of mating type genes that are required for sexual recombination. In this study we used genetic markers, comparative genomics, experimental data, and spatial models to determine the influence of sex on P. marneffei populations, and we found that although there was substantial evidence of sexual recombination, most of the recombination in natural populations was limited to sexual neighborhoods, amongst genetically similar and spatially close individuals. Based on the results of experiments and spatial models we found support for sex occurring in bamboo rats that are known to harbor P. marneffei and the pathogens sexual neighborhoods. Our study suggests that the high levels of effective clonality and endemicity found in P. marneffei may have more to do with specific host interactions than with an innate inability to generate population genetic diversity through sexual recombination.
PLOS25	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance. Output:	Time-varying connectivity attempts to quantify the fluctuating covariance relationship between two or more regions through time. In recent years, it has become popular to do this with fMRI neuroimaging data. There have been many methods proposed to quantify time-varying connectivity, but very few attempts to systematically compare them. In this paper, we present tvc_benchmarker, which is a python package that consists of four simulations. The parameters of the data are justified on fMRI signal properties. Five different methods are evaluated in this paper, but other researchers can use tvc_benchmarker to evaluate their methodologies and their results can be submitted to be included in future reports. Methods are evaluated on their ability to track a fluctuating covariance parameter between time series. Of the evaluated methods, the jackknife correlation method performed the best at tracking a fluctuating covariance parameter in these four simulations.
PLOS26	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: For the last three decades, evolutionary biologists have sought to understand which factors modulate the evolution of parasite virulence. Although theory has identified several of these modulators, their effect has seldom been analysed experimentally. We investigated the role of two such major factors—the mode of transmission, and host adaptation in response to parasite evolution—in the evolution of virulence of the plant virus Cucumber mosaic virus (CMV) in its natural host Arabidopsis thaliana. To do so, we serially passaged three CMV strains under strict vertical and strict horizontal transmission, alternating both modes of transmission. We quantified seed (vertical) transmission rate, virus accumulation, effect on plant growth and virulence of evolved and non-evolved viruses in the original plants and in plants derived after five passages of vertical transmission. Our results indicated that vertical passaging led to adaptation of the virus to greater vertical transmission, which was associated with reductions of virus accumulation and virulence. On the other hand, horizontal serial passages did not significantly modify virus accumulation and virulence. The observed increases in CMV seed transmission, and reductions in virus accumulation and virulence in vertically passaged viruses were due also to reciprocal host adaptation during vertical passages, which additionally reduced virulence and multiplication of vertically passaged viruses. This result is consistent with plant-virus co-evolution. Host adaptation to vertically passaged viruses was traded-off against reduced resistance to the non-evolved viruses. Thus, we provide evidence of the key role that the interplay between mode of transmission and host-parasite co-evolution has in determining the evolution of virulence. Output:	Virulence is a key property of parasites, and is linked to the emergence of new diseases and to the reduction of ecosystem biodiversity. Consequently, scientists have devoted a great effort to build theoretical models that predict which factors may modulate virulence evolution. However, whether (and how) these factors affect virulence evolution has been seldom analysed experimentally. Using the plant virus Cucumber mosaic virus (CMV) and its natural host Arabidopsis thaliana, we studied the role of two such factors: the mode of transmission, and host adaptation in response to parasite evolution. We serially passaged CMV under strict vertical and strict horizontal transmission, and a combination of both. Subsequently, we analysed differences in CMV seed (vertical) transmission rate, accumulation and virulence between evolved and non-evolved viruses. We also compared whether these differences varied in original plants and in plants evolved during vertical passaging. Vertical passaging increased CMV seed transmission, and reduced accumulation and virulence, while horizontal passaging had no effect. Changes during vertical passaging were determined also by reciprocal host adaptation, which additionally reduced virulence and accumulation of vertically transmitted viruses. Hence, we provide evidence that the interplay between the transmission mode and host-parasite co-evolution is central in determining virulence evolution.
PLOS27	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Schistosomiasis is a helminthic disease that affects more than 200 million people. An effective vaccine would be a major step towards eliminating the disease. Studies suggest that T follicular helper (Tfh) cells provide help to B cells to generate the long-term humoral immunity, which would be a crucial component of successful vaccines. Thus, understanding the biological characteristics of Tfh cells in patients with schistosomiasis, which has never been explored, is essential for vaccine design. In this study, we investigated the biological characteristics of peripheral memory Tfh cells in schistosomiasis patients by flow cytometry. Our data showed that the frequencies of total and activated peripheral memory Tfh cells in patients were significantly increased during Schistosoma japonicum infection. Moreover, Tfh2 cells, which were reported to be a specific subpopulation to facilitate the generation of protective antibodies, were increased more greatly than other subpopulations of total peripheral memory Tfh cells in patients with schistosomiasis japonica. More importantly, our result showed significant correlations of the percentage of Tfh2 cells with both the frequency of plasma cells and the level of IgG antibody. In addition, our results showed that the percentage of T follicular regulatory (Tfr) cells was also increased in patients with schistosomiasis. Our report is the first characterization of peripheral memory Tfh cells in schistosomasis patients, which not only provides potential targets to improve immune response to vaccination, but also is important for the development of vaccination strategies to control schistosomiasis. Output:	Schistosomiasis affects more than 200 million people worldwide and causes more than 280,000 deaths per year. Current control strategies are based on chemotherapy, but recurrent reinfection of people living in endemic areas makes researchers search for an effective vaccine to provide long-term protection against schistosomiasis. The generation of long-lived high-affinity antibodies after vaccination is a pivotal step for anti-schistosome vaccine to eliminate schistosomiasis. Considering it is well-known that Tfh cells are specialized effector CD4+ T cells that provide help for germinal center (GC) formation and induce GC B cells to develop protective antibody responses, understanding the biology of Tfh cells in schistosomiasis patients is fundamental for vaccine strategy development. Here, for the first time, we documented increased frequencies of total and activated peripheral memory Tfh cells in schistosomiasis patients. Furthermore, we showed that Tfh2 cells were a major contributor to increased frequency of peripheral memory Tfh cells in patients with schistosomiasis japonica. More importantly, we found the significant correlations of the percentage of Tfh2 cells with both the frequency of plasma cells and the level of total IgG antibody in schistosomiasis patients.
PLOS28	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The correspondence between protein sequences and structures, or sequence-structure map, relates to fundamental aspects of structural, evolutionary and synthetic biology. The specifics of the mapping, such as the fraction of accessible sequences and structures, or the sequences' ability to fold fast, are dictated by the type of interactions between the monomers that compose the sequences. The set of possible interactions between monomers is encapsulated by the potential energy function. In this study, I explore the impact of the relative forces of the potential on the architecture of the sequence-structure map. My observations rely on simple exact models of proteins and random samples of the space of potential energy functions of binary alphabets. I adopt a graph perspective and study the distribution of viable sequences and the structures they produce, as networks of sequences connected by point mutations. I observe that the relative proportion of attractive, neutral and repulsive forces defines types of potentials, that induce sequence-structure maps of vastly different architectures. I characterize the properties underlying these differences and relate them to the structure of the potential. Among these properties are the expected number and relative distribution of sequences associated to specific structures and the diversity of structures as a function of sequence divergence. I study the types of binary potentials observed in natural amino acids and show that there is a strong bias towards only some types of potentials, a bias that seems to characterize the folding code of natural proteins. I discuss implications of these observations for the architecture of the sequence-structure map of natural proteins, the construction of random libraries of peptides, and the early evolution of the natural amino acid alphabet. Output:	If we were to design a proteome, what types and what proportion of amino acids would we use in order to optimize properties such as the diversity of sequences and structures, their robustness to mutations, or their ability to fold efficiently? Here, I use simple models to study the sequence-structure map of proteins from a design and evolutionary perspective. These models can be used to explore all sequences and structures, as a function of the types of interactions encoded by the sequence. I study the range of possible binary interactions between monomers, which include natural and artificial amino acids. The results indicate that different amino acid compositions induce vastly different sequences-structure maps. I classify and study the properties of these maps and relate their features back to the type of energy interactions. I compare these observations to the types of interactions observed in natural amino acids. My observations provide insights for our current view of the sequence-structure map of natural proteins, guiding principles for the construction of random libraries of peptides, and suggests constraints for the early evolution of the natural amino acid alphabet.
PLOS29	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Cells employ multiple levels of regulation, including transcriptional and translational regulation, that drive core biological processes and enable cells to respond to genetic and environmental changes. Small-molecule metabolites are one category of critical cellular intermediates that can influence as well as be a target of cellular regulations. Because metabolites represent the direct output of protein-mediated cellular processes, endogenous metabolite concentrations can closely reflect cellular physiological states, especially when integrated with other molecular-profiling data. Here we develop and apply a network reconstruction approach that simultaneously integrates six different types of data: endogenous metabolite concentration, RNA expression, DNA variation, DNA–protein binding, protein–metabolite interaction, and protein–protein interaction data, to construct probabilistic causal networks that elucidate the complexity of cell regulation in a segregating yeast population. Because many of the metabolites are found to be under strong genetic control, we were able to employ a causal regulator detection algorithm to identify causal regulators of the resulting network that elucidated the mechanisms by which variations in their sequence affect gene expression and metabolite concentrations. We examined all four expression quantitative trait loci (eQTL) hot spots with colocalized metabolite QTLs, two of which recapitulated known biological processes, while the other two elucidated novel putative biological mechanisms for the eQTL hot spots. Output:	It is now possible to score variations in DNA across whole genomes, RNA levels and alternative isoforms, metabolite levels, protein levels and protein state information, protein–protein interactions, and protein–DNA interactions, in a comprehensive fashion in populations of individuals. Interactions among these molecular entities define the complex web of biological processes that give rise to all higher order phenotypes, including disease. The development of analytical approaches that simultaneously integrate different dimensions of data is essential if we are to extract the meaning from large-scale data to elucidate the complexity of living systems. Here, we use a novel Bayesian network reconstruction algorithm that simultaneously integrates DNA variation, RNA levels, metabolite levels, protein–protein interaction data, protein–DNA binding data, and protein–small-molecule interaction data to construct molecular networks in yeast. We demonstrate that these networks can be used to infer causal relationships among genes, enabling the identification of novel genes that modulate cellular regulation. We show that our network predictions either recapitulate known biology or can be prospectively validated, demonstrating a high degree of accuracy in the predicted network.
PLOS30	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The sexually transmitted bacterium Neisseria gonorrhoeae has developed resistance to all antibiotic classes that have been used for treatment and strains resistant to multiple antibiotic classes have evolved. In many countries, there is only one antibiotic remaining for empirical N. gonorrhoeae treatment, and antibiotic management to counteract resistance spread is urgently needed. Understanding dynamics and drivers of resistance spread can provide an improved rationale for antibiotic management. In our study, we first used antibiotic resistance surveillance data to estimate the rates at which antibiotic-resistant N. gonorrhoeae spread in two host populations, heterosexual men (HetM) and men who have sex with men (MSM). We found higher rates of spread for MSM (0.86 to 2.38 y−1, mean doubling time: 6 months) compared to HetM (0.24 to 0.86 y−1, mean doubling time: 16 months). We then developed a dynamic transmission model to reproduce the observed dynamics of N. gonorrhoeae transmission in populations of heterosexual men and women (HMW) and MSM. We parameterized the model using sexual behavior data and calibrated it to N. gonorrhoeae prevalence and incidence data. In the model, antibiotic-resistant N. gonorrhoeae spread with a median rate of 0.88 y−1 in HMW and 3.12 y−1 in MSM. These rates correspond to median doubling times of 9 (HMW) and 3 (MSM) months. Assuming no fitness costs, the model shows the difference in the host population’s treatment rate rather than the difference in the number of sexual partners explains the differential spread of resistance. As higher treatment rates result in faster spread of antibiotic resistance, treatment recommendations for N. gonorrhoeae should carefully balance prevention of infection and avoidance of resistance spread. Output:	More and more infectious disease treatments fail because the causative pathogens are resistant to the drugs used for treatment. For the treatment of Neisseria gonorrhoeae, a sexually transmitted bacterium, drug resistance is a particularly big problem: there is only a single antibiotic left that is recommended for treatment. We aimed to understand how antibiotic-resistant N. gonorrhoeae spread in a sexually active host population and how the spread of resistance can be slowed. From antibiotic resistance surveillance data, we first estimated the rate at which antibiotic-resistant N. gonorrhoeae spread. Second, we reproduced the observed dynamics in a mathematical model describing the transmission between hosts. We found that antibiotic-resistant N. gonorrhoeae spread faster in host populations of men who have sex with men than in host populations of heterosexuals. We could attribute the faster spread of resistant pathogens to higher treatment rates. This finding implies that promoting screening to control antibiotic-resistant N. gonorrhoeae could in fact accelerate their spread.
PLOS31	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis, is the most prevalent invasive fungal disease in South America. Systemic mycoses are the 10th most common cause of death among infectious diseases in Brazil and PCM is responsible for more than 50% of deaths due to fungal infections. PCM is typically treated with sulfonamides, amphotericin B or azoles, although complete eradication of the fungus may not occur and relapsing disease is frequently reported. A 15-mer peptide from the major diagnostic antigen gp43, named P10, can induce a strong T-CD4+ helper-1 immune response in mice. The TEPITOPE algorithm and experimental data have confirmed that most HLA-DR molecules can present P10, which suggests that P10 is a candidate antigen for a PCM vaccine. In the current work, the therapeutic efficacy of plasmid immunization with P10 and/or IL-12 inserts was tested in murine models of PCM. When given prior to or after infection with P. brasiliensis virulent Pb 18 isolate, plasmid-vaccination with P10 and/or IL-12 inserts successfully reduced the fungal burden in lungs of infected mice. In fact, intramuscular administration of a combination of plasmids expressing P10 and IL-12 given weekly for one month, followed by single injections every month for 3 months restored normal lung architecture and eradicated the fungus in mice that were infected one month prior to treatment. The data indicate that immunization with these plasmids is a powerful procedure for prevention and treatment of experimental PCM, with the perspective of being also effective in human patients. Output:	Paracoccidioidomycosis (PCM) is the predominant systemic mycosis in Latin America causing half of the total deaths among systemic fungal infectious diseases in Brazil. Chemotherapy is the standard treatment, but the long time required, severe cases of immunosuppression and frequent relapses indicate that additional methods should be introduced such as immunotherapy combined with antifungal drugs. Previously, the protective activity of P10, a peptide derived from the major diagnostic antigen gp43, was demonstrated, alone or combined with chemotherapy. P10 elicited a vigorous IFN-γ mediated Th-1 immune response. Presently, the reduction of fungal load, and even sterilization, was attempted using a specific DNA vaccine encoding P10. Plasmid pcDNA3 expression vector with P10 insert was tested as a vaccine in intratracheally infected BALB/c and B10.A mice. Our results showed that vaccination with pP10 induced a significant reduction of the fungal burden in the lung. Co-vaccination of pP10 with a plasmid encoding mouse IL-12 proved to be even more effective in the elimination of the fungus with virtual sterilization in a long term infection and treatment assay system. The data suggest that immunization with these plasmids, without the need of an adjuvant, could be used in the prevention and treatment of PCM in human patients.
PLOS32	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression, though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance in future gene drive applications. Output:	Gene drives are selfish genetic elements that are able to bias their own inheritance among offspring. Starting from very low frequencies they can rapidly invade a population in just a few generations, even when imposing a fitness cost. Gene drives based on the precise DNA cutting enzyme CRISPR have been shown recently to be highly efficient at copying themselves from one chromosome to the other during the process of gamete formation in mosquitoes, resulting in transmission to 99% of offspring instead of the 50% expected for a single gene copy. One proposed use for CRISPR-based gene drives is in the control of mosquitoes by designing the gene drive to target mosquito genes involved in fertility, thereby reducing their overall reproductive output and leading to population suppression. Like any intervention designed to suppress a population these gene drives are expected to select for mutations in the mosquito that are resistant to the drive and restore fertility to mosquitoes. We have analyzed the origin and selection of resistant alleles in caged populations of mosquitoes initiated with a gene drive construct targeting a female fertility gene. We find the selected alleles are in-frame insertions and deletions that are resistant to cleavage and restore female fertility. Our findings allow us to improve predictions on gene drive behaviour and to make concrete recommendations on how to improve future gene drive designs by decreasing the likelihood that they generate resistance.
PLOS33	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP) latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given stimulus that code for its ability to induce persistent activity and predict differential roles of RS and IB neurons in persistent activity expression. Output:	Memory, referred to as the ability to retain, store and recall information, represents one of the most fundamental cognitive functions in daily life. A significant feature of memory processes is selectivity to particular events or items that are important to our survival and relevant to specific situations. For long-term memory, the selectivity to a specific stimulus is seen both at the behavioral as well as the cellular level. For working memory, a type of short-term memory involved in decision making and attention processes, stimulus selectivity has been observed in vivo using spatial working memory tasks. In addition, persistent activity, which is the cellular correlate of working memory, is also selective to specific stimuli for each neuron, suggesting that each neuron has a ‘memory field’. Our study proposes that both the location of incoming inputs onto the neuronal dendritic tree and specific temporal features of the neuronal response can be used to predict the emergence of persistent activity in two neuron models with different firing patterns, revealing possible mechanisms for generating and propagating stimulus-selectivity in working memory processes. The study also reveals that neurons with different firing patterns may have different roles in persistent activity expression.
PLOS34	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Paenibacillus larvae, the etiological agent of the globally occurring epizootic American Foulbrood (AFB) of honey bees, causes intestinal infections in honey bee larvae which develop into systemic infections inevitably leading to larval death. Massive brood mortality might eventually lead to collapse of the entire colony. Molecular mechanisms of host-microbe interactions in this system and of differences in virulence between P. larvae genotypes are poorly understood. Recently, it was demonstrated that the degradation of the peritrophic matrix lining the midgut epithelium is a key step in pathogenesis of P. larvae infections. Here, we present the isolation and identification of PlCBP49, a modular, chitin-degrading protein of P. larvae and demonstrate that this enzyme is crucial for the degradation of the larval peritrophic matrix during infection. PlCBP49 contains a module belonging to the auxiliary activity 10 (AA10, formerly CBM33) family of lytic polysaccharide monooxygenases (LPMOs) which are able to degrade recalcitrant polysaccharides. Using chitin-affinity purified PlCBP49, we provide evidence that PlCBP49 degrades chitin via a metal ion-dependent, oxidative mechanism, as already described for members of the AA10 family. Using P. larvae mutants lacking PlCBP49 expression, we analyzed in vivo biological functions of PlCBP49. In the absence of PlCBP49 expression, peritrophic matrix degradation was markedly reduced and P. larvae virulence was nearly abolished. This indicated that PlCBP49 is a key virulence factor for the species P. larvae. The identification of the functional role of PlCBP49 in AFB pathogenesis broadens our understanding of this important family of chitin-binding and -degrading proteins, especially in those bacteria that can also act as entomopathogens. Output:	American Foulbrood and its etiological agent, Paenibacillus larvae, pose a serious threat to global honey bee health. So far, molecular mechanisms of host-microbe interactions are poorly understood in this system and no key virulence factor for the entire species has been identified. Here, we demonstrate that P. larvae expresses a chitin-binding and -degrading protein PlCBP49 harboring one module that belongs to the auxiliary activity 10 (AA10) family of lytic polysaccharide monooxygenases (LPMOs). We provide evidence that PlCBP49 degrades chitin via a metal ion-dependent, oxidative mechanism, as already described for other members of the AA10 enzyme family. Using P. larvae mutants lacking PlCBP49 expression, we demonstrate that PlCBP49 is crucial for the degradation of the chitin-rich peritrophic matrix, a key step in pathogenesis of P. larvae infections. In the absence of PlCBP49 expression the peritrophic matrix remained nearly intact and about 95% of the infected larvae survived infection. This clearly indicated that PlCBP49 is a key virulence factor of P. larvae. These results constitute important progress in our understanding of both P. larvae pathogenesis and the biological role of LPMOs in entomopathogens. Furthermore, knowing PlCBP49 and its role in pathogenesis opens new possibilities to develop curative measures for this disease.
PLOS35	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders. Output:	Cerebral malaria (CM) is a deadly consequence of Plasmodium falciparum infection. Severe neurologic deficits are frequent during CM. Although most resolve within 6 months, several retrospective studies have described high frequencies of long-lasting cognitive impairment after an episode of CM. We developed behavioral tests to identify cognitive impairment due to experimental CM. During infection with Plasmodium berghei ANKA (PbA), mice susceptible to CM (C57BL/6) developed long-lasting cognitive impairment in contextual and aversive memory. The same profile was seen in Swiss Webster mice infected with Plasmodium yoelii XL, a lethal strain that also induces neurological dysfunctions in susceptible mice strains, confirming that the cognitive dysfunction is closely associated to the development of CM. Reactive oxygen species are described as mediators of neurological and cognitive impairment associated to sepsis and Alzheimer's disease. Here we found enhanced production of malondialdeyde and conjugated dienes in brains of PbA-infected C57BL/6 mice, indicating oxidative stress. Antioxidant therapy with N-acetylcisteine and desferroxamine, as an additive to chloroquine, prevented the cognitive impairment, confirming the importance of oxidative stress in CM-associated cognitive sequellae. Administration of additive antioxidants may be a successful therapeutic strategy to control long-lasting consequences of CM and in other severe systemic inflammatory syndromes with neurological involvement.
PLOS36	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Leishmania (L.) killicki (syn. L. tropica), which causes cutaneous leishmaniasis in Maghreb, was recently described in this region and identified as a subpopulation of L. tropica. The present genetic analysis was conducted to explore the spatio-temporal distribution of L. killicki (syn. L. tropica) and its transmission dynamics. To better understand the evolution of this parasite, its population structure was then compared with that of L. tropica populations from Morocco. In total 198 samples including 85 L. killicki (syn. L. tropica) (from Tunisia, Algeria and Libya) and 113 L. tropica specimens (all from Morocco) were tested. Theses samples were composed of 168 Leishmania strains isolated from human skin lesions, 27 DNA samples from human skin lesion biopsies, two DNA samples from Ctenodactylus gundi bone marrow and one DNA sample from a Phlebotomus sergenti female. The sample was analyzed by using MultiLocus Enzyme Electrophoresis (MLEE) and MultiLocus Microsatellite Typing (MLMT) approaches. Analysis of the MLMT data support the hypothesis that L. killicki (syn. L. tropica) belongs to the L. tropica complex, despite its strong genetic differentiation, and that it emerged from this taxon by a founder effect. Moreover, it revealed a strong structuring in L. killicki (syn. L. tropica) between Tunisia and Algeria and within the different Tunisian regions, suggesting low dispersion of L. killicki (syn. L. tropica) in space and time. Comparison of the L. tropica (exclusively from Morocco) and L. killicki (syn. L. tropica) population structures revealed distinct genetic organizations, reflecting different epidemiological cycles. Output:	Leishmania killicki (syn. L. tropica) was discovered in 1986. Few studies have been conducted on this parasite exclusively described in Maghreb. Consequently, many elements on its epidemiology, transmission, population structure and dynamics remain unknown. To better understand the evolution of this parasite, its population structure has been compared with that of L. tropica populations from Morocco using Multilocus Enzyme Electrophoresis (MLEE) and MultiLocus Microsatellite Typing (MLMT) typing. MLMT data support the hypothesis that L. killicki (syn. L. tropica) belongs to the L. tropica complex despite the strong genetic differentiation between them. Despite the probable recent divergence between L. killicki (syn. L. tropica) and L. tropica, they seem to evolve differently. Indeed, L. killicki (syn. L. tropica) appears slightly polymorphic and highly structured in space and time, while L. tropica was genetically heterogeneous, slightly structured geographically and temporally. The different population structures revealed distinct genetic organizations, reflecting different epidemiological cycles. Several parameters could explain these opposite epidemiological and genetic patterns such as ecosystems, vectors and reservoirs.
PLOS37	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Genome engineering is a powerful approach to study how chromosomal architecture impacts phenotypes. However, quantifying the fitness impact of translocations independently from the confounding effect of base substitutions has so far remained challenging. We report a novel application of the CRISPR/Cas9 technology allowing to generate with high efficiency both uniquely targeted and multiple concomitant reciprocal translocations in the yeast genome. Targeted translocations are constructed by inducing two double-strand breaks on different chromosomes and forcing the trans-chromosomal repair through homologous recombination by chimerical donor DNAs. Multiple translocations are generated from the induction of several DSBs in LTR repeated sequences and promoting repair using endogenous uncut LTR copies as template. All engineered translocations are markerless and scarless. Targeted translocations are produced at base pair resolution and can be sequentially generated one after the other. Multiple translocations result in a large diversity of karyotypes and are associated in many instances with the formation of unanticipated segmental duplications. To test the phenotypic impact of translocations, we first recapitulated in a lab strain the SSU1/ECM34 translocation providing increased sulphite resistance to wine isolates. Surprisingly, the same translocation in a laboratory strain resulted in decreased sulphite resistance. However, adding the repeated sequences that are present in the SSU1 promoter of the resistant wine strain induced sulphite resistance in the lab strain, yet to a lower level than that of the wine isolate, implying that additional polymorphisms also contribute to the phenotype. These findings illustrate the advantage brought by our technique to untangle the phenotypic impacts of structural variations from confounding effects of base substitutions. Secondly, we showed that strains with multiple translocations, even those devoid of unanticipated segmental duplications, display large phenotypic diversity in a wide range of environmental conditions, showing that simply reconfiguring chromosome architecture is sufficient to provide fitness advantages in stressful growth conditions. Output:	Chromosomes are highly dynamic objects that often undergo large structural variations such as reciprocal translocations. Such rearrangements can have dramatic functional consequences, as they can disrupt genes, change their regulation or create novel fusion genes at their breakpoints. For instance, 90–95% of patients diagnosed with chronic myeloid leukemia carry the Philadelphia chromosome characterized by a reciprocal translocation between chromosomes 9 and 22. In addition, translocations reorganize the genetic information along chromosomes, which in turn can modify the 3D architecture of the genome and potentially affect its functioning. Quantifying the fitness impact of translocations independently from the confounding effect of base substitutions has so far remained challenging. Here, we report a novel CRISPR/Cas9-based technology allowing to generate with high efficiency and at a base-pair precision either uniquely targeted or multiple reciprocal translocations in yeast, without leaving any marker or scar in the genome. Engineering targeted reciprocal translocations allowed us for the first time to untangle the phenotypic impacts of large chromosomal rearrangements from that of point mutations. In addition, the generation of multiple translocations led to a large reorganization of the genetic information along the chromosomes, often including unanticipated large segmental duplications. We showed that reshuffling the genome resulted in the emergence of fitness advantage in stressful environmental conditions, even in strains where no gene was disrupted or amplified by the translocations.
PLOS38	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery. Output:	Both the cost to launch a new drug and the attrition rate during the late stage of the drug discovery and development process are increasing. Torcetrapib is a case in point, having been withdrawn from phase III clinical trials after 15 years of development and an estimated cost of US $800 M. Torcetrapib represents a new class of therapies for the treatment of cardiovascular disease; however, clinical studies indicated that Torcetrapib has deadly side-effects as a result of hypertension. To understand the origins of these adverse drug reactions from Torcetrapib and other related drugs undergoing clinical trials, we introduce a systematic strategy to identify off-targets in the human structural proteome and investigate the roles of these off-targets in impacting human physiology and pathology using biochemical pathway analysis. Our findings suggest that potential side-effects of a new drug can be identified at an early stage of the development cycle and be minimized by fine-tuning multiple off-target interactions. The hope is that this can reduce both the cost of drug development and the mortality rates during clinical trials.
PLOS39	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The Global Programme to Eliminate Lymphatic Filariasis (LF) aims to eliminate the disease as a public health problem by 2020 by conducting mass drug administration (MDA) and controlling morbidity. Once elimination targets have been reached, surveillance is critical for ensuring that programmatic gains are sustained, and challenges include timely identification of residual areas of transmission. WHO guidelines encourage cost-efficient surveillance, such as integration with other population-based surveys. In American Samoa, where LF is caused by Wuchereria bancrofti, and Aedes polynesiensis is the main vector, the LF elimination program has made significant progress. Seven rounds of MDA (albendazole and diethycarbamazine) were completed from 2000 to 2006, and Transmission Assessment Surveys were passed in 2010/2011 and 2015. However, a seroprevalence study using an adult serum bank collected in 2010 detected two potential residual foci of transmission, with Og4C3 antigen (Ag) prevalence of 30.8% and 15.6%. We conducted a follow up study in 2014 to verify if transmission was truly occurring by comparing seroprevalence between residents of suspected hotspots and residents of other villages. In adults from non-hotspot villages (N = 602), seroprevalence of Ag (ICT or Og4C3), Bm14 antibody (Ab) and Wb123 Ab were 1.2% (95% CI 0.6–2.6%), 9.6% (95% CI 7.5%-12.3%), and 10.5% (95% CI 7.6–14.3%), respectively. Comparatively, adult residents of Fagali’i (N = 38) had significantly higher seroprevalence of Ag (26.9%, 95% CI 17.3–39.4%), Bm14 Ab (43.4%, 95% CI 32.4–55.0%), and Wb123 Ab 55.2% (95% CI 39.6–69.8%). Adult residents of Ili’ili/Vaitogi/Futiga (N = 113) also had higher prevalence of Ag and Ab, but differences were not statistically significant. The presence of transmission was demonstrated by 1.1% Ag prevalence (95% CI 0.2% to 3.1%) in 283 children aged 7–13 years who lived in one of the suspected hotspots; and microfilaraemia in four individuals, all of whom lived in the suspected hotspots, including a 9 year old child. Our results provide field evidence that integrating LF surveillance with other surveys is effective and feasible for identifying potential hotspots, and conducting surveillance at worksites provides an efficient method of sampling large populations of adults. Output:	Lymphatic filariasis (LF) is caused by infection with filarial worms that are transmitted by mosquito bites. The Global Programme to Eliminate Lymphatic Filariasis aims to eliminate the disease as a public health problem by 2020. Once elimination targets have been reached, cost-effective surveillance strategies are required to ensure that any areas of ongoing transmission or resurgence are quickly identified and managed. Potential options include the integration of LF surveillance with other public health activities. In American Samoa, blood samples collected in 2010 for a research project on a different disease (leptospirosis) were used to test for evidence of LF infection, and the study found two possible areas of ongoing transmission. We conducted a follow up study in 2014 to verify whether LF infection was truly occurring in these two areas, and found that infection rates in both areas were significantly higher compared to other parts of American Samoa. Our results therefore provide field evidence that integrating LF surveillance activities with other population-based surveys are potentially effective and feasible, and provide a cost-effective method for identifying residual areas of transmission.
PLOS40	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain–containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)–brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator. Output:	In mammals, circadian rhythms are generated by a molecular oscillator in which the circadian locomotor output cycles protein kaput (CLOCK)–brain and muscle ARNT-like protein 1 (BMAL1) transcription factors drive expression of the genes coding for their own repressors, the CRYPTOCHROME (CRY) and PERIOD (PER) proteins. A key feature of the oscillator is that the protein stability of its components is highly regulated. Previous studies had implicated the JmjC domain–containing protein 5 (JMJD5) in regulation of the circadian clock in plants and flies. Here, we show that cells and livers that lack JMJD5 exhibit dysregulation of circadian gene expression. Mechanistically, JMJD5 is required for CRY1 degradation, including its destabilization by AMP-regulated protein kinase (AMPK), by facilitating its interaction with the proteasome. We found that JMJD5 is needed for normal CRY1-mediated transcriptional repression, thereby uncovering an inverse relationship between CRY1 stability and circadian repression. Finally, we showed that JMJD5 impinges on non-clock roles of F-box/leucine-rich repeat protein 3 (FBXL3) and CRY1. Altogether, our studies demonstrate that JMJD5 is a novel link between the oscillator and other physiological processes.
PLOS41	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections. Output:	Influenza virus or flu epidemics represent a recurrent threat to the public health, especially for individuals which are part of a high-risk group such as children, elderly or immune-compromised people. Sporadic pandemic flu outbreaks, such as the Spanish flu of 1918, may cause high grades of mortality among healthy persons. A better understanding of how the immune system deals with these pathogens is of key importance. The protein A20 is an important negative regulator of both innate and adaptive immune responses. We show that the specific deletion of A20 in myeloid cells, such as macrophages and neutrophils, improves the resistance against otherwise lethal influenza infections. This protective effect is mediated by an enhanced innate immune response following respiratory challenge with influenza virus. Although exaggerated pulmonary immune responses are believed to be the primary cause of often life threatening influenza virus induced pneumonia, we demonstrate that boosting the innate immune response by selectively targeting the functionality of A20 in myeloid cells is beneficial for the host survival. This finding provides us with a novel valuable approach for treating influenza and potentially other respiratory viral infections.
PLOS42	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Melioidosis is an often fatal infectious disease affecting humans and animals in tropical regions and is caused by the saprophytic environmental bacterium Burkholderia pseudomallei. Domestic gardens are not only a common source of exposure to soil and thus to B. pseudomallei, but they also have been found to contain more B. pseudomallei than other environments. In this study we addressed whether anthropogenic manipulations common to gardens such as irrigation or fertilizers change the occurrence of B. pseudomallei. We conducted a soil microcosm experiment with a range of fertilizers and soil types as well as a longitudinal interventional study over three years on an experimental fertilized field site in an area naturally positive for B. pseudomallei. Irrigation was the only consistent treatment to increase B. pseudomallei occurrence over time. The effects of fertilizers upon these bacteria depended on soil texture, physicochemical soil properties and biotic factors. Nitrates and urea increased B. pseudomallei load in sand while phosphates had a positive effect in clay. The high buffering and cation exchange capacities of organic material found in a commercial potting mix led to a marked increase in soil salinity with no survival of B. pseudomallei after four weeks in the potting mix sampled. Imported grasses were also associated with B. pseudomallei occurrence in a multivariate model. With increasing population density in endemic areas these findings inform the identification of areas in the anthropogenic environment with increased risk of exposure to B. pseudomallei. Output:	Melioidosis cases are on the rise in endemic areas of northern Australia and Thailand. This potentially severe infectious disease affecting humans and animals in the tropical belt is caused by the gram negative bacterium Burkholderia pseudomallei. Domestic gardens are a common point of exposure to these environmental bacteria and B. pseudomallei are more prevalent in the dry season in gardens when compared to other areas. This is why we analysed whether common gardening practices such as regular watering (irrigation) or soil fertilizing change the occurrence of B. pseudomallei. We conducted a soil microcosm experiment with a range of fertilizers and soil types as well as a longitudinal interventional study over three years on an experimental fertilized field site in an area naturally positive for B. pseudomallei. Irrigation was the only consistent treatment to increase B. pseudomallei occurrence over time. The effects of fertilizers upon these bacteria depended on soil texture, physicochemical properties such as pH or salinity and vegetation. B. pseudomallei occurrence was also associated with imported grasses. With increasing populations in endemic areas, these findings inform the identification of areas in the anthropogenic environment with increased risk of exposure to B. pseudomallei.
PLOS43	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Reporting bias in the literature occurs when there is selective revealing or suppression of results, influenced by the direction of findings. We assessed the risk of reporting bias in the epidemiological literature on health-related behavior (tobacco, alcohol, diet, physical activity, and sedentary behavior) and cardiovascular disease mortality and all-cause mortality and provided a comparative assessment of reporting bias between health-related behavior and statin (in primary prevention) meta-analyses. We searched Medline, Embase, Cochrane Methodology Register Database, and Web of Science for systematic reviews synthesizing the associations of health-related behavior and statins with cardiovascular disease mortality and all-cause mortality published between 2010 and 2016. Risk of bias in systematic reviews was assessed using the ROBIS tool. Reporting bias in the literature was evaluated via small-study effect and excess significance tests. We included 49 systematic reviews in our study. The majority of these reviews exhibited a high overall risk of bias, with a higher extent in health-related behavior reviews, relative to statins. We reperformed 111 meta-analyses conducted across these reviews, of which 65% had statistically significant results (P < 0.05). Around 22% of health-related behavior meta-analyses showed small-study effect, as compared to none of statin meta-analyses. Physical activity and the smoking research areas had more than 40% of meta-analyses with small-study effect. We found evidence of excess significance in 26% of health-related behavior meta-analyses, as compared to none of statin meta-analyses. Half of the meta-analyses from physical activity, 26% from diet, 18% from sedentary behavior, 14% for smoking, and 12% from alcohol showed evidence of excess significance bias. These biases may be distorting the body of evidence available by providing inaccurate estimates of preventive effects on cardiovascular and all-cause mortality. Output:	In the scientific literature, reporting bias occurs when communication and publication of results are influenced by the direction of findings. Reporting bias can distort scientific evidence and may misguide subsequent clinical and public health efforts. Our study provided an assessment of the degree of reporting bias in the literature on health-related behavior (smoking, alcohol, diet, physical activity, and sedentary behavior) and statins and their association with cardiovascular disease and mortality. We analyzed recently published systematic reviews. Most of the systematic reviews (90%) had a high risk of bias related to study eligibility criteria, identification and selection of studies, data collection and study appraisal, and synthesis and findings. We found evidence of reporting bias in about one-fifth of health-related behavior meta-analyses but none of the statin-related meta-analyses. Readers should be aware of the extent of reporting bias in these research areas when interpreting meta-analytical results.
PLOS44	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5’ leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature. Output:	Eukaryotic cells alter their developmental programs in response to environmental signals. Histoplasma capsulatum (Hc), a ubiquitous fungal pathogen of humans, establishes unique transcriptional programs to specify growth in either a multicellular hyphal form or unicellular yeast form in response to temperature. Since hyphae and yeast are specialized to function in infectivity or pathogenesis, respectively, Hc provides a clinically relevant system in which to query eukaryotic regulatory processes. Here we used next-generation sequencing approaches to annotate the transcriptomes of four distinct Hc strains in response to temperature. We found that a fraction of Hc transcripts have differential transcript architecture in hyphae and yeast, exhibiting 5’ leader sequences that differ markedly in length between morphogenetic states. To begin to understand the effect of these differential leader sequences on expression, we performed the first ribosome density and mRNA abundance measurements in Hc, thereby uncovering transcriptional and translational control that contribute to cell-type regulation.
PLOS45	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Leishmania is a protozoan parasite that alternates its life cycle between the sand-fly vector and the mammalian host. This alternation involves environmental changes and leads the parasite to dynamic modifications in morphology, metabolism, cellular signaling and regulation of gene expression to allow for a rapid adaptation to new conditions. The L-arginine pathway in L. amazonensis is important during the parasite life cycle and interferes in the establishment and maintenance of the infection in mammalian macrophages. Host arginase is an immune-regulatory enzyme that can reduce the production of nitric oxide by activated macrophages, directing the availability of L-arginine to the polyamine pathway, resulting in parasite replication. In this work, we performed transcriptional profiling to identify differentially expressed genes in L. amazonensis wild-type (La-WT) versus L. amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. A total of 8253 transcripts were identified in La-WT and La-arg- promastigotes and axenic amastigotes, about 60% of them codifying hypothetical proteins and 443 novel transcripts, which did not match any previously annotated genes. Our RNA-seq data revealed that 85% of genes were constitutively expressed. The comparison of transcriptome and metabolome data showed lower levels of arginase and higher levels of glutamate-5-kinase in La-WT axenic amastigotes compared to promastigotes. The absence of arginase activity in promastigotes increased the levels of pyrroline 5-carboxylate reductase, but decreased the levels of arginosuccinate synthase, pyrroline 5-carboxylate dehydrogenase, acetylornithine deacetylase and spermidine synthase transcripts levels. These observations can explain previous metabolomic data pointing to the increase of L-arginine, citrulline and L-glutamate and reduction of aspartate, proline, ornithine and putrescine. Altogether, these results indicate that arginase activity is important in Leishmania gene expression modulation during differentiation and adaptation to environmental changes. Here, we confirmed this hypothesis with the identification of differential gene expression of the enzymes involved in biosynthesis of amino acids, arginine and proline metabolism and arginine biosynthesis. All data provided information about the transcriptomic profiling and the expression levels of La-WT and La-arg- promastigotes and axenic amastigotes. These findings revealed the importance of arginase in parasite survival and differentiation, and indicated the existence of a coordinated response in the absence of arginase activity related to arginine and polyamine pathways. Output:	Leishmania are auxotrophic for many essential nutrients, including amino acids. In this way, the parasite needs to uptake the amino acids from the environment. The uptake of amino acids is mediated by amino acid transporters that are unique for Leishmania. As part of polyamine pathway, the arginase converts L-arginine to ornithine and furthermore to putrescine, products which are essential for parasite growth. On the other hand, the absence of arginase activity could alter the metabolism of the parasite to surpass the external signals during the life cycle and the fate of infection. The transcriptional profiling of La-WT and La-arg- promastigotes and axenic amastigotes revealed 8253 transcripts, 60% encoding hypothetical proteins and 443 novel transcripts. In addition, our data revealed that 85% of the genes were constitutively expressed. Among the 15% (1268 genes) of the differentially expressed genes, we identified genes up- and down-regulated comparing the transcript abundance from different life cycle stages of the parasite and in the presence or absence of arginase. We also combined the transcriptional with metabolic profile that revealed a proportional correlation between enzyme and metabolites in the polyamine pathway. The differentiation of promastigotes to amastigotes alters the expression of enzymes from polyamines biosynthesis, which modulates ornithine, L-glutamate, proline and putrescine levels. In addition, the absence of arginase activity increased the levels of L-arginine, citrulline and L-glutamate and decreased the levels of aspartate, proline, ornithine and putrescine in promastigotes by differential modulation of genes involved in its metabolism. Altogether these data provided additional insights into how Leishmania is able to modulate its biological functions in the presence or absence of arginase activity to survive during environmental changes.
PLOS46	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Dengue is one of the most significant public health problems in tropical and subtropical countries, and is increasingly being detected in traditionally non-endemic areas. In Bhutan, dengue virus (DENV) has only recently been detected and limited information is available. In this study, we analyzed the epidemiological and molecular characteristics of DENV in two southern districts in Bhutan from 2013–2014. During this period, 379 patients were clinically diagnosed with suspected dengue, of whom 119 (31.4%) were positive for DENV infection by NS1 ELISA and/or nested RT-PCR. DENV serotypes 1, 2 and 3 were detected with DENV-1 being predominant. Phylogenetic analysis of DENV-1 using envelope gene demonstrated genotype V, closely related to strains from northern India. Output:	We describe the epidemiological and molecular features of DENV currently circulating in the two southwestern districts of Bhutan, demonstrating a shift in serotype dominance from previous DENV-3 (2004–2006) to current DENV-1 (2013–2014). The presence of the dengue virus in Bhutan is a relatively recent one. Unfortunately, dengue epidemiological and molecular data in this country is scarce. A fever outbreak in 2013 and 2014 saw patients seeking care at medical facilities in two district of southwestern Bhutan bordering with India. Analyses of serum specimens collected from these patients indicated that dengue virus was at least a major source of this outbreak. These specimens were analyzed in the Public Health Laboratory in Bhutan and in AFRIMS, Thailand. With a combination of three different assays, we established that 31% of all cases captured were caused by dengue virus, although the proportion was higher in 2013 than in 2014. Three different serotypes of dengue virus were found: DENV-1, -2 and -3. No DENV-4 was found. We successfully isolated DENV-1, from which was sequenced the E gene for further analyses. Our analyses revealed that the current DENV-1 in Bhutan probably originated from India.
PLOS47	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Homeostatic proliferation ensures the longevity of central memory T-cells by inducing cell proliferation in the absence of cellular differentiation or activation. This process is governed mainly by IL-7. Central memory T-cells can also be stimulated via engagement of the T-cell receptor, leading to cell proliferation but also activation and differentiation. Using an in vitro model of HIV-1 latency, we have examined in detail the effects of homeostatic proliferation on latently infected central memory T cells. We have also used antigenic stimulation via anti-CD3/anti-CD28 antibodies and established a comparison with a homeostatic proliferation stimulus, to evaluate potential differences in how either treatment affects the dynamics of latent virus populations. First, we show that homeostatic proliferation, as induced by a combination of IL-2 plus IL-7, leads to partial reactivation of latent HIV-1 but is unable to reduce the size of the reservoir in vitro. Second, latently infected cells are able to homeostatically proliferate in the absence of viral reactivation or cell differentiation. These results indicate that IL-2 plus IL-7 may induce a detrimental effect by favoring the maintenance of the latent HIV-1 reservoir. On the other hand, antigenic stimulation efficiently reactivated latent HIV-1 in cultured central memory cells and led to depletion of the latently infected cells via virus-induced cell death. Output:	HIV-1 latently infected cells are considered the last barrier towards viral eradication and cure. However, the low number of latently infected cells found in patients makes studies extremely difficult. Here, using a model of primary CD4 T-cells we study the behavior of latently infected central memory T cells when undergoing homeostatic proliferation. Homeostatic proliferation ensures the longevity of the central memory population, as it does not involve cellular differentiation. In the context of HIV infection, IL-7 has been reported to induce viral outgrowth from latently infected cells in different cellular models. However, those studies did not examine the relationship between cell proliferation and viral reactivation. We here report that the strong effect of IL-7 on the proliferation of memory cells counteracts this cytokine's modest ability to purge latent viruses. Thus, central memory cells are subject to homeostatic proliferation, a physiological effect that may contribute to the longevity of the latent reservoir in HIV-1 infected patients.
PLOS48	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The cellular response to DNA double-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals), which recruits the checkpoint kinase Tel1/ATM to DSBs. In Saccharomyces cerevisiae, the role of Tel1 at DSBs remains enigmatic, as tel1Δ cells do not show obvious hypersensitivity to DSB-inducing agents. By performing a synthetic phenotype screen, we isolated a rad50-V1269M allele that sensitizes tel1Δ cells to genotoxic agents. The MRV1269MX complex associates poorly to DNA ends, and its retention at DSBs is further reduced by the lack of Tel1. As a consequence, tel1Δ rad50-V1269M cells are severely defective both in keeping the DSB ends tethered to each other and in repairing a DSB by either homologous recombination (HR) or nonhomologous end joining (NHEJ). These data indicate that Tel1 promotes MRX retention to DSBs and this function is important to allow proper MRX-DNA binding that is needed for end-tethering and DSB repair. The role of Tel1 in promoting MRX accumulation to DSBs is counteracted by Rif2, which is recruited to DSBs. We also found that Rif2 enhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, suggesting that Rif2 can regulate MRX activity at DSBs by modulating ATP-dependent conformational changes of Rad50. Output:	Many tumors contain mutations that confer defects in repairing DNA double-strand breaks (DSBs). In both yeast and mammals, the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals) plays critical functions in repairing a DSB by either nonhomologous end joining (NHEJ) or homologous recombination (HR). Furthermore, it recruits the checkpoint kinase Tel1/ATM. Although ATM is considered to be a tumor suppressor, up-regulation of ATM signaling promotes chemoresistance, radioresistance and metastasis. For this reason, cancer therapies targeting ATM have been developed to increase the effectiveness of standard genotoxic treatments and/or to set up synthetic lethal approaches in cancers with DNA repair defects. We aimed to identify the precise role of ATM/Tel1 in these processes. By performing a synthetic phenotype screen, we identified a mutation (rad50-V1269M) altering the Rad50 subunit of the MRX complex, which sensitizes cells lacking Tel1 to genotoxic agents. Genetic and biochemical characterization of MRV1269MX protein complex revealed that Tel1 promotes MRX association at DSBs to allow proper MRX-DNA binding that is needed for DSB repair. The role of Tel1 in promoting MRX retention on DSBs is counteracted by Rif2, which can regulate MRX activity at DSBs by modulating ATP-dependent conformational changes in Rad50. Our finding that MRX dysfunctions can be synthetically lethal with Tel1 loss in the presence of genotoxic agents suggests that ATM inhibitors could be beneficial in patients whose tumors have defective MRN functions.
PLOS49	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: For Chagas disease, the most serious infectious disease in the Americas, effective disease control depends on elimination of vectors through spraying with insecticides. Molecular genetic research can help vector control programs by identifying and characterizing vector populations and then developing effective intervention strategies. The population genetic structure of Triatoma infestans (Hemiptera: Reduviidae), the main vector of Chagas disease in Bolivia, was investigated using a hierarchical sampling strategy. A total of 230 adults and nymphs from 23 localities throughout the department of Chuquisaca in Southern Bolivia were analyzed at ten microsatellite loci. Population structure, estimated using analysis of molecular variance (AMOVA) to estimate FST (infinite alleles model) and RST (stepwise mutation model), was significant between western and eastern regions within Chuquisaca and between insects collected in domestic and peri-domestic habitats. Genetic differentiation at three different hierarchical geographic levels was significant, even in the case of adjacent households within a single locality (RST = 0.14, FST = 0.07). On the largest geographic scale, among five communities up to 100 km apart, RST = 0.12 and FST = 0.06. Cluster analysis combined with assignment tests identified five clusters within the five communities. Some houses are colonized by insects from several genetic clusters after spraying, whereas other households are colonized predominately by insects from a single cluster. Significant population structure, measured by both RST and FST, supports the hypothesis of poor dispersal ability and/or reduced migration of T. infestans. The high degree of genetic structure at small geographic scales, inferences from cluster analysis and assignment tests, and demographic data suggest reinfesting vectors are coming from nearby and from recrudescence (hatching of eggs that were laid before insecticide spraying). Suggestions for using these results in vector control strategies are made. Output:	Chagas disease is a protozoan infection caused by the parasite Trypanosoma cruzi. Chagas is prevalent throughout Central and South America, and it remains a chief concern in Bolivia. A movement that began in 1991 called the Southern Cone Initiative has been successful in reducing the incidence of Chagas disease in the Southern Cone countries of Argentina, Brazil, Chile, and Uruguay; but due to socio-economic and other factors, incidence remains high in Bolivia. The most important mode of transmission of T. cruzi to humans and other mammals is through feces of triatomine bugs. Thus, disease control and transmission prevention focus on elimination of triatomine vectors, and more specifically in Bolivia, it focuses on the elimination of Triatoma infestans. This study focuses on T. infestans in the Department of Chuquisaca, Bolivia. Ten highly variable microsatellite markers were used to analyze the population structure of insects collected in different towns. Statistical analyses show that T. infestans are highly structured, which means that they colonize on a small geographic scale. The results also suggest little active dispersal. These findings should be implemented during control efforts so that insecticide spraying focuses on geographic areas of colonization and re-colonization.
PLOS50	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Recent advances in experimental techniques have allowed the simultaneous recordings of populations of hundreds of neurons, fostering a debate about the nature of the collective structure of population neural activity. Much of this debate has focused on the empirical findings of a phase transition in the parameter space of maximum entropy models describing the measured neural probability distributions, interpreting this phase transition to indicate a critical tuning of the neural code. Here, we instead focus on the possibility that this is a first-order phase transition which provides evidence that the real neural population is in a ‘structured’, collective state. We show that this collective state is robust to changes in stimulus ensemble and adaptive state. We find that the pattern of pairwise correlations between neurons has a strength that is well within the strongly correlated regime and does not require fine tuning, suggesting that this state is generic for populations of 100+ neurons. We find a clear correspondence between the emergence of a phase transition, and the emergence of attractor-like structure in the inferred energy landscape. A collective state in the neural population, in which neural activity patterns naturally form clusters, provides a consistent interpretation for our results. Output:	Neurons encoding the natural world are correlated in their activities. The structure of this correlation fundamentally changes the population code, and these effects increase in larger neural populations. We experimentally recorded from populations of 100+ retinal ganglion cells and probed the structure of their joint probability distribution with a series of analytical tools inspired by statistical physics. We found a robust ‘collective state’ in the neural population that resembles the low temperature state of a disordered magnet. This state generically emerges at sufficient correlation strength, where the energy landscape develops an attractor-like structure that naturally clusters neural activity.
PLOS51	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The live attenuated Japanese encephalitis (JE) vaccine SA14-14-2 has been used in Nepal for catch-up campaigns and is now included in the routine immunisation schedule. Previous studies have shown good vaccine efficacy after one dose in districts with a high incidence of JE. The first well-documented dengue outbreak occurred in Nepal in 2006 with ongoing cases now thought to be secondary to migration from India. Previous infection with dengue virus (DENV) partially protects against JE and might also influence serum neutralising antibody titres against JEV. This study aimed to determine whether serum anti-JEV neutralisation titres are: 1. maintained over time since vaccination, 2. vary with historic local JE incidence, and 3. are associated with DENV neutralising antibody levels. We conducted a cross-sectional study in three districts of Nepal: Banke, Rupandehi and Udayapur. Udayapur district had been vaccinated against JE most recently (2009), but had been the focus of only one campaign, compared with two in Banke and three in Rupandehi. Participants answered a short questionnaire and serum was assayed for anti-JEV and anti-DENV IgM and IgG (by ELISA) and 50% plaque reduction neutralisation titres (PRNT50) against JEV and DENV serotypes 1–4. A titre of ≥1:10 was considered seropositive to the respective virus. JEV neutralising antibody seroprevalence (PRNT50 ≥ 1:10) was 81% in Banke and Rupandehi, but only 41% in Udayapur, despite this district being vaccinated more recently. Sensitivity of ELISA for both anti-JEV and anti-DENV antibodies was low compared with PRNT50. DENV neutralising antibody correlated with the JEV PRNT50 ≥1:10, though the effect was modest. IgM (indicating recent infection) against both viruses was detected in a small number of participants. We also show that DENV IgM is present in Nepali subjects who have not travelled to India, suggesting that DENV may have become established in Nepal. We therefore propose that further JE vaccine campaigns should be considered in Udayapur district, and similar areas that have had fewer vaccination campaigns. Output:	In Nepal, immunisation using a live attenuated vaccine is given against Japanese encephalitis (JE), caused by the mosquito-transmitted JE virus (JEV). JE immunisation has taken place via catch-up campaigns and is now part of the routine immunisation programme. Although previous studies have shown good vaccine efficacy in areas where there is a lot of natural exposure to the virus (high endemicity), it is suggested that the efficacy may wane in areas where transmission is lower. Dengue virus (DENV) belongs to the same family and genus as JEV. Previous infection with DENV may also influence the immune response to JEV. Therefore, we conducted a cross-sectional study in Nepal to measure immunity to JE, in districts of differing historic JE incidence, and time from JE vaccination. This showed that neutralising antibody to JEV was found more frequently in districts which had been the subject of more vaccination campaigns, rather than in the most recently vaccinated district. In addition, we cannot rule out a role for natural exposure to JEV in maintaining higher antibody levels. Additionally, the study showed that previous exposure to DENV was positively associated with an immune response to JEV, though this effect was modest. We conclude that there is a need to consider further JE vaccine catch up campaigns in some areas especially given that we could detect JEV IgM, indicating ongoing transmission. We show that ELISA yielded many false negative results for exposure to JEV or vaccination, when compared with neutralising antibody. We also identified some individuals during the course of the study with DENV IgM in their blood, but with no history of travel to India. This suggests that DENV may have become established in some areas of Nepal.
PLOS52	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated. Output:	Until now, most efforts in cancer genomics have focused on identifying genes and pathways driving tumor development. Although this has been unquestionably a success, as evidenced by the fact that we now have an extensive catalogue of cancer driver genes and pathways, there is still a poor understanding of why patients with the same affected driver genes may have different disease outcomes or drug responses. This is precisely the aim of this work-to show how by considering proteins as multifunctional factories instead of monolithic black boxes, it is possible to identify novel cancer driver genes and propose molecular hypotheses to explain such heterogeneity. To that end we have mapped the mutation profiles of 5,989 cancer patients from TCGA to more than 10,000 protein structures, leading us to identify 103 protein interaction interfaces enriched in somatic mutations. Finally, we have integrated clinical annotations as well as proteomics data to show how tumors apparently driven by the same gene can display different behaviors, including patient outcomes, depending on which specific interfaces are mutated.
PLOS53	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Alien species are a major component of human-induced environmental change. Variation in the numbers of alien species found in different areas is likely to depend on a combination of anthropogenic and environmental factors, with anthropogenic factors affecting the number of species introduced to new locations, and when, and environmental factors influencing how many species are able to persist there. However, global spatial and temporal variation in the drivers of alien introduction and species richness remain poorly understood. Here, we analyse an extensive new database of alien birds to explore what determines the global distribution of alien species richness for an entire taxonomic class. We demonstrate that the locations of origin and introduction of alien birds, and their identities, were initially driven largely by European (mainly British) colonialism. However, recent introductions are a wider phenomenon, involving more species and countries, and driven in part by increasing economic activity. We find that, globally, alien bird species richness is currently highest at midlatitudes and is strongly determined by anthropogenic effects, most notably the number of species introduced (i.e., “colonisation pressure”). Nevertheless, environmental drivers are also important, with native and alien species richness being strongly and consistently positively associated. Our results demonstrate that colonisation pressure is key to understanding alien species richness, show that areas of high native species richness are not resistant to colonisation by alien species at the global scale, and emphasise the likely ongoing threats to global environments from introductions of species. Output:	The introduction of alien species is one of the primary ways in which human actions are changing the environment. Alien species have been responsible for numerous global and local extinctions and are eroding the uniqueness of many natural environments. There is thus a basic need to understand which areas end up with more alien species. Here, we use a major new global database on the distribution of alien birds to show, first, how patterns in the number of species introduced to a location (colonisation pressure) have changed over time. We show that historical introductions were driven largely by European, and especially British, colonialism. However, the rate of bird introductions is increasing, with shifts in the locations of origin and introduction of species probably driven by the cage bird trade. We then combine information on where bird species have been introduced with a global map of alien bird species richness to identify the main drivers of richness. We show that colonisation pressure is the strongest predictor of alien bird species richness, but that there are other anthropogenic and environmental drivers. Most notably, once colonisation pressure has been accounted for, alien bird species richness is higher in areas where native bird species richness is higher.
PLOS54	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The peritrophic matrix (PM) plays a key role in compartmentalization of the blood meal and as barrier to pathogens in many disease vectors. To establish an infection in sand flies, Leishmania must escape from the endoperitrophic space to prevent excretion with remnants of the blood meal digestion. In spite of the role played regarding Leishmania survival, little is known about sand fly PM molecular components and structural organization. We characterized three peritrophins (PpPer1, PpPer2, and PpPer3) from Phlebotomus papatasi. PpPer1 and PpPer2 display, respectively, four and one chitin-binding domains (CBDs). PpPer3 on the other hand has two CBDs, one mucin-like domain, and a putative domain with hallmarks of a CBD, but with changes in key amino acids. Temporal and spatial expression analyses show that PpPer1 is expressed specifically in the female midgut after blood feeding. PpPer2 and PpPer3 mRNAs were constitutively expressed in midgut and hindgut, with PpPer3 also being expressed in Malpighian tubules. PpPer2 was the only gene expressed in developmental stages. Interestingly, PpPer1 and PpPer3 expression are regulated by Le. major infection. Recombinant PpPer1, PpPer2 and PpPer3 were obtained and shown to display similar biochemical profiles as the native; we also show that PpPer1 and PpPer2 are able to bind chitin. Knockdown of PpPer1 led to a 44% reduction in protein, which in spite of producing an effect on the percentage of infected sand flies, resulted in a 39% increase of parasite load at 48 h. Our data suggest that PpPer1 is a component for the P. papatasi PM and likely involved in the PM role as barrier against Le. major infection. Output:	For a successful development within the midgut of the sand fly vector, Leishmania must overcome several barriers imposed by the vector that include the digestive proteases secreted within the midgut following a blood meal by the insect, the need to escape from the endoperitrophic space, and attachment to the midgut epithelia to prevent excretion with the remnants of the blood meal. The sand fly peritrophic matrix (PM) constitutes an important barrier against the establishment of Leishmania within the sand fly and if trapped within the PM these parasites will be passed along with the remnants of the blood meal. Despite the role of sand fly PM on Leishmania development, characterization of its molecular components and assessment of their roles against Leishmania are lacking. Thereby, we performed the molecular characterization of three P. papatasi peritrophins named PpPer1, PpPer2, and PpPer3. Overall, we demonstrated that: (1) PpPer3 displays a putative CBD domain that might have undertaken neo-functionalization, (2) PpPer1 and PpPer3 genes display differential gene expression upon Le. major infection; and (3) PpPer1 seems to be an important component for the function of P. papatasi PM as a barrier against Le. major infection.
PLOS55	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Animal African trypanosomosis (AAT) is a neglected tropical disease which imposes a heavy burden on the livestock industry in Sub-Saharan Africa. Its causative agents are Trypanosoma parasites, with T. congolense and T. vivax being responsible for the majority of the cases. Recently, we identified a Nanobody (Nb474) that was employed to develop a homologous sandwich ELISA targeting T. congolense fructose-1,6-bisphosphate aldolase (TcoALD). Despite the high sequence identity between trypanosomatid aldolases, the Nb474-based immunoassay is highly specific for T. congolense detection. The results presented in this paper yield insights into the molecular principles underlying the assay’s high specificity. The structure of the Nb474-TcoALD complex was determined via X-ray crystallography. Together with analytical gel filtration, the structure reveals that a single TcoALD tetramer contains four binding sites for Nb474. Through a comparison with the crystal structures of two other trypanosomatid aldolases, TcoALD residues Ala77 and Leu106 were identified as hot spots for specificity. Via ELISA and surface plasmon resonance (SPR), we demonstrate that mutation of these residues does not abolish TcoALD recognition by Nb474, but does lead to a lack of detection in the Nb474-based homologous sandwich immunoassay. The results show that the high specificity of the Nb474-based immunoassay is not determined by the initial recognition event between Nb474 and TcoALD, but rather by its homologous sandwich design. This (i) provides insights into the optimal set-up of the assay, (ii) may be of great significance for field applications as it could explain the potential detection escape of certain T. congolense strains, and (iii) may be of general interest to those developing similar assays. Output:	Sub-Saharan Africa is plagued by many diseases, which impede its socio-economical development. One of these diseases, Animal African Trypanosomosis, affects livestock and is caused by the parasites of the Trypanosoma genus (T. vivax and T. congolense). Animal African Trypanosomosis leads to considerable economic losses and renders sustainable livestock industry in Sub-Saharan Africa very difficult. In order to proceed with the selective treatment of infected animals, they need to be properly diagnosed. We recently described the use of an assay to specifically detect T. congolense infections in both experimentally and naturally infected animals. The diagnostic assay employs a Nanobody (Nb), which is the smallest antigen-binding unit derived from camelid heavy-chain only antibodies. Our previous results showed that the Nb-based diagnostic test specifically recognizes T. congolense fructose-1,6-bisphosphate aldolase, a glycolytic enzyme that is well conserved amongst other Trypanosoma species. In this paper, we studied the molecular mechanisms underlying the high specificity of the Nb-based diagnostic assay. The principles derived from this work may be important for the design and improvement of similar diagnostic tests.
PLOS56	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: In this work we studied the folding process of the hybrid-1 type human telomeric DNA G-quadruplex with solvent and ions explicitly modeled. Enabled by the powerful bias-exchange metadynamics and large-scale conventional molecular dynamic simulations, the free energy landscape of this G-DNA was obtained for the first time and four folding intermediates were identified, including a triplex and a basically formed quadruplex. The simulations also provided atomistic pictures for the structures and cation binding patterns of the intermediates. The results showed that the structure formation and cation binding are cooperative and mutually supporting each other. The syn/anti reorientation dynamics of the intermediates was also investigated. It was found that the nucleotides usually take correct syn/anti configurations when they form native and stable hydrogen bonds with the others, while fluctuating between two configurations when they do not. Misfolded intermediates with wrong syn/anti configurations were observed in the early intermediates but not in the later ones. Based on the simulations, we also discussed the roles of the non-native interactions. Besides, the formation process of the parallel conformation in the first two G-repeats and the associated reversal loop were studied. Based on the above results, we proposed a folding pathway for the hybrid-1 type G-quadruplex with atomistic details, which is new and more complete compared with previous ones. The knowledge gained for this type of G-DNA may provide a general insight for the folding of the other G-quadruplexes. Output:	G-quadruplexes are high-order DNA/RNA structures. They are involved in the regulation of telomere maintenance, DNA replication, transcription and translation, and are also attractive drug designing targets for treating cancers and promising building blocks for molecular nanodevices. The knowledge of their formation process will improve our understanding of how they achieve their functional structures and then facilitate designing of artificial G-quadruplexes with novel functions. The study of their formation process is also of academic importance, since they involve many different physical chemical factors or interactions, including the hydrogen bonds, the electrostatic effect associated with metal ions, and the syn/anti reorientation of the glycosidic bonds. These make the G-quadruplex a fascinating model system for studying the structure formation of bio-molecules. Furthermore, the study of their formations may enrich the free energy landscape theory that has been well developed for protein folding, but yet to be verified in the other biomolecular systems. Here we computationally study the folding process of the hybrid-1 type human telomeric DNA G-quadruplex and infer a new folding picture, which may also cast a light to the formation of the other G-quadruplexes.
PLOS57	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The complexity in composition and function of the eukaryotic nucleus is achieved through its organization in specialized nuclear compartments. The Drosophila chromatin remodeling ATPase ISWI plays evolutionarily conserved roles in chromatin organization. Interestingly, ISWI genetically interacts with the hsrω gene, encoding multiple non-coding RNAs (ncRNA) essential, among other functions, for the assembly and organization of the omega speckles. The nucleoplasmic omega speckles play important functions in RNA metabolism, in normal and stressed cells, by regulating availability of hnRNPs and some other RNA processing proteins. Chromatin remodelers, as well as nuclear speckles and their associated ncRNAs, are emerging as important components of gene regulatory networks, although their functional connections have remained poorly defined. Here we provide multiple lines of evidence showing that the hsrω ncRNA interacts in vivo and in vitro with ISWI, regulating its ATPase activity. Remarkably, we found that the organization of nucleoplasmic omega speckles depends on ISWI function. Our findings highlight a novel role for chromatin remodelers in organization of nucleoplasmic compartments, providing the first example of interaction between an ATP-dependent chromatin remodeler and a large ncRNA. Output:	Chromatin structure and function are regulated by the concerted activity of covalent modifiers of chromatin, nucleosome remodeling factors, and several emerging classes of non-coding RNAs. ISWI is an evolutionarily conserved ATP-dependent chromatin remodeler playing essential roles in chromosome condensation, gene expression, and DNA replication. ISWI activity has been involved in a variety of nuclear functions including telomere silencing, stem cell renewal, neural morphogenesis, and epigenetic reprogramming. Using an in vivo assay to identify factors regulating ISWI activity in the model system Drosophila melanogaster, we recovered a genetic interaction between ISWI and hsrω. The hsrω gene encodes multiple non-coding RNAs (ncRNAs), of which the >10 kb nuclear hsrω-n RNA, with functional homolog in mammals, is essential for the assembly and organization of hnRNP-containing nucleoplasmic omega speckles. These special nuclear compartments play essential roles in the storage/sequestration of hnRNP family and other proteins, thus playing important roles in mRNA maturation and other regulatory processes. Here we show that the hsrω-n ncRNA interacts in vivo and in vitro with ISWI to directly regulate its ATPase activity. We also provide in vivo data showing that omega speckle nuclear organization depends on ISWI function, highlighting a novel role for chromatin remodelers in nuclear speckles organization.
PLOS58	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer. Output:	The identification of cells that give origin to cancer is critical in order to design effective therapeutic strategies. To this end, the early stages of cancer are the most informative but they are seldom associated with clinical symptoms and therefore pass unnoticed in human patients. Studies on animal tumors are invaluable to this research area. In this study, we determined the cells originating an infectious lung cancer of sheep (ovine pulmonary adenocarcinoma, OPA) that is similar to some forms of human pulmonary adenocarcinoma. OPA is caused by a virus known as Jaagsiekte sheep retrovirus (JSRV). We show that OPA is caused by JSRV infection of proliferating type 2 pneumocytes (lung alveolar proliferating cells, LAPCs). We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection while healthy adult sheep exhibit a relatively low number of LAPCs and are resistant to OPA induction. However, adult sheep were susceptible to JSRV infection when the presence of LAPCs was stimulated by induction of a mild injury to the respiratory epithelium. Thus, our study identifies the cells originating lung adenocarcinoma in OPA and shows that inflammation to the respiratory epithelium can predispose to retrovirus infection and cancer.
PLOS59	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase. Output:	Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children, but the underlying pathogenesis of this infection remains unclear. Hes1, an important effector of Notch signaling, governs the fate of neural progenitor cells (NPCs) and fetal brain development. Here we demonstrate that: (1) HCMV infection results in loss of Hes1 protein in NPCs; (2) the HCMV immediate-early 1 protein (IE1) mediates Hes1 protein downregulation through direct interaction, which requires amino acids 451–475; (3) IE1 assembles a Hes1 ubiquitination complex and mediates Hes1 ubiquitination; and (4) IE1 also assembles an Sp100A ubiquitination complex and mediates Sp100A ubiquitination, but does not require amino acids 451–475. These results suggest that HCMV IE1 is a potential E3 ubiquitin ligase. Downregulation of Hes1 by HCMV infection and IE1 implies a novel mechanism linking Hes1 depletion to virus-induced neuropathogenesis.
PLOS60	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Neuronal differentiation often requires target-derived signals from the cells they innervate. These signals typically activate neural subtype-specific genes, but the gene regulatory mechanisms remain largely unknown. Highly restricted expression of the FMRFa neuropeptide in Drosophila Tv4 neurons requires target-derived BMP signaling and a transcription factor code that includes Apterous. Using integrase transgenesis of enhancer reporters, we functionally dissected the Tv4-enhancer of FMRFa within its native cellular context. We identified two essential but discrete cis-elements, a BMP-response element (BMP-RE) that binds BMP-activated pMad, and a homeodomain-response element (HD-RE) that binds Apterous. These cis-elements have low activity and must be combined for Tv4-enhancer activity. Such combinatorial activity is often a mechanism for restricting expression to the intersection of cis-element spatiotemporal activities. However, concatemers of the HD-RE and BMP-RE cis-elements were found to independently generate the same spatiotemporal expression as the Tv4-enhancer. Thus, the Tv4-enhancer atypically combines two low-activity cis-elements that confer the same output from distinct inputs. The activation of target-dependent genes is assumed to 'wait' for target contact. We tested this directly, and unexpectedly found that premature BMP activity could not induce early FMRFa expression; also, we show that the BMP-insensitive HD-RE cis-element is activated at the time of target contact. This led us to uncover a role for the nuclear receptor, seven up (svp), as a repressor of FMRFa induction prior to target contact. Svp is normally downregulated immediately prior to target contact, and we found that maintaining Svp expression prevents cis-element activation, whereas reducing svp gene dosage prematurely activates cis-element activity. We conclude that the target-dependent FMRFa gene is repressed prior to target contact, and that target-derived BMP signaling directly activates FMRFa gene expression through an atypical gene regulatory mechanism. Output:	Nerve cells extend long processes that grow out to contact the target cells with which they communicate. When the nerve cell makes initial contact, the target cells send a retrograde signal back to the nerve cell. Such target-derived signals activate and maintain important genes that make the nerve cell functional, such as genes determining neurotransmitter type. This is a well-characterized phenomenon throughout the nervous systems of flies to mammals, but we still do not know how these signals actually activate gene expression. We now provide details regarding target-dependent signal regulation of nerve cell genes. We model this in Tv4 neurons of Drosophila melanogaster, which require target-derived BMP signaling to trigger FMRFa neuropeptide expression. Our study shows how DNA-binding transcription factors of the BMP signaling pathway integrate with other transcription factors at specific regulatory DNA sequences to activate FMRFa expression, and define the atypical logic by which this occurs. We also provide novel insight into how target-dependent genes are regulated before target contact. Instead of simply waiting for target-dependent activation, these genes seem to be blocked from being expressed prior to target contact. These findings have relevance to mammals because the role of target-derived BMP signaling in nerve cell gene regulation is conserved between vertebrates and invertebrates.
PLOS61	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Determining the three dimensional arrangement of proteins in a complex is highly beneficial for uncovering mechanistic function and interpreting genetic variation in coding genes comprising protein complexes. There are several methods for determining co-complex interactions between proteins, among them co-fractionation / mass spectrometry (CF-MS), but it remains difficult to identify directly contacting subunits within a multi-protein complex. Correlation analysis of CF-MS profiles shows promise in detecting protein complexes as a whole but is limited in its ability to infer direct physical contacts among proteins in sub-complexes. To identify direct protein-protein contacts within human protein complexes we learn a sparse conditional dependency graph from approximately 3,000 CF-MS experiments on human cell lines. We show substantial performance gains in estimating direct interactions compared to correlation analysis on a benchmark of large protein complexes with solved three-dimensional structures. We demonstrate the method’s value in determining the three dimensional arrangement of proteins by making predictions for complexes without known structure (the exocyst and tRNA multi-synthetase complex) and by establishing evidence for the structural position of a recently discovered component of the core human EKC/KEOPS complex, GON7/C14ORF142, providing a more complete 3D model of the complex. Direct contact prediction provides easily calculable additional structural information for large-scale protein complex mapping studies and should be broadly applicable across organisms as more CF-MS datasets become available. Output:	Proteins physically associate into complexes in order to carry out the essential functions of life. Knowing how proteins are physically arranged three dimensionally in these complexes provides clues towards how they work. In principle, the associations between proteins in large-scale proteomics datasets should often reflect direct physical contacts between proteins in each complex. Here, we describe a statistical method to discover which subunits within complexes directly contact each other based on their co-purification behavior in published co-fractionation mass spectrometry datasets. Within our predictions, we recover many known protein-protein contacts, serving to validate our method, as well as unknown contacts that can inform future studies of these complexes. Specifically, we observe confident contacts between subunits within the exocyst and tRNA multi-synthetase complexes, two complexes that have incomplete structural information. Using our method, we further provide structural information for a previously missing subunit of the EKC/KEOPS complex. We anticipate that this method and the associated predictions will help to better inform our understanding of the functions and structures of diverse protein complexes.
PLOS62	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: It is often assumed that animals and people adjust their behavior to maximize reward acquisition. In visually cued reinforcement schedules, monkeys make errors in trials that are not immediately rewarded, despite having to repeat error trials. Here we show that error rates are typically smaller in trials equally distant from reward but belonging to longer schedules (referred to as “schedule length effect”). This violates the principles of reward maximization and invariance and cannot be predicted by the standard methods of Reinforcement Learning, such as the method of temporal differences. We develop a heuristic model that accounts for all of the properties of the behavior in the reinforcement schedule task but whose predictions are not different from those of the standard temporal difference model in choice tasks. In the modification of temporal difference learning introduced here, the effect of schedule length emerges spontaneously from the sensitivity to the immediately preceding trial. We also introduce a policy for general Markov Decision Processes, where the decision made at each node is conditioned on the motivation to perform an instrumental action, and show that the application of our model to the reinforcement schedule task and the choice task are special cases of this general theoretical framework. Within this framework, Reinforcement Learning can approach contextual learning with the mixture of empirical findings and principled assumptions that seem to coexist in the best descriptions of animal behavior. As examples, we discuss two phenomena observed in humans that often derive from the violation of the principle of invariance: “framing,” wherein equivalent options are treated differently depending on the context in which they are presented, and the “sunk cost” effect, the greater tendency to continue an endeavor once an investment in money, effort, or time has been made. The schedule length effect might be a manifestation of these phenomena in monkeys. Output:	Theories of rational behavior are built on a number of principles, including the assumption that subjects adjust their behavior to maximize their long-term returns and that they should work equally hard to obtain a reward in situations where the effort to obtain reward is the same (called the invariance principle). Humans, however, are sensitive to the manner in which equivalent choices are presented, or “framed,” and often have a greater tendency to continue an endeavor once an investment in money, effort, or time has been made, a phenomenon known as “sunk cost” effect. In a similar manner, when monkeys must perform different numbers of trials to obtain a reward, they work harder as the number of trials already performed increases, even though both the work remaining and the forthcoming reward are the same in all situations. Methods from the theory of Reinforcement Learning, which usually provide learning strategies aimed at maximizing returns, cannot model this violation of invariance. Here we generalize a prominent method of Reinforcement Learning so as to explain the violation of invariance, without losing the ability to model behaviors explained by standard Reinforcement Learning models. This generalization extends our understanding of how animals and humans learn and behave.
PLOS63	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debate. Motivated by experimental data suggesting differing stabilities for homomers of the cognate human β1- and β2-adrenergic receptors, we have carried out approximately 160 microseconds of biased molecular dynamics simulations to calculate the dimerization free energy of crystal structure-based models of these receptors, interacting at two interfaces that have often been implicated in GPCR association under physiological conditions. Specifically, results are presented for simulations of coarse-grained (MARTINI-based) and atomistic representations of each receptor, in homodimeric configurations with either transmembrane helices TM1/H8 or TM4/3 at the interface, in an explicit lipid bilayer. Our results support a definite contribution to the relative stability of GPCR dimers from both interface sequence and configuration. We conclude that β1- and β2-adrenergic receptor homodimers with TM1/H8 at the interface are more stable than those involving TM4/3, and that this might be reconciled with experimental studies by considering a model of oligomerization in which more stable TM1 homodimers diffuse through the membrane, transiently interacting with other protomers at interfaces involving other TM helices. Output:	G Protein-Coupled Receptors (GPCRs) are the largest family of membrane proteins targeted by drugs in clinical practice. Despite being at the forefront of biomedical research for many years, there is still considerable uncertainty about how GPCRs function at a molecular level. Although substantial evidence exists in support of their association in cell membranes, it is unclear how general and/or long-lasting this phenomenon is and whether it plays a significant role in GPCR function. This observation highlights the importance of understanding the rules that govern receptor-receptor interactions in living cells. Here, we report the results of computer simulations from which we estimated the relative stability of dimers formed by different, yet highly homologous, prototypic GPCRs. Our results suggest overall transiency in receptor-receptor interactions at the simulated different dimerization interfaces, but a variable strength of association depending on the specific residue composition or shape of the interface. The methodology we propose is expected to provide a level of molecular detail that is unattainable using current experimental techniques. Our ultimate goal is to generate unique hypotheses of receptor-receptor inter-helical interactions that can be tested experimentally to help elucidate the role of receptor association in GPCR function.
PLOS64	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The evolution of bacterial populations has recently become considerably better understood due to large-scale sequencing of population samples. It has become clear that DNA sequences from a multitude of genes, as well as a broad sample coverage of a target population, are needed to obtain a relatively unbiased view of its genetic structure and the patterns of ancestry connected to the strains. However, the traditional statistical methods for evolutionary inference, such as phylogenetic analysis, are associated with several difficulties under such an extensive sampling scenario, in particular when a considerable amount of recombination is anticipated to have taken place. To meet the needs of large-scale analyses of population structure for bacteria, we introduce here several statistical tools for the detection and representation of recombination between populations. Also, we introduce a model-based description of the shape of a population in sequence space, in terms of its molecular variability and affinity towards other populations. Extensive real data from the genus Neisseria are utilized to demonstrate the potential of an approach where these population genetic tools are combined with an phylogenetic analysis. The statistical tools introduced here are freely available in BAPS 5.2 software, which can be downloaded from http://web.abo.fi/fak/mnf/mate/jc/software/baps.html. Output:	The study of bacterial population biology is complicated by the fact that, although bacteria are largely asexual, they can also exchange genetic materials through homologous recombination. Unlike eukaryotes, recombination in bacteria is not an obligatory process. Furthermore, the recombination mechanisms are subject to many biological and ecological factors that can vary even within different populations of the same species. Although increasing evidence for homologous recombination has been found in many bacterial species, determining the frequency of recombination and understanding the influence that it exerts upon the evolution of bacterial populations remains a challenging work. In this article, we provide a dynamic picture of recombination within and between closely related bacteria species. Through an integration of several Bayesian statistical models, our method highlights the importance of a quantitative estimation of recombination. Our analyses of a challenging multi-locus sequence typing (MLST) database demonstrate that combined analyses using both traditional phylogenetic methods, explorative MLST tools and Bayesian population genetic models can together yield interesting biological insights that cannot easily be reached by any of the approaches alone.
PLOS65	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Signal output from receptor–G-protein–effector modules is a dynamic function of the nucleotide exchange activity of the receptor, the GTPase-accelerating activity of GTPase-activating proteins (GAPs), and their interactions. GAPs may inhibit steady-state signaling but may also accelerate deactivation upon removal of stimulus without significantly inhibiting output when the receptor is active. Further, some effectors (e.g., phospholipase C-β) are themselves GAPs, and it is unclear how such effectors can be stimulated by G proteins at the same time as they accelerate G protein deactivation. The multiple combinations of protein–protein associations and interacting regulatory effects that allow such complex behaviors in this system do not permit the usual simplifying assumptions of traditional enzyme kinetics and are uniquely subject to systems-level analysis. We developed a kinetic model for G protein signaling that permits analysis of both interactive and independent G protein binding and regulation by receptor and GAP. We evaluated parameters of the model (all forward and reverse rate constants) by global least-squares fitting to a diverse set of steady-state GTPase measurements in an m1 muscarinic receptor–Gq–phospholipase C-β1 module in which GTPase activities were varied by ∼104-fold. We provide multiple tests to validate the fitted parameter set, which is consistent with results from the few previous pre-steady-state kinetic measurements. Results indicate that (1) GAP potentiates the GDP/GTP exchange activity of the receptor, an activity never before reported; (2) exchange activity of the receptor is biased toward replacement of GDP by GTP; (3) receptor and GAP bind G protein with negative cooperativity when G protein is bound to either GTP or GDP, promoting rapid GAP binding and dissociation; (4) GAP indirectly stabilizes the continuous binding of receptor to G protein during steady-state GTPase hydrolysis, thus further enhancing receptor activity; and (5) receptor accelerates GDP/GTP exchange primarily by opening an otherwise closed nucleotide binding site on the G protein but has minimal effect on affinity (Kassoc = kassoc/kdissoc) of G protein for nucleotide. Model-based simulation explains how GAP activity can accelerate deactivation >10-fold upon removal of agonist but still allow high signal output while the receptor is active. Analysis of GTPase flux through distinct reaction pathways and consequent accumulation of specific GTPase cycle intermediates indicate that, in the presence of a GAP, the receptor remains bound to G protein throughout the GTPase cycle and that GAP binds primarily during the GTP-bound phase. The analysis explains these behaviors and relates them to the specific regulatory phenomena described above. The work also demonstrates the applicability of appropriately data-constrained system-level analysis to signaling networks of this scale. Output:	Throughout the eukaryotes, G proteins convey information from receptors for diverse stimuli—neurotransmitters, hormones, light, odors, and pheromones—to intracellular regulatory proteins collectively known as effectors. G proteins function by transiting a dynamic cycle of activation and deactivation. Receptors accelerate activation, which allows G proteins to regulate effectors, and receptors thus increase signal output. GTPase-activating proteins, GAPs, accelerate deactivation. GAPs can thus attenuate signaling, but GAPs can also accelerate signal termination when stimulus is removed without inhibiting signal output while stimulus is present. Surprisingly, some effectors are also GAPs for the G proteins that activate them, essentially turning off their activator. We developed a mathematical model that describes control of G protein signaling by receptor and GAP and used experimental data to determine its important parameters. We show that GAPs actually potentiate G protein activation by receptor, a previously unsuspected effect. Further, GAPs indirectly stabilize receptor–G protein binding during stimulation, which we had previously predicted based on inconsistencies among other experimental results. The present results elucidate how GAPs can independently control signaling kinetics and amplitude and thus clarify how effectors can both respond to G proteins and act as G protein GAPs.
PLOS66	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: We sequenced and compared the genomes of the Dothideomycete fungal plant pathogens Cladosporium fulvum (Cfu) (syn. Passalora fulva) and Dothistroma septosporum (Dse) that are closely related phylogenetically, but have different lifestyles and hosts. Although both fungi grow extracellularly in close contact with host mesophyll cells, Cfu is a biotroph infecting tomato, while Dse is a hemibiotroph infecting pine. The genomes of these fungi have a similar set of genes (70% of gene content in both genomes are homologs), but differ significantly in size (Cfu >61.1-Mb; Dse 31.2-Mb), which is mainly due to the difference in repeat content (47.2% in Cfu versus 3.2% in Dse). Recent adaptation to different lifestyles and hosts is suggested by diverged sets of genes. Cfu contains an α-tomatinase gene that we predict might be required for detoxification of tomatine, while this gene is absent in Dse. Many genes encoding secreted proteins are unique to each species and the repeat-rich areas in Cfu are enriched for these species-specific genes. In contrast, conserved genes suggest common host ancestry. Homologs of Cfu effector genes, including Ecp2 and Avr4, are present in Dse and induce a Cf-Ecp2- and Cf-4-mediated hypersensitive response, respectively. Strikingly, genes involved in production of the toxin dothistromin, a likely virulence factor for Dse, are conserved in Cfu, but their expression differs markedly with essentially no expression by Cfu in planta. Likewise, Cfu has a carbohydrate-degrading enzyme catalog that is more similar to that of necrotrophs or hemibiotrophs and a larger pectinolytic gene arsenal than Dse, but many of these genes are not expressed in planta or are pseudogenized. Overall, comparison of their genomes suggests that these closely related plant pathogens had a common ancestral host but since adapted to different hosts and lifestyles by a combination of differentiated gene content, pseudogenization, and gene regulation. Output:	We compared the genomes of two closely related pathogens with very different lifestyles and hosts: C. fulvum (Cfu), a biotroph of tomato, and D. septosporum (Dse), a hemibiotroph of pine. Some differences in gene content were identified that can be directly related to their different hosts, such as the presence of a gene involved in degradation of a tomato saponin only in Cfu. However, in general the two species share a surprisingly large proportion of genes. Dse has functional homologs of Cfu effector genes, while Cfu has genes for biosynthesis of dothistromin, a toxin probably associated with virulence in Dse. Cfu also has an unexpectedly large content of genes for biosynthesis of other secondary metabolites and degradation of plant cell walls compared to Dse, contrasting with its host preference and lifestyle. However, many of these genes were not expressed in planta or were pseudogenized. These results suggest that evolving species may retain genetic signatures of the host and lifestyle preferences of their ancestor and that evolution of new genes, gene regulation, and pseudogenization are important factors in adaptation.
PLOS67	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The adaptation of the CRISPR-Cas9 system as a genome editing technique has generated much excitement in recent years owing to its ability to manipulate targeted genes and genomic regions that are complementary to a programmed single guide RNA (sgRNA). However, the efficacy of a specific sgRNA is not uniquely defined by exact sequence homology to the target site, thus unintended off-targets might additionally be cleaved. Current methods for sgRNA design are mainly concerned with predicting off-targets for a given sgRNA using basic sequence features and employ elementary rules for ranking possible sgRNAs. Here, we introduce CRISTA (CRISPR Target Assessment), a novel algorithm within the machine learning framework that determines the propensity of a genomic site to be cleaved by a given sgRNA. We show that the predictions made with CRISTA are more accurate than other available methodologies. We further demonstrate that the occurrence of bulges is not a rare phenomenon and should be accounted for in the prediction process. Beyond predicting cleavage efficiencies, the learning process provides inferences regarding patterns that underlie the mechanism of action of the CRISPR-Cas9 system. We discover that attributes that describe the spatial structure and rigidity of the entire genomic site as well as those surrounding the PAM region are a major component of the prediction capabilities. Output:	The CRISPR-Cas9 system, a microbial adaptive immune system, was recently exploited for modulating DNA sequences within the endogenous genome in many organisms. This system has emerged as a technology of choice for genome editing with promising therapeutic and research advancements. However, these exciting developments were not paralleled by deep understanding of CRISPR-Cas9 cleavage efficiency. Indeed, while numerous studies have been conducted in order to define better guidelines to determine CRISPR-Cas9 specificity, much ambiguity remains surrounding its mechanism of action. Here, we present a machine-learning based algorithm that was trained on genome-wide experimental data. The algorithm considers a broad range of features that describe different attributes that potentially impact the cleavage efficacy of CRISPR-Cas9 including genomic attributes, RNA thermodynamics, and those concerning sequence similarity. We further found that incorporating the possibility for DNA or RNA bulges play an important role in prediction accuracy. Together, these result in a predictive model that can be used both to predict the cleavage propensity of a new genomic site according to the genomic context, as well as to learn on the importance of different features on CRISPR-Cas9 efficiency and selectivity.
PLOS68	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Human cytomegalovirus (HCMV), a β-herpesvirus, has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. Induction of IL-8 is particularly important during HCMV infection as neutrophils, primarily attracted by IL-8, play a key role in virus dissemination. Moreover, IL-8 has a positive effect in the replication of HCMV. This work has identified an HCMV gene (UL76), with the relevant property of inducing IL-8 expression at both transcriptional and protein levels. Up-regulation of IL-8 by UL76 results from activation of the NF-kB pathway as inhibition of both IKK-β activity or degradation of Ikβα abolishes the IL-8 induction and, concomitantly, expression of UL76 is associated with the translocation of p65 to the nucleus where it binds to the IL-8 promoter. Furthermore, the UL76-mediated induction of IL-8 requires ATM and is correlated with the phosphorylation of NEMO on serine 85, indicating that UL76 activates NF-kB pathway by the DNA Damage response, similar to the impact of genotoxic drugs. More importantly, a UL76 deletion mutant virus was significantly less efficient in stimulating IL-8 production than the wild type virus. In addition, there was a significant reduction of IL-8 secretion when ATM -/- cells were infected with wild type HCMV, thus, indicating that ATM is also involved in the induction of IL-8 by HCMV. In conclusion, we demonstrate that expression of UL76 gene induces IL-8 expression as a result of the DNA damage response and that both UL76 and ATM have a role in the mechanism of IL-8 induction during HCMV infection. Hence, this work characterizes a new role of the activation of DNA Damage response in the context of host-pathogen interactions. Output:	The importance of herpesviruses is evident by their prevalence in the human population and the diverse range of diseases that they provoke. Their ability to establish latency provides a compelling example of how herpesviruses successfully evade the immune system and manipulate cellular biology. One promising approach for the development of novel anti-viral strategies is to study viral proteins involved in these host-pathogen interactions. One example is the induction of the pro-inflammatory chemokine IL-8 by HCMV which enhances viral replication and dissemination of the virus by neutrophils. Here, we have identified HCMV UL76 gene, conserved in all herpesviruses, as an inducer of IL-8, and thus with an important impact on HCMV pathogenesis. The induction of IL-8 by UL76 results from activation of the DNA Damage response, which may also explain why UL76 also induces cell cycle arrest. These findings are a clear example of how viruses manipulate intracellular signaling pathways with different outcomes that will be beneficial for viral infection. Finally, the fact that UL76 is a non-homologous gene substantiates the premise that many such pathogen genes without homology may indeed have evolved for host manipulation, and are a repository of potential useful tools for experimental manipulation in health and disease.
PLOS69	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: An important question in the literature focusing on motor control is to determine which laws drive biological limb movements. This question has prompted numerous investigations analyzing arm movements in both humans and monkeys. Many theories assume that among all possible movements the one actually performed satisfies an optimality criterion. In the framework of optimal control theory, a first approach is to choose a cost function and test whether the proposed model fits with experimental data. A second approach (generally considered as the more difficult) is to infer the cost function from behavioral data. The cost proposed here includes a term called the absolute work of forces, reflecting the mechanical energy expenditure. Contrary to most investigations studying optimality principles of arm movements, this model has the particularity of using a cost function that is not smooth. First, a mathematical theory related to both direct and inverse optimal control approaches is presented. The first theoretical result is the Inactivation Principle, according to which minimizing a term similar to the absolute work implies simultaneous inactivation of agonistic and antagonistic muscles acting on a single joint, near the time of peak velocity. The second theoretical result is that, conversely, the presence of non-smoothness in the cost function is a necessary condition for the existence of such inactivation. Second, during an experimental study, participants were asked to perform fast vertical arm movements with one, two, and three degrees of freedom. Observed trajectories, velocity profiles, and final postures were accurately simulated by the model. In accordance, electromyographic signals showed brief simultaneous inactivation of opposing muscles during movements. Thus, assuming that human movements are optimal with respect to a certain integral cost, the minimization of an absolute-work-like cost is supported by experimental observations. Such types of optimality criteria may be applied to a large range of biological movements. Output:	When performing reaching and grasping movements, the brain has to choose one trajectory among an infinite set of possibilities. Nevertheless, because human and animal movements provide highly stereotyped features, motor strategies used by the brain were assumed to be optimal according to certain optimality criteria. In this study, we propose a theoretical model for motor planning of arm movements that minimizes a compromise between the absolute work exerted by the muscles and the integral of the squared acceleration. We demonstrate that under these assumptions agonistic and antagonistic muscles are inactivated during overlapping periods of time for quick enough movements. Moreover, it is shown that only this type of criterion can predict these inactivation periods. Finally, experimental evidence is in agreement with the predictions of the model. Indeed, we report the existence of simultaneous inactivation of opposing muscles during fast vertical arm movements. Therefore, this study suggests that biological movements partly optimize the energy expenditure, integrating both inertial and gravitational forces during the motor planning process.
PLOS70	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively explained. That model consisted of reactions involving 23 molecular species among which the concentrations of HIF and oxygen were linked through a complex set of reactions. In this paper, we analyze this previous model using a combination of mathematical tools to draw out the key components of the network and explain quantitatively how they contribute to the sharp oxygen response. We find that the switch-like behavior is due to pathway-switching wherein HIF degrades rapidly under normoxia in one pathway, while the other pathway accumulates HIF to trigger downstream genes under hypoxia. The analytic technique is potentially useful in studying larger biomedical networks. Output:	A complex biomolecular network utilizes different pathways to perform different functions. However, the interactions within the network are typically so complicated that the pathway structure is usually hidden. By some mathematical techniques, the pathways can be identified and possibly decoupled, whereby the insightful details of the network can be exposed. As an example, we study in this paper the hypoxia response network that manifests a dramatic switch-like behavior for certain sets of rate constants: a slight change of the oxygen concentration close to a critical value will lead to distinct reaction patterns. By a technique called extreme pathway analysis, the network is decoupled into three major and some minor pathways. Flux distribution among these pathways can thus be measured by integrating the ordinary differential equations for any given set of rate constants. For the sets of rate constants where the switch-like behavior is observed, we found that such a behavior is due to the switching of flux between two of the three major pathways.
PLOS71	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis. Output:	The ability of an organism to adapt to sudden changes in environmental osmolarity is critical to ensure growth, propagation, and survival. The synthesis of organic osmolytes is a common adaptive strategy to survive hyperosmotic stress. However, it was not well understood, which biosynthetic pathways and storage strategies were used by organisms to rapidly generate osmolytes upon acute hyperosmotic stress. Here, we demonstrate that glycogen is an essential reservoir that is used upon acute hyperosmotic stress to generate the organic osmolyte glycerol promoting fast and efficient protection. Importantly, we show that this pathway is regulated by FLCN-1, an ortholog of the human tumor suppressor Folliculin responsible for the Birt-Hogg-Dubé cancer syndrome, and by AMPK, the master regulator of energy homeostasis.
PLOS72	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11YF/YF), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11YF/YF and Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number of repair foci increased during oocyte development, indicating the induction of S phase-independent, de novo DNA damage. In wild type pachytene oocytes we observed meiotic silencing in two types of pseudo XY bodies, one type containing DMC1 and RAD51 foci on unsynapsed axes, and another type containing only RAD51 foci, mainly on synapsed axes. Taken together, our results indicate that in addition to asynapsis, persistent SPO11-induced DSBs are important for the initiation of MSCI and MSUC, and that SPO11-independent DNA repair foci contribute to the MSUC response in oocytes. Output:	Meiosis is a special cell division that generates genetically divergent haploid germ cells. At the very beginning of this process, during meiotic prophase, the enzyme SPO11 generates hundreds of DNA double-strand breaks (DSBs). Meiotic DSBs are repaired via a mechanism that requires the presence of an intact homologous template. This repair process stimulates homologous chromosome pairing, and the formation of a protein complex that connects the paired chromosome axes, reaching a state called synapsis. Male mammals carry a pair of largely heterologous sex chromosomes, the X and Y, which show delayed DSB repair and extensive asynapsis. In addition, the X and Y chromosomes are transcriptionally silenced by a mechanism named Meiotic Sex Chromosome Inactivation (MSCI). This mechanism is a specialization of a more general silencing mechanism, named Meiotic Silencing of Unsynapsed Chromatin (MSUC), that is induced when any pairing problem between homologous chromosomes results in asynapsis, in male as well as female meiotic prophase cells. Here, we demonstrate that in addition to asynapsis, the persistent presence of DNA repair foci is a hallmark of meiotic silencing. In addition, we show that SPO11-independent DNA repair foci form during normal oocyte development. We propose that these foci represent sites of unrepaired DSBs that are capable of inducing transcriptional silencing, irrespective of synapsis.
PLOS73	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3) or HJURP (GALHJURP) caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability. Output:	Proper chromosome segregation is essential for normal cell proliferation. Segregation errors lead to aneuploidy, a direct cause of birth defects and a hallmark of cancer. The kinetochore (centromeric DNA and associated proteins) is one of the key determinants for faithful chromosome transmission. Misregulation of kinetochore proteins such as HJURP has been observed in various cancers, however the biological relevance of this observation is not well understood. We determined that altered dosage of HJURP and its budding yeast homolog SCM3 leads to defects in chromosome segregation in yeast and human cells. We identified the centromeric DNA–interacting domain of Scm3p and determined that association of Scm3p devoid of Cse4p leads to chromosome segregation defects. Our findings suggest that stringent regulation of Scm3p/HJURP, Cse4p, and histone H4 is critical for maintenance of genome stability.
PLOS74	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: We present ggsashimi, a command-line tool for the visualization of splicing events across multiple samples. Given a specified genomic region, ggsashimi creates sashimi plots for individual RNA-seq experiments as well as aggregated plots for groups of experiments, a feature unique to this software. Compared to the existing versions of programs generating sashimi plots, it uses popular bioinformatics file formats, it is annotation-independent, and allows the visualization of splicing events even for large genomic regions by scaling down the genomic segments between splice sites. ggsashimi is freely available at https://github.com/guigolab/ggsashimi. It is implemented in python, and internally generates R code for plotting. Output:	Efficient visualization of splicing events from RNA sequencing data is key for the computational analysis of alternative splicing. This process, that results in a single gene giving rise to multiple transcripts, is usually illustrated through sashimi plots: a representation of the read coverage and the support of each splicing junction in the region of interest. However, available tools for this purpose present several limitations that significantly hinder their applicability. Among them, dependence on event annotation, visualization difficulties with moderate sample sizes and long introns, use of non-standard file formats or inefficient implementations. With ggsashimi, we comprehensively overcome these flaws and provide the user with a fast, stand-alone application that generates publication-ready sashimi plots. Furthermore, ggsashimi supports the display of aggregated experiments, a crucial feature in order to explore alternative splicing in the era of large RNA sequencing projects.
PLOS75	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine release). We demonstrate via cross-validation that classification and regression approaches can effectively use the antibody features to robustly predict qualitative and quantitative functional outcomes. This integration of antibody feature and function data within a machine learning framework provides a new, objective approach to discovering and assessing multivariate immune correlates. Output:	Antibodies are one of the central mechanisms that the human immune system uses to eliminate infection: an antibody can recognize a pathogen or infected cell using its Fab region while recruiting additional immune cells through its Fc that help destroy the offender. This mechanism may have been key to the reduced risk of infection observed among some of the vaccine recipients in the RV144 HIV vaccine trial. In order to gain insights into the properties of antibodies that support recruitment of effective functional responses, we developed and applied a machine learning-based framework to find and model associations among properties of antibodies and corresponding functional responses in a large set of data collected from RV144 vaccine recipients. We characterized specific important relationships between antibody properties and functional responses, and demonstrated that models trained to encapsulate relationships in some subjects were able to robustly predict the quality of the functional responses of other subjects. The ability to understand and build predictive models of these relationships is of general interest to studies of the antibody response to vaccination and infection, and may ultimately lead to the development of vaccines that will better steer the immune system to produce antibodies with beneficial activities.
PLOS76	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed genome-wide microarray analysis using Affymetrix U133 Plus 2.0 Arrays, real-time PCR, and immunohistochemistry in brain tissues from seven treated and eight untreated HAND patients and six uninfected controls. We also determined brain virus burdens by real-time PCR. Treated and untreated HAND brains had distinct gene expression profiles with ART transcriptomes clustering with HIV-1-negative controls. The molecular disease profile of untreated HAND showed dysregulated expression of 1470 genes at p<0.05, with activation of antiviral and immune responses and suppression of synaptic transmission and neurogenesis. The overall brain transcriptome changes in these patients were independent of histological manifestation of HIV-1 encephalitis and brain virus burdens. Depending on treatment compliance, brain transcriptomes from patients on ART had 83% to 93% fewer dysregulated genes and significantly lower dysregulation of biological pathways compared to untreated patients, with particular improvement indicated for nervous system functions. However a core of about 100 genes remained similarly dysregulated in both treated and untreated patient brain tissues. These genes participate in adaptive immune responses, and in interferon, cell cycle, and myelin pathways. Fluctuations of cellular gene expression in the brain correlated in Pearson's formula analysis with plasma but not brain virus burden. Our results define for the first time an aberrant genome-wide brain transcriptome of untreated HAND and they suggest that antiretroviral treatment can be broadly effective in reducing pathophysiological changes in the brain associated with HAND. Aberrantly expressed transcripts common to untreated and treated HAND may contribute to neurocognitive changes defying ART. Output:	HAND is a common complication of HIV-1 infection in the nervous system presenting a varied spectrum of clinical manifestations with cognitive, motor and behavioral symptoms. Introduction of ART has greatly reduced morbidity and mortality in HIV-1 infection; however HAND persists and its overall prevalence appears to have increased despite treatment. The effects of the treatment on neurological disease are not well understood. Here, we used genomic analysis to compare gene expression profiles in brain tissues from treated and untreated patients who died with HAND. We identified a large number of genes and biological pathways dysregulated in untreated HAND compared with uninfected controls. ART appears to be effective in mitigating aberrant gene expression in brain tissues of patients with HAND but a fraction of genes remained dysregulated under ART and the patients continued to manifest HAND in the last evaluation prior to death. Our study provides new insights into the molecular changes in brain tissues of patients with HAND and the effect of the treatment on brain transcriptome. The identification of aberrantly expressed genes common to untreated and treated HAND may contribute to understand the neurocognitive impairment observed in patients under ART.
PLOS77	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8–/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8–/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. Output:	Chronic helminth infections can cause significant morbidity and organ damage in their definitive mammalian hosts. Managing this collateral damage can reduce morbidity and preserve vital tissues for normal organ function. One particular consequence of some chronic helminth infections is the deposition of fibrotic scar tissue, following immune responses directed towards helminth material. In this study we tested the role of a particular signalling kinase, TPL-2, and identified that it critically regulated the magnitude of fibrotic scarring following infection. Using several murine models with genetic deletions of TPL-2 in either all cells or specific deletion in subsets of immune cells (Map3k8–/–Map3k8fl/fl) we identified that expression of TPL-2 in myeloid cells was essential to prevent severe immune-mediated pathology. Using genome-wide analyses and metabolic assays, we discovered that TPL-2 was required for normal lipid metabolism and appropriate activation of myeloid cells / macrophages to limit fibrosis. These results revealed a previously unappreciated role for TPL-2 in preventing severe pathology following infection. Thus, activating this pathway may limit immune mediated pathology following chronic helminth infection. More broadly, this pathway is being targeted to treat inflammatory diseases and cancer [1, 2]. This study would suggest that caution should be taken to prevent untoward co-morbidities and fibrosis-related pathologies in patients when targeting TPL-2.
PLOS78	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Yersinia pseudotuberculosis binds to β1 integrin receptors, and uses the type III secretion proteins YopB and YopD to introduce pores and to translocate Yop effectors directly into host cells. Y. pseudotuberculosis lacking effectors that inhibit Rho GTPases, YopE and YopT, have high pore forming activity. Here, we present evidence that Y. pseudotuberculosis selectively modulates Rho activity to induce cellular changes that control pore formation and effector translocation. Inhibition of actin polymerization decreased pore formation and YopE translocation in HeLa cells infected with Y. pseudotuberculosis. Inactivation of Rho, Rac, and Cdc42 by treatment with Clostridium difficile toxin B inhibited pore formation and YopE translocation in infected HeLa cells. Expression of a dominant negative form of Rac did not reduce the uptake of membrane impermeable dyes in HeLa cells infected with a pore forming strain YopEHJT−. Similarly, the Rac inhibitor NSC23766 did not decrease pore formation or translocation, although it efficiently hindered Rac-dependent bacterial uptake. In contrast, C. botulinum C3 potently reduced pore formation and translocation, implicating Rho A, B, and/or C in the control of the Yop delivery. An invasin mutant (Y. pseudotuberculosis invD911E) that binds to β1 integrins, but inefficiently transduces signals through the receptors, was defective for YopE translocation. Interfering with the β1 integrin signaling pathway, by inhibiting Src kinase activity, negatively affected YopE translocation. Additionally, Y. pseudotuberculosis infection activated Rho by a mechanism that was dependent on YopB and on high affinity bacteria interaction with β1 integrin receptors. We propose that Rho activation, mediated by signals triggered by the YopB/YopD translocon and from engagement of β1 integrin receptors, stimulates actin polymerization and activates the translocation process, and that once the Yops are translocated, the action of YopE or YopT terminate delivery of Yops and prevents pore formation. Output:	The type III secretion system (TTSS) is essential for the virulence of a number of Gram-negative human pathogens of enormous clinical significance. The molecular mechanisms by which TTSS effector proteins are translocated into the host cell are not well understood. The work presented here proposes a new model in which the enteropathogen Yersinia pseudotuberculosis manipulates the host cell machinery to control effector translocation. This involves activation of the host cell Rho GTPase by the cooperative action of adhesin-mediated high affinity binding to specific cell receptor molecules known as β1 integrins, and interaction of components of the TTSS with the host cell membrane. This molecular mechanism of controlling TTSS may not be restricted to Y. pseudotuberculosis and might take place during infection of host cells with other pathogens that encode homologues of Yersinia TTSS proteins. Our findings provide a good starting point to study the molecular nature of the complex interaction between bacterial pathogens bearing TTSSs and the host cell. Importantly, components that act by modulating the TTSS are potential targets for novel antimicrobials.
PLOS79	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus has a sophisticated system for the acquisition of inositol from the environment suggests that host inositol utilization may contribute to the development of cryptococcal meningitis. In this study, we found that inositol plays an important role in Cryptococcus traversal across the blood-brain barrier (BBB) both in an in vitro human BBB model and in in vivo animal models. The capacity of inositol to stimulate BBB crossing was dependent upon fungal inositol transporters, indicated by a 70% reduction in transmigration efficiency in mutant strains lacking two major inositol transporters, Itr1a and Itr3c. Upregulation of genes involved in the inositol catabolic pathway was evident in a microarray analysis following inositol treatment. In addition, inositol increased the production of hyaluronic acid in Cryptococcus cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent Cryptococcus traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by Cryptococcus contributes to CNS infection. Output:	Cryptococcus neoformans is an AIDS-associated human fungal pathogen that annually causes over 1 million cases of meningitis world-wide, and more than 600,000 attributable deaths. Cryptococcus often causes lung and brain infection and is the leading cause of fungal meningitis in immunosuppressed patients. Why Cryptococcus frequently infects the central nervous system to cause fatal meningitis is an unanswered critical question. Our previous studies revealed a sophisticated inositol acquisition system in Cryptococcus that plays a central role in utilizing environmental inositol to complete its sexual cycle. Here we further demonstrate that inositol acquisition is also important for fungal infection in the brain, where abundant inositol is available. We found that inositol promotes the traversal of Cryptococcus across the blood-brain barrier (BBB), and such stimulation is fungal inositol transporter dependent. We also identified the effects of host inositol on fungal cellular functions that contribute to the stimulation of fungal penetration of the BBB. We propose that inositol utilization is a novel virulence factor for CNS cryptococcosis. Our work lays an important foundation for understanding how fungi respond to available host inositol and indicates the impact of host inositol acquisition on the development of cryptococcal meningitis.
PLOS80	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elements typically fuse a molecular recognition domain (aptamer) with a catalytic signal generator (ribozyme). Although the rational design of aptazymes has begun to be explored, the relationships between the thermodynamics of aptazyme conformational changes and aptazyme performance in vitro and in vivo have not been examined in a quantitative framework. We have therefore developed a quantitative and predictive model for aptazymes as biosensors in vitro and as riboswitches in vivo. In the process, we have identified key relationships (or dimensionless parameters) that dictate aptazyme performance, and in consequence, established equations for precisely engineering aptazyme function. In particular, our analysis quantifies the intrinsic trade-off between ligand sensitivity and the dynamic range of activity. We were also able to determine how in vivo parameters, such as mRNA degradation rates, impact the design and function of aptazymes when used as riboswitches. Using this theoretical framework we were able to achieve quantitative agreement between our models and published data. In consequence, we are able to suggest experimental guidelines for quantitatively predicting the performance of aptazyme-based riboswitches. By identifying factors that limit the performance of previously published systems we were able to generate immediately testable hypotheses for their improvement. The robust theoretical framework and identified optimization parameters should now enable the precision design of aptazymes for biotechnological and clinical applications. Output:	Aptamers are nucleic acids that bind their cognate ligands (ranging from metal ions to small molecules to proteins) specifically and tightly. Through rational design and/or directed evolution, aptamers can be engineered into allosteric nucleic acids whose conformations can be regulated by their ligands. Aptamer beacons, aptazymes, and riboswitches all undergo ligand-dependent conformational changes, and have been adapted to signal the concentration of their ligands. However, there is currently no model that can be used to predict how the energetics of conformational change affects signaling, either in vitro or in vivo. We have developed a model that identifies what parameters can be optimized to best yield signals. By focusing on these parameters, it should be possible to more readily design or select more effective conformation-switching nucleic acid biosensors.
PLOS81	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies. Output:	4E10 is an antibody that neutralizes a broad variety of HIV strains. However, 4E10 is uncommon in infected patients and has not been successfully elicited by any vaccine approach attempted. Hurdles to re-eliciting 4E10 include the accumulation of many mutations during development, demonstrated reactivity against host proteins and significant structural flexibility. Lacking a confirmed sequence for precursors of 4E10, we studied the recognition and biophysical properties of an ensemble of eight of the likeliest candidates. Surprisingly, 4E10 gained host reactivity and structural flexibility, but lost stability during development when compared to candidate precursors. However, recognition of HIV was remarkably conserved, despite a considerable improvement in binding. Since these results run counter to those expected from conventional vaccination protocols, 4E10 is unlikely to serve as the basis of a useful HIV vaccine.
PLOS82	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery. Output:	Virus surface proteins mediate interactions with target cells during the initial events in the process of infection. Inhibiting these proteins is therefore a major target for the development of antiviral drugs. However, there are a very large number of different viruses, each with their own distinct surface proteins and, with just a few exceptions, it is not clear how to build novel molecules to inhibit them. Here we applied a computational binding optimization strategy to an atomic resolution structure of dengue virus serotype 2 envelope protein to generate peptide sequences that should interact strongly with this protein. We picked dengue virus as a target because it is the causative agent for the most important mosquito transmitted viral disease. Out of a small number of candidates designed and tested, we identified two different highly inhibitory peptides. To verify our results, we showed that these peptides block virus:cell binding, interfere with a step during viral entry, alter the surface structure of dengue viral particles, and that they interact directly with dengue virus envelope protein. We expect that our approach may be generally applicable to other viral surface proteins where a high resolution structure is available.
PLOS83	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Several outbreaks of trichinellosis associated with the consumption of raw pork have occurred in Laos since 2004. This cross-sectional study was conducted in four provinces of northern Laos to investigate the seroepidemiology of trichinellosis in the human population and determine the prevalence and species of Trichinella infection in the domestic pig population. Serum samples and questionnaire data were obtained from 1419 individuals. Serum samples were tested for Trichinella antibodies by ELISA using larval excretory–secretory (ES) antigens and a subset of 68 positive samples were tested by western blot. The seroprevalence of Trichinella antibodies was 19.1% (95% confidence interval (CI) = 17.1–21.1%). The risk of having antibodies detected by ELISA using ES antigens increased with age, being of Lao-Tai ethnicity, living in Oudomxay province and being male. Tongue and diaphragm muscle samples were collected from 728 pigs and tested for Trichinella larvae by the artificial digestion method. Trichinella larvae were isolated from 15 pigs (2.1%) of which 13 were identified as T. spiralis by molecular typing; the species of the two remaining isolates could not be determined due to DNA degradation. Trichinella spp. are endemic in the domestic environment of northern Laos and targeted preventative health measures should be initiated to reduce the risk of further outbreaks occurring. Output:	Trichinellosis is one of the most widely distributed parasitic zoonoses worldwide and is caused by infection with nematodes of the genus Trichinella. Infection occurs after consuming larvae in the muscle of infected animals. Several outbreaks of trichinellosis have occurred in Laos since 2004, resulting in a substantial public health problem. The principal risk factor for trichinellosis is consumption of uncooked or partially cooked meat from domestic pigs and game. We visited communities in four ethnically diverse provinces of northern Laos to determine the seroprevalence of trichinellosis in the human population and explore the population and individual level risk factors of exposure. In addition, we also examined muscle samples collected from pigs post-slaughter to determine the prevalence of Trichinella infection and identify the species of Trichinella circulating in the domestic pig population. Our findings indicate that Trichinella spp. are endemic in the domestic environment of northern Laos and consumption of uncooked pork is common for all ethnic groups. Targeted preventative health measures, taking a one health approach by bringing together medical, veterinary and health sociology professionals, should be initiated to prevent the transmission of Trichinella and other foodborne pathogens in Laos.
PLOS84	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Neuronal assemblies often exhibit stimulus-induced rhythmic activity in the gamma range (30–80 Hz), whose magnitude depends on the attentional load. This has led to the suggestion that gamma rhythms form dynamic communication channels across cortical areas processing the features of behaviorally relevant stimuli. Recently, attention has been linked to a normalization mechanism, in which the response of a neuron is suppressed (normalized) by the overall activity of a large pool of neighboring neurons. In this model, attention increases the excitatory drive received by the neuron, which in turn also increases the strength of normalization, thereby changing the balance of excitation and inhibition. Recent studies have shown that gamma power also depends on such excitatory–inhibitory interactions. Could modulation in gamma power during an attention task be a reflection of the changes in the underlying excitation–inhibition interactions? By manipulating the normalization strength independent of attentional load in macaque monkeys, we show that gamma power increases with increasing normalization, even when the attentional load is fixed. Further, manipulations of attention that increase normalization increase gamma power, even when they decrease the firing rate. Thus, gamma rhythms could be a reflection of changes in the relative strengths of excitation and normalization rather than playing a functional role in communication or control. Output:	Brain signals often show a stimulus-induced rhythm in the “gamma” band (30–80 Hz) whose magnitude depends on attentional load, leading to suggestions that gamma rhythm plays a functional role in routing signals across cortical areas. However, gamma power also depends on simple stimulus features such as size or contrast, which suggests that gamma could arise from basic cortical processes involving excitation–inhibition interactions. One such process is divisive normalization, a mechanism that suppresses the response of a neuron by the overall activity of a large pool of neighboring neurons. Recent studies have shown that attention increases the strength of both excitation and normalization. We hypothesized that the increase in gamma power in an attention task is due to the effect of attention on excitation and normalization. By manipulating the normalization strength independent of attentional load in macaque monkeys, we show that gamma power increases with increasing normalization, even when attentional load is held fixed. Thus, gamma rhythms could be a reflection of changes in the relative strengths of excitation and normalization rather than playing a functional role in communication or control.
PLOS85	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population. We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity. We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 99% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting. In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded. Output:	Typhoid fever is an infection caused by the bacterium Salmonella Typhi. Typhoid fever is rare in developed countries but remains high in the developing world. Effective treatment is available but accurate diagnosis of typhoid fever is challenging as typhoid fever can be difficult to distinguish from other infections. Bone marrow culture is the most accurate diagnostic test for typhoid fever however is invasive and not feasible in many settings. New vaccines for typhoid and the need for improved estimates of burden increases the demand for improved understanding of diagnostic accuracy. Comparing the diagnostic accuracy of tests for typhoid fever is challenging as head-to-head studies are few. We applied newly developed methods for comparative evaluation of diagnostic tests for typhoid fever in children using statistical approaches that allowed for the proper incorporation of uncertainty and comparison of tests that had not been compared directly. The lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests all had good diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. Finally, while South Asia has the most informed set of data on typhoid diagnostic testing accuracy, the evidence base in other important regions needs to be expanded.
PLOS86	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Melioidosis is a serious infectious disease caused by the Category B select agent and environmental saprophyte, Burkholderia pseudomallei. Most cases of naturally acquired infection are assumed to result from skin inoculation after exposure to soil or water. The aim of this study was to provide evidence for inoculation, inhalation and ingestion as routes of infection, and develop preventive guidelines based on this evidence. A prospective hospital-based 1∶2 matched case-control study was conducted in Northeast Thailand. Cases were patients with culture-confirmed melioidosis, and controls were patients admitted with non-infectious conditions during the same period, matched for gender, age, and diabetes mellitus. Activities of daily living were recorded for the 30-day period before onset of symptoms, and home visits were performed to obtain drinking water and culture this for B. pseudomallei. Multivariable conditional logistic regression analysis based on 286 cases and 512 controls showed that activities associated with a risk of melioidosis included working in a rice field (conditional odds ratio [cOR] = 2.1; 95% confidence interval [CI] 1.4–3.3), other activities associated with exposure to soil or water (cOR = 1.4; 95%CI 0.8–2.6), an open wound (cOR = 2.0; 95%CI 1.2–3.3), eating food contaminated with soil or dust (cOR = 1.5; 95%CI 1.0–2.2), drinking untreated water (cOR = 1.7; 95%CI 1.1–2.6), outdoor exposure to rain (cOR = 2.1; 95%CI 1.4–3.2), water inhalation (cOR = 2.4; 95%CI 1.5–3.9), current smoking (cOR = 1.5; 95%CI 1.0–2.3) and steroid intake (cOR = 3.1; 95%CI 1.4–6.9). B. pseudomallei was detected in water source(s) consumed by 7% of cases and 3% of controls (cOR = 2.2; 95%CI 0.8–5.8). We used these findings to develop the first evidence-based guidelines for the prevention of melioidosis. These are suitable for people in melioidosis-endemic areas, travelers and military personnel. Public health campaigns based on our recommendations are under development in Thailand. Output:	Melioidosis is a serious infectious disease caused by the environmental saprophyte, Burkholderia pseudomallei. The infection is potentially preventable, but developing prevention guidelines is hampered by a lack of evidence on which to base them. The purpose of this study was to provide evidence for inoculation, inhalation and ingestion as routes of infection. To achieve this, we undertook a matched case-control study and performed home visits to obtain drinking water and culture this for B. pseudomallei. We found that activities associated with increased risk of developing melioidosis included working in a rice field, other activities associated with exposure to soil or water, an open wound, eating food contaminated with soil or dust, drinking untreated water, outdoor exposure to rain, water inhalation, current smoking and steroid intake. Presence of B. pseudomallei in drinking water source(s) doubled the odds of acquiring melioidosis. This is the first study to show that ingestion is an important route of human B. pseudomallei infection, and that exposure to rain is an independent risk factor for melioidosis. We used this finding to develop the first evidence-based guidelines for the prevention of melioidosis. These are suitable for people in melioidosis-endemic areas, travelers and military personnel.
PLOS87	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions. Output:	The coevolution of genes and languages has been a subject of enduring interest among geneticists and linguists. Progress has been limited by the available data and by the methods employed to compare patterns of genetic and linguistic variation. Here, we use high-quality data and novel methods to test two models of genetic and linguistic coevolution in Northern Island Melanesia, a region known for its complex history and remarkable biological and linguistic diversity. The first model predicts that congruent genetic and linguistic trees formed following serial population splits and isolation that occurred early in the settlement history of the region. The second model emphasizes the role of post-settlement exchange among neighboring groups in determining genetic and linguistic affinities. We rejected both models for the larger region, but found strong evidence for the post-settlement exchange model in the rugged interior of its largest island, where people have maintained close ties to their ancestral lands. The exchange (particularly genetic exchange) has obscured but not completely erased signals of early migrations into Island Melanesia, and such exchange has probably obscured early prehistory within other regions. In contrast, local exchange is less likely to have obscured evidence of population history at larger geographic scales.
PLOS88	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The calcium-gated potassium channel SLO-1 in Caenorhabditis elegans was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of slo-1 in Ancylostoma caninum, Cooperia oncophora, and Haemonchus contortus, all important parasitic nematodes in veterinary medicine. Furthermore, functional analyses of these slo-1 orthologues were performed using heterologous expression in C. elegans. We expressed A. caninum and C. oncophora slo-1 in the emodepside-resistant genetic background of the slo-1 loss-of-function mutant NM1968 slo-1(js379). Transformants expressing A. caninum slo-1 from C. elegans slo-1 promoter were highly susceptible (compared to the fully emodepside-resistant slo-1(js379)) and showed no significant difference in their emodepside susceptibility compared to wild-type C. elegans (p = 0.831). Therefore, the SLO-1 channels of A. caninum and C. elegans appear to be completely functionally interchangeable in terms of emodepside sensitivity. Furthermore, we tested the ability of the 5′ flanking regions of A. caninum and C. oncophora slo-1 to drive expression of SLO-1 in C. elegans and confirmed functionality of the putative promoters in this heterologous system. For all transgenic lines tested, expression of either native C. elegans slo-1 or the parasite-derived orthologue rescued emodepside sensitivity in slo-1(js379) and the locomotor phenotype of increased reversal frequency confirming the reconstitution of SLO-1 function in the locomotor circuits. A potent mammalian SLO-1 channel inhibitor, penitrem A, showed emodepside antagonising effects in A. caninum and C. elegans. The study combined the investigation of new anthelmintic targets from parasitic nematodes and experimental use of the respective target genes in C. elegans, therefore closing the gap between research approaches using model nematodes and those using target organisms. Considering the still scarcely advanced techniques for genetic engineering of parasitic nematodes, the presented method provides an excellent opportunity for examining the pharmacofunction of anthelmintic targets derived from parasitic nematodes. Output:	In parasitic nematodes, experiments at the molecular level are currently not feasible, since in vitro culture and genetic engineering are still in their infancy. In the present study we chose the model organism Caenorhabditis elegans not only as a mere expression system for genes from parasitic nematodes, but used the transformants to examine the functionality of the expressed proteins for mediating anthelmintic effects in vivo. The results of our experiments confirmed that SLO-1 channels mediate the activity of the new anthelmintic drug emodepside and showed that the mode of action is conserved through several nematode species. The chosen method allowed us to examine the functionality of proteins from parasitic nematodes in a defined genetic background. Notably, expression of the parasitic nematode gene in anthelmintic-resistant C. elegans completely restored drug susceptibility. As C. elegans is highly tractable to molecular genetic and pharmacological approaches, the generation of lines expressing the parasite drug target will greatly facilitate structure-function analysis of the interaction between emodepside and ion channels with direct relevance to its anthelmintic properties. In a broader context, the demonstration of C. elegans as a heterologous expression system for functional analysis of parasite proteins further strengthens this as a model for anthelmintic studies.
PLOS89	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility. Output:	Severe short stature in humans has many causes including defects in skeletal and hormonal growth regulation. Primordial dwarfisms are congenital growth defects that involve mutations in genes for DNA repair, DNA replication, splicing of U12 introns, and centrosome dynamics. We discovered that the spontaneous, dwarf mouse mutant chagun is caused by loss-of-function of the gene Poc1a, which encodes protein of the centriole 1A. Mutants exhibit disproportionate dwarfism, and bones formed by endochondral and intramembranous ossification processes are affected. The epiphyseal growth plates of their long bones are disorganized. The chagun males are infertile due to Sertoli cell dysfunction and the failure of germ cells to complete meiosis. The chagun mouse is a model for human dwarfism and provides insight into the mechanism whereby this centriolar protein affects bone growth and spermatogenesis.
PLOS90	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Repressors are frequently deployed to limit the transcriptional response to signalling pathways. For example, several co-repressors interact directly with the DNA-binding protein CSL and are proposed to keep target genes silenced in the absence of Notch activity. However, the scope of their contributions remains unclear. To investigate co-repressor activity in the context of this well defined signalling pathway, we have analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, and of a second CSL interacting repressor, SMRTER. As predicted there was significant overlap between Hairless and its CSL DNA-binding partner, both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. However, while the Hairless complex was widely present at some Notch regulated enhancers in the wing disc, no binding was detected at others, indicating that it is not essential for silencing per se. Further analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved. Output:	The communication between cells that occurs during development, as well as in disease contexts, involves a small number of signalling pathways of which the Notch pathway is one. One outstanding question is how these pathways can bring about different gene responses in different contexts. As gene expression is co-ordinated by a mixture of activators and repressors, we set out to investigate whether the distribution of repressors across the genome is important in shaping whether genes are able to respond to Notch activity. Our results from analyzing the binding profile of two repressors, Hairless and SMRTER, show that, in many cases, they are not essential for preventing a gene from responding. Instead they are deployed at a limited number of genetic loci where they gate the response, helping to set a threshold for gene activation. Perturbations to their function lead to enhanced gene expression in limited territories rather than to new programmes of gene expression. Their main role therefore is to restrict the time or levels of signal that a gene needs to receive before it will respond.
PLOS91	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Accurate diagnostic techniques for schistosomiasis are essential for prevalence determination and identification of positive patients. A point-of-care test for detecting schistosome circulating cathodic antigen (POC-CCA) has been evaluated for its accuracy in different endemic regions. This reagent strip/dipstick based assay has showed high sensitivity for individuals with high or moderate worm burden, but the interpretation of light infections is less clear, especially for trace readings. We introduced a urine lyophilization step to the POC-CCA assay to improve its sensitivity and clarify the interpretation of traces. We evaluated POC-CCA sensitivity and specificity within individuals with low parasite burdens in a Brazilian endemic area where a high number of traces were detected. Patients that were positive for other helminths were also evaluated for cross reactions. In all cases, a combined parasitological diagnosis using Kato-Katz (24 slides) and Saline Gradient (1 g of feces) were used as reference. At baseline, diagnosis by POC-CCA (1–2 cassettes) showed 6% sensitivity, inaccurately predicting a low prevalence of Schistosoma mansoni infections (2 POC-CCA positives/32 egg positives). After urine lyophilization, the sensitivity was increased significantly (p < 0.05). Prevalence rates changed from 2% to 32% (27 POC-CCA positives/32 egg positives), equivalent to parasitological techniques. Most of the trace readings changed to positive after lyophilization while some negatives turned into traces. Cross reaction analysis confirmed the specificity of POC-CCA. Trace readings cannot be primarily defined as positive or negative cases. It is critical to verify case-by-case by concentrating urine 10 fold by lyophilization for the diagnosis. Following lyophilization, persistent trace readings should be read as negatives. No trained technician is needed and cost is restricted to the cost of a lyophilizer and the electricity to run it. Output:	Schistosomiasis mansoni is a relevant disease affecting millions of individuals in different countries, in particular countries in Africa, and Brazil. Diagnosis performed by Kato-Katz technique for the detection of eggs in stool and a point-of-care test for circulating cathodic antigen detection in urine (POC-CCA) has been evaluated. Both methods have decreased sensitivity when diagnosing patients with low parasite burdens, which can lead to infected individuals not receiving treatment. Here, we focused on interpretation of POC-CCA results in persons with low parasite burdens. We noted a high number (49%) of indeterminate results, including false negatives and trace readings. A urine concentration step was included to improve the test’s sensitivity. Important differences on sensitivity and prevalence rates were noted when comparing diagnosis by POC-CCA before and after urine concentration. Notably, indeterminate results were easily defined after introduction of this step. Cross reaction analysis confirmed the specificity of POC-CCA, with exceptions noted for individuals with hookworm infection. In conclusion, trace readings cannot be primarily defined as positive or negative cases. It is imperative to analyze each case individually by concentrating urine prior to the introduction of treatment, instead of relying on a point-of-care test with indeterminate results.
PLOS92	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The mechanisms that regulate how dendrites target different neurons to establish connections with specific cell types remain largely unknown. In particular, the formation of cell-type–specific connectivity during postnatal neurogenesis could be either determined by the local environment of the mature neuronal circuit or by cell-autonomous properties of the immature neurons, already determined by their precursors. Using retroviral fate mapping, we studied the lamina-specific dendritic targeting of one neuronal type as defined by its morphology and intrinsic somatic electrical properties in neonatal and adult neurogenesis. Fate mapping revealed the existence of two separate populations of neuronal precursors that gave rise to the same neuronal type with two distinct patterns of dendritic targeting—innervating either a deep or superficial lamina, where they connect to different types of principal neurons. Furthermore, heterochronic and heterotopic transplantation demonstrated that these precursors were largely restricted to generate neurons with a predetermined pattern of dendritic targeting that was independent of the host environment. Our results demonstrate that, at least in the neonatal and adult mammalian brain, the pattern of dendritic targeting of a given neuron is a cell-autonomous property of their precursors. Output:	The mammalian brain contains a large number of different classes of neurons that are connected in a specific manner. A long-standing question is how such stereotyped connections emerge during the assembly of the brain. Here, we investigated whether neonatal and adult brain stem cells give rise to neurons whose connections can be influenced by the partners that they encounter while maturing, or alternatively, whether these connections are predetermined from the moment that a neuron is born. We observed the existence of distinct populations of precursor cells committed to generating neurons with a specific pattern of connections. Furthermore, the pattern of connections formed by these neurons was largely independent of the environment in which the neurons matured. These results have important implications for the formation of neuronal circuits, as they indicate that the connections of a new neuron can be determined in their precursors. In particular, these observations suggest that for neuronal replacement therapies to be successful, it will be necessary to understand the genetic programs that control how stem cells are prespecified to produce neurons with a stereotypic pattern of connections.
PLOS93	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Balancing selection provides a plausible explanation for the maintenance of deleterious alleles at moderate frequency in livestock, including lethal recessives exhibiting heterozygous advantage in carriers. In the current study, a leg weakness syndrome causing mortality of piglets in a commercial line showed monogenic recessive inheritance, and a region on chromosome 15 associated with the syndrome was identified by homozygosity mapping. Whole genome resequencing of cases and controls identified a mutation causing a premature stop codon within exon 3 of the porcine Myostatin (MSTN) gene, similar to those causing a double-muscling phenotype observed in several mammalian species. The MSTN mutation was in Hardy-Weinberg equilibrium in the population at birth, but significantly distorted amongst animals still in the herd at 110 kg, due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, suggesting that the deleterious allele was maintained at moderate frequency due to heterozygous advantage (allele frequency, q = 0.22). Knockout of the porcine MSTN by gene editing has previously been linked to problems of low piglet survival and lameness. This MSTN mutation is an example of putative balancing selection in livestock, providing a plausible explanation for the lack of disrupting MSTN mutations in pigs despite many generations of selection for lean growth. Output:	Lameness is an important problem in livestock production for both animal welfare and economic reasons. A severe piglet lameness syndrome was observed in a commercial pig population. The incidence of the condition was low (6.3%), but was higher in affected families (~25%), which suggested a genetic basis and a recessive mode of inheritance. We discovered a region on Chromosome 15 where cases shared the same alleles that were different to healthy piglets. In this region, we discovered a mutation that causes a premature stop codon in the myostatin gene. Myostatin causes ‘double-muscle’ phenotype in several mammalian species. Piglets with two copies of this mutant allele suffer the lameness syndrome and do not survive post 40 kg live weight. However, those that carry a single copy have higher muscle depth and lower fat depth compared to wild type. We suggest that despite the negative consequences of the mutant allele in homozygous form, the mutation was maintained in the herd due to positive selection for this allele in heterozygous form. This is an interesting example of so-called ‘balancing selection’ and may explain why naturally occurring myostatin mutations have not previously been reported in pigs despite centuries of selection for lean growth.
PLOS94	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Merkel cell polyomavirus (MCV or MCPyV) appears to be a causal factor in the development of Merkel cell carcinoma, a rare but highly lethal form of skin cancer. Although recent reports indicate that MCV virions are commonly shed from apparently healthy human skin, the precise cellular tropism of the virus in healthy subjects remains unclear. To begin to explore this question, we set out to identify the cellular receptors or co-receptors required for the infectious entry of MCV. Although several previously studied polyomavirus species have been shown to bind to cell surface sialic acid residues associated with glycolipids or glycoproteins, we found that sialylated glycans are not required for initial attachment of MCV virions to cultured human cell lines. Instead, glycosaminoglycans (GAGs), such as heparan sulfate (HS) and chondroitin sulfate (CS), serve as initial attachment receptors during the MCV infectious entry process. Using cell lines deficient in GAG biosynthesis, we found that N-sulfated and/or 6-O-sulfated forms of HS mediate infectious entry of MCV reporter vectors, while CS appears to be dispensable. Intriguingly, although cell lines deficient in sialylated glycans readily bind MCV capsids, the cells are highly resistant to MCV reporter vector-mediated gene transduction. This suggests that sialylated glycans play a post-attachment role in the infectious entry process. Results observed using MCV reporter vectors were confirmed using a novel system for infectious propagation of native MCV virions. Taken together, the findings suggest a model in which MCV infectious entry occurs via initial cell binding mediated primarily by HS, followed by secondary interactions with a sialylated entry co-factor. The study should facilitate the development of inhibitors of MCV infection and help shed light on the infectious entry pathways and cellular tropism of the virus. Output:	Strong evidence suggests that Merkel cell polyomavirus (MCV or MCPyV) is a causative factor in the development of a large proportion of cancers arising from epidermal Merkel cells. While Merkel cell carcinoma is rare, it appears that infection with MCV is common, and many healthy people chronically shed MCV virions from the surface of their skin. In an effort to better understand the factors controlling MCV tissue tropism, we sought to characterize the cellular receptors that mediate MCV attachment to cultured cells. Several previously-examined polyomaviruses utilize sialic acid-containing glycolipids and glycoproteins to mediate cell binding and infectious entry. Our results show that, in contrast to other polyomaviruses, MCV does not require sialic acid-bearing glycans for attachment to cells, but instead uses a different group of carbohydrates called glycosaminoglycans for the initial attachment step of the infectious entry process. Interestingly, although sialic acid-bearing glycans are dispensable for initial attachment to cells, data using cells deficient in sialylated glycans suggest that sialic acids may form an essential element of a possible co-receptor that is engaged after the initial attachment of MCV to the cell via glycosaminoglycans.
PLOS95	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: In animals, gas exchange between blood and tissues occurs in narrow vessels, whose diameter is comparable to that of a red blood cell. Red blood cells must deform to squeeze through these narrow vessels, transiently blocking or occluding the vessels they pass through. Although the dynamics of vessel occlusion have been studied extensively, it remains an open question why microvessels need to be so narrow. We study occlusive dynamics within a model microvascular network: the embryonic zebrafish trunk. We show that pressure feedbacks created when red blood cells enter the finest vessels of the trunk act together to uniformly partition red blood cells through the microvasculature. Using mathematical models as well as direct observation, we show that these occlusive feedbacks are tuned throughout the trunk network to prevent the vessels closest to the heart from short-circuiting the network. Thus occlusion is linked with another open question of microvascular function: how are red blood cells delivered at the same rate to each micro-vessel? Our analysis shows that tuning of occlusive feedbacks increase the total dissipation within the network by a factor of 11, showing that uniformity of flows rather than minimization of transport costs may be prioritized by the microvascular network. Output:	Arterial trees shuttle red blood cells from the heart to billions of capillaries distributed throughout the body. These trees have long been thought to be organized to minimize transport costs. Yet red blood cells are tightly squeezed within the finest vessels, meaning that these vessels account for as much as half of the total transport costs within the arterial network. It is unclear why vessel diameters and red blood cell diameters are so closely matched in a network that is presumed to optimize transport. Here, we use mathematical modeling and direct observations of red blood cell movements in embryonic zebrafish to show that occlusive feedbacks—the pressure feedbacks that alter the flows into a vessel when it is nearly blocked by a red blood cell—can optimally distribute red blood cells through microvessels. In addition to revealing an adaptive function for the matching of vessel and red blood cell diameters, this work shows that uniformity of red blood cell fluxes can be a unifying principle for understanding the elegant hydraulic organization of microvascular networks.
PLOS96	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: The cell envelope of gram-negative bacteria, a structure comprising an outer (OM) and an inner (IM) membrane, is essential for life. The OM and the IM are separated by the periplasm, a compartment that contains the peptidoglycan. The OM is tethered to the peptidoglycan via the lipoprotein, Lpp. However, the importance of the envelope’s multilayered architecture remains unknown. Here, when we removed physical coupling between the OM and the peptidoglycan, cells lost the ability to sense defects in envelope integrity. Further experiments revealed that the critical parameter for the transmission of stress signals from the envelope to the cytoplasm, where cellular behaviour is controlled, is the IM-to-OM distance. Augmenting this distance by increasing the length of the lipoprotein Lpp destroyed signalling, whereas simultaneously increasing the length of the stress-sensing lipoprotein RcsF restored signalling. Our results demonstrate the physiological importance of the size of the periplasm. They also reveal that strict control over the IM-to-OM distance is required for effective envelope surveillance and protection, suggesting that cellular architecture and the structure of transenvelope protein complexes have been evolutionarily co-optimised for correct function. Similar strategies are likely at play in cellular compartments surrounded by 2 concentric membranes, such as chloroplasts and mitochondria. Output:	Antibiotic resistance is one of the greatest threats that humanity faces today. In particular, the emergence of multidrug-resistant gram-negative bacteria has become a pressing issue. Infections caused by resistant gram-negative bacteria are indeed difficult to treat because of the presence of a double-membraned envelope that renders these bacteria less permeable to many antibiotics. Bacteria invest a great deal in protecting their envelope. They have evolved complex stress-sensing systems that allow them to monitor envelope integrity in order to detect and fix damage when it occurs. Here, using the model bacterium Escherichia coli, we show that the ability to sense and respond to stress depends on the architecture of the cell envelope, in general, and on the distance between the 2 membranes, in particular. Thus, searching for drugs targeting envelope architecture is an attractive strategy for new antibacterials. In addition, our work reveals the physiological function of the Braun’s lipoprotein (Lpp), the numerically most abundant protein in E. coli and the first lipoprotein that was discovered several decades ago.
PLOS97	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis. Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope). The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d’Ivoire. One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy. Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa. The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively. The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8–99.6%) and 81.1% (95% CI 71.2–88.3%), respectively, and specificities of 99.5% (95% CI 97.0–100%) and 97.1% (95% CI 92.2–99.1%), respectively. The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4–74.6%) and 35.6% (95% CI 25.9–46.4%), respectively, and specificities of 99.5% (95% CI 97.0–100%) and 100% (95% CI 86.7–100%), respectively. For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1–94.7%) and 83.3% (95% CI 36.5–99.1%), respectively, and 100% specificity. Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites. Output:	Handheld light microscopes are new technologies that may be helpful in enabling better access to diagnostic testing for people living in resource-constrained settings in tropical and subtropical countries. Recent studies evaluating the accuracy of such devices have focused on their use by expert microscopists and were mainly conducted in laboratories. We evaluated the operating performance of two handheld microscopes (Newton Nm1 microscope and clip-on version of the reversed-lens CellScope) in comparison to conventional microscopy for the diagnosis of urogenital and intestinal schistosomiasis, when integrated into routine use in a community-based survey carried out in Côte d’Ivoire. Additionally, we evaluated the same microscopist’s diagnostic performance with the Newton Nm1 microscope for intestinal protozoa in a laboratory set-up. The Newton Nm1 microscope demonstrated excellent diagnostic sensitivity and specificity for schistosomiasis and intestinal protozoa. The CellScope had high specificity but only modest sensitivity for schistosomiasis diagnosis. Taken together, handheld diagnostic tools show promise to improve the quality of clinical and public health care delivered in resource-constrained settings.
PLOS98	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: Chromosome segregation in bacteria occurs concomitantly with DNA replication, and the duplicated regions containing the replication origin oriC are generally the first to separate and migrate to their final specific location inside the cell. In numerous bacterial species, a three-component partition machinery called the ParABS system is crucial for chromosome segregation. This is the case in the gammaproteobacterium Pseudomonas aeruginosa, where impairing the ParABS system is very detrimental for growth, as it increases the generation time and leads to the formation of anucleate cells and to oriC mispositioning inside the cell. In this study, we investigate in vivo the ParABS system in P. aeruginosa. Using chromatin immuno-precipitation coupled with high throughput sequencing, we show that ParB binds to four parS site located within 15 kb of oriC in vivo, and that this binding promotes the formation of a high order nucleoprotein complex. We show that one parS site is enough to prevent anucleate cell formation, therefore for correct chromosome segregation. By displacing the parS site from its native position on the chromosome, we demonstrate that parS is the first chromosomal locus to be separated upon DNA replication, which indicates that it is the site of force exertion of the segregation process. We identify a region of approximatively 650 kb surrounding oriC in which the parS site must be positioned for chromosome segregation to proceed correctly, and we called it “competence zone” of the parS site. Mutant strains that have undergone specific genetic rearrangements allow us to propose that the distance between oriC and parS defines this “competence zone”. Implications for the control of chromosome segregation in P. aeruginosa are discussed. Output:	Accurate transmission of the genetic information relies on replication and segregation, two processes essential to all living organisms. In bacteria, these processes occur concomitantly. Replication of the bacterial circular chromosome initiates at a single specific sequence called oriC, and proceed bi-directionally along the chromosome arms. A partition system called ParABS is involved in chromosome segregation in many bacteria. It involves the binding of the ParB protein to parS sequences, which are often found in the close vicinity of oriC. The importance of this system for chromosome segregation varies according to species, ranging from essential to dispensable. In Pseudomonas aeruginosa, an important opportunistic pathogen, the ParABS system plays an important role in chromosome segregation, as mutants affected in this system present a severe growth defect as well as anucleate cells formation, but is not essential. In this study, we characterize the activity of the different determinants of the ParABS system in P. aeruginosa and demonstrate that it is critical for the parS site to be located close to oriC, which suggest that the timing of separation of regions close to oriC after replication is important, and that it could be a function of the ParABS system to keep this timing.
PLOS99	*TASK* the task is to simplify the input abstract of a biomedical literature *INPUT* the input is the abstract of a biomedical literature *OUTPUT* the output is the simplified abstract for the input abstract of a biomedical literature *DOCUMENTATION* *EXAMPLES* Input: To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and molecules capable of presenting HIV antigens to the immune system (MHC-I). To accomplish this, Nef binds to the cytoplasmic tails of both molecules and then, by mechanisms that are not well understood, disrupts the trafficking of each molecule in different ways. Specifically, Nef promotes CD4 internalization after it has been transported to the cell surface, whereas Nef uses the clathrin adaptor, AP-1, to disrupt normal transport of MHC-I from the TGN to the cell surface. Despite these differences in initial intracellular trafficking, we demonstrate that MHC-I and CD4 are ultimately found in the same Rab7+ vesicles and are both targeted for degradation via the activity of the Nef-interacting protein, β-COP. Moreover, we demonstrate that Nef contains two separable β-COP binding sites. One site, an arginine (RXR) motif in the N-terminal α helical domain of Nef, is necessary for maximal MHC-I degradation. The second site, composed of a di-acidic motif located in the C-terminal loop domain of Nef, is needed for efficient CD4 degradation. The requirement for redundant motifs with distinct roles supports a model in which Nef exists in multiple conformational states that allow access to different motifs, depending upon which cellular target is bound by Nef. Output:	HIV is unique among viral pathogens in its capacity to cause chronic and progressive disease in almost all infected people. To accomplish this, HIV must evade the host immune response, especially cytotoxic T lymphocytes (CTLs), which normally function to lyse virally infected cells. HIV encodes a factor, Nef, which protects HIV infected cells from lysis by anti-HIV CTLs. To prevent CTL lysis, Nef interferes with the expression of host MHC-I, which is needed for CTL recognition of infected targets. A clear understanding of how Nef works has been hampered by its many complex functions. In addition to MHC-I, Nef protein disrupts the expression of multiple other cellular targets using different mechanisms and it is unclear how one protein can accomplish all these tasks. Here, we provide evidence that Nef acts as a highly flexible adaptor protein that is capable of utilizing different protein binding domains depending on which cellular target it is bound to. For example, we present evidence that Nef binding to MHC-I creates novel motifs that result in the recruitment of AP-1 and subsequently β-COP. This series of events results in the mis-localization of MHC-I from the cell surface to cellular degradative compartments, where MHC-I is destroyed.

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