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Title:
Vacuum-assisted closure vs. bilateral pectoralis major muscle flaps for deep sternal wounds infection.
Abstract:
Background ::: Deep sternal wound infection (DSWI) is a life-threatening complication after cardiac surgery.
The aim of this study was to retrospectively evaluate the outcomes of reconstructing infected poststernotomy wounds with either vacuum-assisted closure (VAC) after previous debridement or bilateral pectoralis major muscle flaps (BPMMFs). ::: ::: ::: Methods ::: In total, 565 patients with postoperative DSWI were enrolled in this study from January 1, 2014, to June 1, 2018.
Of these patients, 247 received BPMMFs.
To address the indicated biases, a 1:1 propensity score-matched cohort was created based on age, body mass index, preoperative diabetes mellitus, chronic obstructive pulmonary disease (COPD), internal thoracic artery grafting (ITAG), type of cardiac surgery, time before treatment for DSWI and wound classification.
After matching, 132 patients who had similar risk profiles were enrolled in the study population (66 in the VAC group: 66 in the BPMMF group). ::: ::: ::: Results ::: At 21.9±12.1 (median: 24, IQR: 14-28) months of follow-up, the survival rate was 93.9% in the BPMMF group and 74.4% in the VAC group (P<0.01).
Compared with the VAC group, the BPMMF group had a significantly decreased length of hospital stay (P<0.01).
At the spirometry assessment, the forced expiratory volume in the 1st second (FEV1), vital capacity (VC), and FEV1/VC ratio showed no significant differences in survival between the VAC group and BPMMF group.
::: ::: ::: Conclusions ::: In our study, compared with VAC therapy, BPMMFs guaranteed better early- and late-term outcomes, as shown by less length of hospital stay, a higher rate of long-term survival and unimpaired respiratory function. | 213,360,038 |
Title:
Systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes
Abstract:
Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied.
Here, we focused on structural cytoskeletal genes involved in critical cellular processes including chromosome segregation, macromolecular transport, and cell shape maintenance.
To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼85% of human cytoskeletal genes across 7 gene families for their ability to complement a growth defect induced by deletion of the corresponding yeast ortholog.
In 5 of 7 families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene.
Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects.
By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but apparently failing to interact with components of the yeast cytoskeleton, thus leading to abnormal cell morphologies.
Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs.
The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts. | 213,382,262 |
Title:
Principles for rational Cas13d guide design
Abstract:
Type VI CRISPR enzymes have recently been identified as programmable RNA-guided, RNA-targeting Cas proteins with nuclease activity that allow for specific and robust target gene knock-down without altering the genome.
However, we currently lack information about optimal Cas13 guide RNA designs for high target RNA knock-down efficacy.
To close this gap, we conducted four massively-parallel Cas13 screens targeting the mRNA of a destabilized green fluorescent protein (GFP) transgene and CD46, CD55 and CD71 cell surface proteins in human cells.
In total, we measured the activity of 24,460 guide RNA including 6,469 perfect match guide RNAs and a diverse set of guide RNA variants and permutations with mismatches relative to the target sequences.
We find that guide RNAs show high diversity in knock-down efficiency driven by crRNA-specific features as well as target site context.
Moreover, while single mismatches generally reduce knock-down to a modest degree, we identify a critical region spanning spacer nucleotides 15 – 21 that is largely intolerant to target site mismatches.
We developed a computational model to identify guide RNAs with high knock-down efficacy.
We confirmed the model’s generalizability across a large number of endogenous target mRNAs and show that Cas13 can be used in forward genetic pooled CRISPR-screens to identify essential genes.
Using this model, we provide a resource of optimized Cas13 guide RNAs to target all protein-coding transcripts in the human genome, enabling transcriptome-wide forward genetic screens. | 213,388,033 |
Title:
The reproductive number R0 of COVID-19 based on estimate of a statistical time delay dynamical system
Abstract:
In this paper, we estimate the reproductive number R0 of COVID-19 based on Wallinga and Lipsitch framework {11} and a novel statistical time delay dynamic system.
We use the observed data reported in CCDC's paper to estimate distribution of the generation interval of the infection and apply the simulation results from the time delay dynamic system as well as released data from CCDC to fit the growth rate.
The conclusion is: Based our Fudan-CCDC model, the growth rate r of COVID-19 is almost in [0.30, 0.32] which is larger than the growth rate 0.1 estimated by CCDC {9}, and the reproductive number R0 of COVID-19 is estimated by 3.25≤ R0 ≤3.4 if we simply use R=1+r*Tc with Tc=7.5, which is bigger than that of SARS.
Some evolutions and predictions are listed. | 213,417,196 |
Title:
Antibody responses to immunization require sensory neurons
Abstract:
Mammals store memories in the nervous and immune systems.
Sensory neurons have been implicated in enhancing neurological memory, but whether neurons participate during immunity to novel antigens is unknown.
Here, mice rendered deficient in transient receptor potential vanilloid 1 (TRPV1)-expressing sensory neurons, termed “nociceptors,” fail to develop competent antibody responses to KLH and hapten-NP.
Moreover, selective optogenetic stimulation of TRPV1 neurons during immunization significantly enhanced antibody responses to antigens.
Thus, TRPV1 nociceptors mediate antibody responses to novel antigen, and stimulating TRPV1 nociceptors enhances antibody responses during immunization.
This is the first genetic and selective functional evidence that nociceptors are required during immunization to produce antigen-specific antibodies.
Summary The first genetic and selective functional evidence showing that TRPV1-expressing nociceptors are required for competent antibody responses to novel antigen, and stimulating TRPV1 nociceptors enhances antibody responses to novel antigen. | 213,476,871 |
Title:
Rethinking causality and data complexity in brain lesion-behaviour inference and its implications for lesion-behaviour modelling
Abstract:
Modelling behavioural deficits based on structural lesion imaging is a popular approach to map functions in the human brain, and efforts to translationally apply lesion-behaviour modelling to predict post-stroke outcomes are on the rise.
The high-dimensional complexity of lesion data, however, evokes challenges in both lesion behaviour mapping and post stroke outcome prediction.
This paper aims to deepen the understanding of this complexity by reframing it from the perspective of causal and non-causal dependencies in the data, and by discussing what this complexity implies for different data modelling approaches.
By means of theoretical discussion and empirical examination, several common strategies and views are challenged, and future research perspectives are outlined.
A main conclusion is that lesion-behaviour inference is subject to a lesion-anatomical bias that cannot be overcome by using multivariate models or any other algorithm that is blind to causality behind relations in the data.
This affects the validity of lesion behaviour mapping and might even wrongfully identify paradoxical effects of lesion-induced functional facilitation – but, as this paper argues, only to a minor degree.
Thus, multivariate lesion-brain inference appears to be a valuable tool to deepen our understanding of the human brain, but only because it takes into account the functional relation between brain areas.
The perspective of causality and inter-variable dependence is further used to point out challenges in improving lesion behaviour models.
Firstly, the dependencies in the data open up different possible strategies of data reduction, and considering those might improve post-stroke outcome prediction.
Secondly, the role of non-topographical causal predictors of post stroke behaviour is discussed.
The present article argues that, given these predictors, different strategies are required in the evaluation of model quality in lesion behaviour mapping and post stroke outcome prediction. | 213,498,386 |
Title:
Incorporating Human Movement Data to Improve Epidemiological Estimates for 2019-nCoV
Abstract:
Estimating the key epidemiological features of the novel coronavirus (2019-nCoV) epidemic proves to be challenging, given incompleteness and delays in early data reporting, in particular, the severe under-reporting bias in the epicenter, Wuhan, Hubei Province, China.
As a result, the current literature reports widely varying estimates.
We developed an alternative geo-stratified debiasing estimation framework by incorporating human mobility with case reporting data in three stratified zones, i.e., Wuhan, Hubei Province excluding Wuhan, and mainland China excluding Hubei.
We estimated the latent infection ratio to be around 0.12% (18,556 people) and the basic reproduction number to be 3.24 in Wuhan before the city's lockdown on January 23, 2020.
The findings based on this debiasing framework have important implications to prioritization of control and prevention efforts. | 213,505,075 |
Title:
Neonatal Mastauxe (Breast Enlargement of the Newborn)
Abstract:
Neonatal Mastauxe (NM) represents a common, well known and physiologic condition that requires simple observation and parental reassurance.
"Giant" NM (exceeding 3 cm of diameter) is an infrequent clinical picture, potentially mimicking a bacterial infection.
Being aware of this clinical entity and (in dubious cases) performing blood tests and/or ultrasound investigation may help clinicians in making the correct diagnosis and permits parental reassurance on one hand, and to avoid unnecessary therapies on the other hand. | 213,524,911 |
Title:
EUS-B for suspected left adrenal metastasis in lung cancer.
Abstract:
Background ::: Several studies have reported the efficacy of esophageal ultrasound-guided fine needle aspiration (EUS-FNA) for the detection of metastases in the left adrenal gland (LAG) in patients with lung cancer.
Currently we have only limited evidence based on small studies on the usefulness of EUS-B [endobronchial ultrasound (EBUS) scope into the esophagus] to provide tissue proof of suspected LAG metastases.
The objectives of this study are to investigate feasibility, safety and diagnostic yield of EUS-B-FNA in LAG analysis in patients with proven or suspected lung cancer. ::: ::: ::: Methods ::: In two Danish hospitals, a systematic search in the electronic database for patients who underwent EUS-B-FNA of the LAG for suspected or proven lung cancer was performed retrospectively between January 1st, 2015 and December 31st, 2017.
Computed tomography (CT), positron emission tomography-CT, endoscopy, pathology and follow-up data were acquired. ::: ::: ::: Results ::: One hundred and thirty-five patients were included; the prevalence of biopsy proven LAG malignancy was 30% (40/135).
A total of 87% (117/135) of EUS-B-FNA samples were adequate (i.e., containing adrenal or malignant cells).
No complications were observed.
::: ::: ::: Conclusions ::: We present the largest cohort of patients ever reported showing that EUS-B-FNA of the LAG is a safe and feasible procedure and should therefore be used for staging purposes in patients with lung cancer and a suspicious LAG. | 213,531,576 |
Title:
Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019-nCoV), Wuhan, China through a drug-target interaction deep learning model
Abstract:
The infection of a novel coronavirus found in Wuhan of China (2019-nCoV) is rapidly spreading, and the incidence rate is increasing worldwide.
Due to the lack of effective treatment options for 2019-nCoV, various strategies are being tested in China, including drug repurposing.
In this study, we used our pretrained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of 2019-nCoV. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing a inhibitory potency with Kd of 94.94 nM against the 2019-nCoV 3C-like proteinase, followed by efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM).
Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases.
However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra, could be used for the treatment of 2019-nCoV, although there is no real-world evidence supporting the prediction.
Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for 2019-nCoV. | 213,587,930 |
Title:
Ethambutol Induced Optic Neuropathy: A Rare Case Report
Abstract:
Ethambutol (EMB) is one of the first-line drugs in the treatment of tuberculosis.
Ethambutol-induced optic neuropathy (EON) is a very well known side effect which is either dose or duration related.
The ocular manifestations of EON include painless loss of central vision and cecocentral scotomas in the visual field.
We report a rare case of EMB-induced optic neuritis in a 19 year old female, who was on ATT for spinal tuberculosis for 3 months.
Patient presented with painless diminution of vision in both eyes for 15 days which was not improving on refraction.
Patient was diagnosed as a case of EON on series of ophthalmic examination and ethambutol was stopped immediately.
Patient was given some neurotrophic drugs for 1 month.
After 1 month, patient had BCVA of 6/9 in both eyes.
Fundus and visual fields were also within normal limits except mild temporal disc pallor. | 213,597,306 |
Title:
Vulnerabilities in coronavirus glycan shields despite extensive glycosylation
Abstract:
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential.
Vaccine development has focussed on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein, which mediates receptor recognition and membrane fusion.
Coronavirus S proteins are extensively glycosylated viral fusion proteins, encoding around 69-87 N-linked glycosylation sites per trimeric spike.
Using a multifaceted structural approach, we reveal a specific area of high glycan density on MERS S that results in the formation of under-processed oligomannose-type glycan clusters, which was absent on SARS and HKU1 CoVs.
We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes.
Consistent with the ability of the antibody-mediated immune response to effectively target and neutralize coronaviruses, we demonstrate that the glycans of coronavirus spikes are not able to form an efficacious high-density global shield to thwart the humoral immune response.
Overall, our data reveal how differential organisation of viral glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the viral protein surface. | 213,655,422 |
Title:
Rethinking success, integrity, and culture in research (part 1) — A multi-actor qualitative study on success in science
Abstract:
ABSTRACT Background Success shapes the life and careers of scientists. But success in science is difficult to define, let alone to translate in indicators that can be used for assessment.
In the past few years, several groups expressed their dissatisfaction with the indicators currently used for assessing researchers. But given the lack of agreement on what should constitute success in science, most propositions remain unanswered.
This paper aims to complement our understanding of success in science and to document areas of tension and conflict in research assessments.
Methods We conducted semi-structured interviews and focus groups with policy makers, funders, institution leaders, editors or publishers, research integrity office members, research integrity community members, laboratory technicians, researchers, research students, and former-researchers who changed career to inquire on the topics of success, integrity, and responsibilities in science.
We used the Flemish biomedical landscape as a baseline to be able to grasp the views of interacting and complementary actors in a system setting.
Results Given the breadth of our results, we divided our findings in a two-paper series, with the current paper focusing on what defines and determines success in science.
Respondents depicted success as a multi-factorial, context-dependent, and mutable factor.
Success appeared to be an interaction between characteristics from the researcher (Who), research outputs (What), processes (How), and luck.
Interviewees noted that current research assessments overvalued outputs but largely ignored the processes deemed essential for research quality and integrity.
Interviewees sustained that we need a diversity of indicators to allow a balanced and diverse view of success; that assessments should not blindly depend on metrics but also value human input; that we must value quality over quantity; and that any indicators used must be transparent, robust, and valid.
Conclusions The objective of research assessments may be to encourage good researchers, to benefit society, or simply to advance science.
Yet we show that current assessments fall short on each of these objectives.
Open and transparent inter-actor dialogue is needed to understand what research assessments aim for and how they can best achieve their objective.
Trial Registration osf.io/33v3m | 213,656,937 |
Title:
Analysis of the efficacy of ozone therapy on different types of lumbar disc herniation: a new guidance is coming? [abstract]
Abstract:
PURPOSE: To investigate the sub-types of lumbar disc herniation, compare efficacies of ozone treatment in various types of lumbar disc herniation and analyze the mechanisms. ::: ::: MATERIAL AND METHODS: A total of 250 patients (159 males, 91 females; age range: 14 - 85 years) diagnosed of lumbar disc herniation from January 2009 to Jun 2014 in Nanfang Hospital were enrolled.
Disc Lesions, classified by Magnetic Resonance examinations and images when injecting ozone under Digital Subtraction Angiography, were divided into four types: type I: Non-prominent nucleus pulposus with ruptured fibre ring; type II: Prominent nucleus pulposus with ruptured fibre ring; type III: Non-prominent nucleus pulposus with Non-ruptured fibre ring; type IV: Prominent nucleus pulposus with Non-ruptured fibre ring.
All patients underwent intradiscal and paravertebral injection of oxygen-ozone.
Visual Analogue Scale (VAS) weighted score was administered for the measurement of low back pain before treatment, and the evaluation of efficacy respectively at 1 week, 1 month, 6 month and 12 month follow-up period. ::: ::: RESULTS: Most of the patients (about 4/5) showed better response to ozone treatment.
Herniated disc shrinkage was obtained among type II and IV.
The type II had the most reduction of average score while the type III had the least.
The proportion of patients who had once experienced pain relief at the follow up interval, namely the curative efficacy, showed significant difference: type I occupied the most, type IV occupied the least. ::: ::: CONCLUSION: Ozone treatment is effective and safe for all types of lumbar disc herniation, but efficacy varies according the types, of which type I has the best results and type IV has the worst ones. | 213,737,726 |
Title:
The genetic basis of sex determination in grapevines (Vitis spp.)
Abstract:
Sex determination in grapevine evolved through a complex succession of switches in sexual systems.
Phased genomes built with single molecule real-time sequencing reads were assembled for eleven accessions of cultivated hermaphrodite grapevines and dioecious males and females, including the ancestor of domesticated grapevine and other related wild species.
By comparing the phased sex haplotypes, we defined the sex locus of the Vitis genus and identified polymorphisms spanning regulatory and coding sequences that are in perfect association with each sex-type throughout the genus.
These findings identified a novel male-fertility candidate gene, INP1, and significantly refined the model of sex determination in Vitis and its evolution. | 213,830,778 |
Title:
Structure-based identification and functional characterization of an essential lipocalin in the malaria parasite Plasmodium falciparum
Abstract:
Proteins of the lipocalin family are known to bind small hydrophobic ligands and are involved in various physiological processes ranging from lipid transport to oxidative stress responses.
The genome of the malaria parasite Plasmodium falciparum contains a single protein PF3D7_0925900 with a lipocalin signature.
Using crystallography and small-angle X-ray scattering, we show that the protein has a tetrameric structure of typical lipocalin monomers, hence we name it P. falciparum lipocalin (PfLCN), the first lipocalin structurally and functionally characterized in a single-celled eukaryote.
We show that PfLCN is expressed in the intraerythrocytic stages of the parasite and localizes to the parasitophorous and food vacuoles.
Conditional knockdown of PfLCN impairs parasite development, which can be rescued by treatment with the radical scavenger Trolox or by temporal inhibition of hemoglobin digestion.
This suggests a key function of PfLCN in counteracting oxidative stress induced cell damage during multiplication of parasites within red blood cells. | 213,832,355 |
Title:
Genetic Adaptation in New York City Rats
Abstract:
Brown rats (Rattus norvegicus) thrive in urban environments by navigating the anthropocentric environment and taking advantage of human resources and by-products.
From the human perspective, rats are a chronic problem that causes billions of dollars in damage to agriculture, health and infrastructure.
Did genetic adaptation play a role in the spread of rats in cities?
To approach this question, we collected whole-genome samples from 29 brown rats from New York City (NYC) and scanned for genetic signatures of adaptation.
We applied multiple methods, testing for (i) high-frequency, extended haplotypes that could indicate selective sweeps and (ii) loci of extreme genetic divergence between the NYC sample and a sample from the presumed ancestral range of brown rats in rural north east China.
We found candidate selective sweeps near or inside genes associated with metabolism, diet, organ morphogenesis and locomotory behavior.
The divergence between NYC and rural Chinese rats at putative sweep loci suggests that many sweeps began after the split from the ancestral population.
Together, our results suggest several hypotheses for a genetic component behind the adaptation of rats in response to human activity. | 213,852,001 |
Title:
C-terminal RRM/ACT domain is crucial for fine-tuning the activation of ‘long’ RelA-SpoT Homolog enzymes by ribosomal complexes
Abstract:
The (p)ppGpp-mediated stringent response is a bacterial stress response implicated in virulence and antibiotic tolerance.
Both synthesis and degradation of the (p)ppGpp alarmone nucleotide are mediated by RelA-SpoT Homolog (RSH) enzymes which can be broadly divided in two classes: single-domain short RSHs and multi-domain long RSHs enzymes.
The regulatory ACT (Aspartokinase, Chorismate mutase and TyrA) / RRM (RNA Recognition Motif) domain is a near-universal C-terminal domain of long RSHs.
Deletion of RRM in both monofunctional (synthesis-only) RelA as well as bifunctional (i.e. capable of both degrading and synthesising the alarmone) Rel renders the long RSH cytotoxic due to overproduction of (p)ppGpp.
To probe the molecular mechanism underlying this effect we characterised Escherichia coli RelA and Bacillus subtilis Rel RSHs lacking RRM.
We demonstrate that, first, the cytotoxicity caused by the removal of RRM is counteracted by secondary mutations that disrupt the interaction of the RSH with the starved ribosomal complex - the ultimate inducer of (p)ppGpp production by RelA and Rel - and, second, that the hydrolytic activity of Rel is not abrogated in the truncated mutant.
Therefore, we conclude that the overproduction of (p)ppGpp by RSHs lacking the RRM domain is not explained by lack of auto-inhibition in the absence of RRM or/and a defect in (p)ppGpp hydrolysis.
Instead, we argue that it is driven by misregulation of the RSH activation by the ribosome. | 213,868,187 |
Title:
A clinicoepidemiological study of adult acne
Abstract:
Background: Acne vulgaris is a chronic inflammatory dermatosis of pilosebaceous unit.
Adult acne is defined as presence of acne after the age of 25 years.
Though acne vulgaris has been studied extensively, there is paucity of literature on adult acne.
Methods: A total of 150 patients with adult acne were enrolled in the study.
A detailed history was taken followed by detailed dermatological examination.
Ultrasonography abdomen and pelvis, hormonal evaluation was done in case of women with symptoms and signs of hyperandrogenism.
Results: Out of 150 patients studied, majority (61.3%) were in the age group of 26-30 years.
The mean age of patients with adult acne was 30.1 years.
Females (86%) outnumbered males.
Majority of the patients (53.3%) had persistent adult acne and 46.7% had late onset acne.
Exposure to sunlight (24%) was the most common aggravating factor followed by use of cosmetics in 19.3%.
Menstruation was causing flare up of acne in 72 (55.8%) female patients.
Face was involved in all the patients.
Cheek was the most common site involved followed by forehead.
Post acne scarring was present in 46.6% of the patients.
Majority of the patients (67.3%) had grade 2 acne.
Symptoms and signs of hyperandrogenism were present in 14 female patients.
Conclusions: Adult acne is more common in females.
Persistent acne is more common than late onset acne.
Patients with persistent adult acne are more prone to develop nodulocystic acne and acne scars. | 213,884,787 |
Title:
Interventions targeting air travellers early in the pandemic may delay local outbreaks of SARS-CoV-2
Abstract:
Objectives: To determine if interventions aimed at air travellers can delay establishment of a SARS-CoV-2 outbreak in a previously unaffected country. ::: Design: Simulation study ::: Setting: Countries with no sustained SARS-CoV-2 transmission and with no shared border with affected regions ::: Participants: Infected air travellers ::: Interventions: Syndromic screening at departure and/or arrival & traveller sensitisation to the COVID-2019-like symptoms with the aim to trigger rapid self-isolation and reporting on symptom onset. ::: Main outcome measures: The achievable delay until a major local outbreak is likely to occur ::: Results: We evaluated traveller sensitisation effectiveness in reducing the number of secondary cases of 30, 50 and 70%, and assumed either 1, 10, or 100 infected travellers per week.
Early in the outbreak when only few infected travellers arrive, traveller sensitisation can delay a major outbreak in a previously unaffected region.
For 50% sensitisation effectiveness, and assuming 1 infected traveller per week, we find that in 75% of simulations the outbreak is delayed by at least 11 days (97.5% of simulations: at least 7 days).
The possible delay decreases rapidly for more travellers, lower effectiveness of sensitisation, higher R0 or lower heterogeneity thereof.
Syndromic traveller screening at departure and/or arrival can further enhance outbreak delays.
In combination with sensitisation, syndromic screening can delay an outbreak substantially longer.
In 75% of simulations we find an outbreak delay of at least 111 days (97.5% of simulations: at least 23 days) for 1 infected traveller per week and at least 9 days (97.5% of simulations: at least 4 days) for 10 infected travellers per week. ::: ::: Conclusion: Air-traveller targeted interventions, particularly in combination, can delay local SARS-CoV-2 outbreaks in the magnitude of a few weeks to potentially even months if the number of infected travellers remains low. | 213,898,209 |
Title:
Longitudinal linked read sequencing reveals ecological and evolutionary responses of a human gut microbiome during antibiotic treatment
Abstract:
Gut microbial communities can respond to antibiotic perturbations by rapidly altering their taxonomic and functional composition.
However, little is known about the strain-level processes that drive this collective response.
Here we characterize the gut microbiome of a single individual at high temporal and genetic resolution through a period of health, disease, antibiotic treatment, and recovery.
We used deep, linked-read metagenomic sequencing to track the longitudinal dynamics of thousands of single nucleotide variants within 36 species, which allowed us to contrast these genetic dynamics with the ecological fluctuations at the species level.
We find that antibiotics can drive rapid shifts in the genetic composition of individual species, often involving incomplete genome-wide sweeps of pre-existing variants.
Interestingly, genetic changes frequently occur in species without obvious changes in relative species abundance, emphasizing the importance of monitoring diversity below the species level.
Our results provide new insights into the population genetic forces that shape individual microbiomes on therapeutically relevant timescales, with potential implications for personalized health and disease. | 213,908,769 |
Title:
Inter-quartile analysis of resting heart rate and heart rate variability following spinal adjustment: A case study
Abstract:
Abstract ::: Background: Different clinicians use heart rate tests to answer different questions.
The medical doctor for example might use heart rate to diagnose a medical condition.
One approach in chiropractic practice is | 213,916,003 |
Title:
Nucleotide Analogues as Inhibitors of Viral Polymerases
Abstract:
Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies.
Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3’-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators. | 213,947,455 |
Title:
Disentangling microbial associations from hidden environmental and technical factors via latent graphical models
Abstract:
Detecting community-wide statistical relationships from targeted amplicon-based and metagenomic profiling of microbes in their natural environment is an important step toward understanding the organization and function of these communities.
We present a robust and computationally tractable latent graphical model inference scheme that allows simultaneous identification of parsimonious statistical relationships among microbial species and unobserved factors that influence the prevalence and variability of the abundance measurements.
Our method comes with theoretical performance guarantees and is available within the SParse InversE Covariance estimation for Ecological ASsociation Inference (SPIEC-EASI) framework (‘SpiecEasi’ R-package).
Using simulations, as well as a comprehensive collection of amplicon-based gut microbiome datasets, we illustrate the method’s ability to jointly identify compositional biases, latent factors that correlate with observed technical covariates, and robust statistical microbial associations that replicate across different gut microbial data sets. | 214,102,727 |
Title:
Non-invasive, Real-time Detection of Vascular Disorders in Mice using Bright SWIR-emitting Gold Nanoclusters and Monte Carlo Image Analysis
Abstract:
We present here a new approach for non-invasive high resolution whole-body vascular imaging in depth by combining water-soluble and bright SWIR-emitting gold nanoclusters revealing an anisotropic surface charge with Monte Carlo image processing of the images.
We applied and validated this approach to quantify vessel complexity in transgenic mice presenting vascular disorders. | 214,150,881 |
Title:
Blood clot causing small bowel obstruction after Roux en-Y Gastric bypass: a Case Report & Review of Literature
Abstract:
The gold standard procedure and most commonly performed bariatric surgery internationally is the Roux En-Y Gastric Bypass (RYBG) surgery.
A major complication of the RYGB is small bowel obstruction (SBO; 5% incidence), most frequently caused by intra-abdominal adhesions (65–75%), followed by internal hernias, volvulus, malignancy, intussusception, Crohn’s disease, carcinomatosis, intraluminal blood clot, port site hernias, jejunojejunostomy anastomosis strictures, paralytic ileus, and superior mesenteric artery syndrome.
In this review of literature, we present a small bowl obstruction case caused by a blood clot (inside the lumen) at a bleeding site within a jejunojejunostomy staple line of a surgical patient.
The patient’s past-medical history is significant for recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE).
The SBO was diagnosed by computed tomography (CT) post-operatively and the patient underwent emergent explorative laparoscopy for management.
The intraluminal clot that was found upon examination was evacuated by enterotomy followed by a primary closure with no evidence of continued active bleeding and without need for revision of the jejunojejunal anastomosis.
It was concluded that the anti-coagulant medication (Enoxaparin 50 mg BID) being administered to the patient most likely precipitated the intraluminal bleeding at the anastomosis.
Based on our findings, early diagnosis and management of SBO in the early perioperative period could likely reduce the percent of this complication complication in bariatric patients. | 214,204,578 |
Title:
An electrodiffusive, ion conserving Pinsky-Rinzel model with homeostatic mechanisms
Abstract:
Most neuronal models are based on the assumption that ion concentrations remain constant during the simulated period, and do not account for possible effects of concentration variations on ionic reversal potentials, or of ionic diffusion on electrical potentials.
Here, we present what is, to our knowledge, the first multicompartmental neuron model that accounts for electrodiffusive ion concentration dynamics in a way that ensures a biophysically consistent relationship between ion concentrations, electrical charge, and electrical potentials in both the intra- and extracellular space.
The model, which we refer to as the electrodiffusive Pinsky-Rinzel (edPR) model, is an expanded version of the two-compartment Pinsky-Rinzel (PR) model of a hippocampal CA3 neuron, where we have included homeostatic mechanisms and ion-specific leakage currents.
Whereas the main dynamical variable in the original PR model is the transmembrane potential, the edPR model in addition keeps track of all ion concentrations (Na+, K+, Ca2+, and Cl−), electrical potentials, and the electrical conductivities in the intra- as well as extracellular space.
The edPR model reproduces the membrane potential dynamics of the PR model for moderate firing activity, when the homeostatic mechanisms succeed in maintaining ion concentrations close to baseline.
For higher activity levels, homeostasis becomes incomplete, and the edPR model diverges from the PR model, as it accounts for changes in neuronal firing properties due to deviations from baseline ion concentrations.
Whereas the focus of this work is to present and analyze the edPR model, we envision that it will become useful for the field in two main ways.
Firstly, as it relaxes a set of commonly made modeling assumptions, the edPR model can be used to test the validity of these assumptions under various firing conditions, as we show here for a few selected cases.
Secondly, the edPR model is a supplement to the PR model and should replace it in simulations of scenarios in which ion concentrations vary over time.
As it is applicable to conditions with failed homeostasis, the edPR model opens up for simulating a range of pathological conditions, such as spreading depression or epilepsy.
Author summary Neurons generate their electrical signals by letting ions pass through their membranes.
Despite this fact, most models of neurons apply the simplifying assumption that ion concentrations remain effectively constant during neural activity.
This assumption is often quite good, as neurons contain a set of homeostatic mechanisms that make sure that ion concentrations vary quite little under normal circumstances.
However, under some conditions, these mechanisms can fail, and ion concentrations can vary quite dramatically.
Standard models are thus not able to simulate such conditions.
Here, we present what to our knowledge is the first multicompartmental neuron model that in a biophysically consistent way does account for the effects of ion concentration variations.
We here use the model to explore under which activity conditions the ion concentration variations become important for predicting the neurodynamics.
We expect the model to be of great use for simulating a range of pathological conditions, such as spreading depression or epilepsy, which are associated with large changes in extracellular ion concentrations. | 214,236,544 |
Title:
Adult onset still’s disease: a diagnostic dilemma
Abstract:
Adult onset still’s disease is a rare systemic inflammatory disorder of unknown aetiology, characterized by clinical triad (high spiking fever, evanescent rash and arthritis) and biological triad with lack of serological markers as a true gold standard makes diagnosis difficulty.
Here is a case of 32year old male presented with high grade fever for 2 months, joint pains and swelling for 1month rash for 3 days.
O/E: pallor and B/L tender, swollen ankle and knee joints, and P/A: splenomegaly.
Investigations showed-Hb%. 8 gms, neutrophilic leucocytosis with thrombocytosis, ESR:72 mm/1h, CRP elevated.
ASO-titre, RA factor and Anti CCP antibodies are negative.
Adult onset still’s disease is a heterogenous and rare systemic inflammatory disorder of unknown aetiology with lack of serological diagnostic modalities. | 214,256,852 |
Title:
Multidisciplinary surgical intensive treatment of an extended thoracic wall infiltration by a giant breast sarcoma: a case report
Abstract:
Primary breast sarcoma represents less than 0.1% of breast cancers and less than 5% of all sarcomas.
It derives from the mesenchymal tissues of the breast and can originate a histologically heterogeneous group of neoplasms.
It has a poor prognosis and the median 5-year overall survival is 63.5% (range, 55–73%).
Currently, diagnosis and treatment of this neoplasm are a challenge for pathologists, surgeons and oncologists.
We describe the case of a 56-year-old Macedonian woman, who presented with local recurrence of a high-grade chondrosarcoma of the right breast.
She had been treated elsewhere six months earlier with radical mastectomy and ipsilateral axillary dissection.
The actual heteroplasia was 29 centimeters wide, ulcerated and infected.
The computed tomography (CT) scan documented infiltration of pectoralis muscles, of III and IV right ribs and sternal body, but no distant metastases.
Considering the patient’s clinical conditions and stage of the disease, a multidisciplinary discussion lead to the decision to attempt surgery.
A multidisciplinary surgical teamwork was indispensable for attempting such a highly complex and demolitive surgery and a challenging reconstruction of the thoracic wall and an intensive post- operative monitoring of the patient was needed to manage complications related to tissue loss.
Nowadays it is difficult to find patients suffering from tumors of this size and consequently the treatment is made more complicated by the lack of experience.
With this case report we share our experience in the treatment of an infrequent pathology that has presented itself to us with dimensions rarely reported in the literature. | 214,269,900 |
Title:
Minimally invasive transhiatal esophagectomy
Abstract:
Esophagectomy is used for the treatment of esophageal cancer as well as benign disease.
Transhiatal esophagectomy with a cervical anastomosis was reported by Orringer et al. in 1978 and developed into a safe, reproducible, oncologically sound procedure.
The advantages compared to other types of esophagectomies are the avoidance of thoracic incisions, which decreases respiratory complications; and a cervical anastomosis, which is less morbid if it leaks.
The main criticism is an incomplete thoracic lymph node dissection, since the mediastinal dissection is performed bluntly.
There is no clear difference in oncologic outcomes when comparing the transhiatal esophagectomy to other types.
The first robotic transhiatal esophagectomy was reported by Horgan et al. in 2003, with a robot-assisted abdominal portion and an open cervical portion.
Since then, transhiatal esophagectomy with a combination of robot-assisted and video-assisted approaches in the abdomen and neck have been described.
In this article, we describe a technique in performing a minimally invasive transhiatal esophagectomy, with a robot-assisted abdominal and video-assisted cervical approach.
Using a camera in both the abdominal and cervical portions of the procedure allows a complete thoracic lymph node dissection. | 214,296,694 |
Title:
Targeting HIV Env immunogens to B cell follicles in non-human primates through immune complex or protein nanoparticle formulations
Abstract:
Following immunization, high affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation.
Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process.
However, recombinant protein immunogens such as soluble HIV envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization.
Here we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens.
Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles.
Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single lymph node within 2 days after immunization.
Imaging of LNs collected 7 days post-immunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent germinal centers.
These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with immune complexes or nanoparticles. | 214,312,244 |
Title:
Population genetics of the coral Acropora millepora: Towards a genomic predictor of bleaching
Abstract:
Although reef-building corals are rapidly declining worldwide, responses to bleaching vary both within and among species.
Because these inter-individual differences are partly heritable, they should in principle be predictable from genomic data.
Towards that goal, we generated a chromosome-scale genome assembly for the coral Acropora millepora.
We then obtained whole genome sequences for 237 phenotyped samples collected at 12 reefs distributed along the Great Barrier Reef, among which we inferred very little population structure.
Scanning the genome for evidence of local adaptation, we detected signatures of long-term balancing selection in the heat-shock co-chaperone sacsin.
We further used 213 of the samples to conduct a genome-wide association study of visual bleaching score, incorporating the polygenic score derived from it into a predictive model for bleaching in the wild.
These results set the stage for the use of genomics-based approaches in conservation strategies. | 214,327,495 |
Title:
Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Abstract:
Background: To explore the cellular immunity and cytokines status of NCP patients and to predict the correlation between the cellular immunity levels, cytokines and the severity of patients.
Methods: 123 NCP patients were divided into mild and severe groups.
Peripheral blood was collected, lymphocyte subsets and cytokines were detected.
Correlation analysis was performed on the lymphocyte subsets and cytokines, and the differences between the indexes of the two groups were analyzed.
Results: 102 mild and 21 severe patients were included.
Lymphocyte subsets were reduced in two groups.
The proportion of CD8 + T reduction in the mild and severe group was 28.43% and 61.9%, respectively; The proportion of B cell reduction was 25.49% and 28.57%; The proportion of NK cell reduction was 34.31% and 47.62%; The detection value of IL-6 was 0 in 55.88% of the mild group, mild group has a significantly lower proportion of patients with IL-6 higher than normal than severe group; There was no significant linear correlation between the lymphocyte subsets and cytokines, while significant differences were noticed between the two groups in CD4 + T, CD8 + T, IL-6 and IL-10.
Conclusions: Low levels of CD4+T and CD8+T are common in severe NCP.
IL-6 and IL-10 levels were higher in severe patients.
T cell subsets and cytokines can be used as one of the basis for predicting the transition from mild to severe.
Large number of samples are still needed to confirm the "warning value" of CD4 + T, CD8 + T IL-6 and IL-10. | 214,329,153 |
Title:
Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening
Abstract:
2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China.
Investigations on the transmissibility, severity, and other features associated with this virus are ongoing.
Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen.
In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic.
The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development.
In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV. | 214,349,516 |
Title:
Meta-Learning Biologically Plausible Semi-Supervised Update Rules
Abstract:
The question of how neurons embedded in a network update their synaptic weights to collectively achieve behavioral goals is a longstanding problem in systems neuroscience.
Since Hebb’s hypothesis [10] that cells that fire together strengthen their connections, cellular studies [6] have shed light on potential synaptic mechanisms underlying learning.
These mechanisms have directly driven the careful hand design of biologically plausible models of learning and memory in computational neuroscience [1].
However, these hand designed rules have yet to achieve satisfying success training large neural networks, and are dramatically outperformed by biologically implausible approaches such as backprop.
We propose an alternative paradigm for designing biologically plausible learning rules: using meta-learning to learn a parametric synaptic update rule which is capable of training deep networks.
We demonstrate this approach by meta-learning an update rule for semi-supervised tasks, where sparse labels are provided to a deep network but the majority of inputs are unlabeled.
The meta-learned plasticity rule integrates bottom-up, top-down, and recurrent inputs to each neuron, and generates weight updates as the product of pre- and post- synaptic neuronal outputs.
The way in which the inputs to each neuron are combined to produce a learning signal, however, is itself a meta-learned function, parameterized by a neural network.
Critically, the meta-learned update rule integrates only neuron-local information when proposing updates–that is, our learning rule is spatially localized to individual neurons.
After meta-learning, the resulting synaptic update rule is capable of driving task-relevant learning for semi-supervised tasks.
We demonstrate this capability on two simple classification problems.
In general, we believe meta-learning to be a powerful approach to finding more effective synaptic plasticity rules, which will motivate new hypotheses for biological neural networks, and new algorithms for artificial neural networks. | 214,357,101 |
Title:
Seasonal and social factors associated with spacing in a wild territorial electric fish
Abstract:
The expression of territorial behavior in wild species is especially suited to explore how animals integrate individual traits with dynamic environmental and social contexts.
In this study, we focused on the seasonal variation of the determinants of territory size in the weakly electric fish Gymnotus omarorum.
This species is a seasonal breeder that displays year-long territorial aggression, in which female and male dyads exhibit indistinguishable non-breeding territorial agonistic behavior and the only significant predictor of contest outcome is body size.
We carried out field surveys across seasons that included the identification of individual location, measurements of water physico-chemical variables, characterization of individual morphometric and physiological traits, and their correlation to spatial distribution.
Although Gymnotus omarorum tolerates a wide range of dissolved oxygen concentration, territory size correlated with dissolved oxygen in both seasons.
In the non-breeding season, we show that territory size is sexually monomorphic and explained only by body size.
In the breeding season, while body size no longer correlated with territory size, evidence of sexual differences in territory size determinants emerged.
First, the overall spatial arrangement adopted a sexual bias.
Second, territory size depended on gonadal hormones in both sexes, which was expected for males, but not previously reported in females.
Third, females’ territory size correlated with gonadal size and females showed relatively larger territories than males, probably to meet sexually dimorphic energetic requirements.
This study provides evidence of seasonal changes in factors correlated with territory size and contributes to the understanding of the mechanisms underlying behavioral plasticity. | 214,368,038 |
Title:
Phospholipase Cζ (PLCζ) versus postacrosomal sheath WW domain‐binding protein (PAWP): Which molecule will survive as a sperm factor?
Abstract:
During mammalian fertilization, sperm is fused with the oocyte's membrane, triggering the resumption of meiosis from the metaphase II arrest, the extrusion of the second polar body, and the exocytosis of cortical granules; these events are collectively called 'oocyte activation.' In all species studied to date, the transient rise in the cytosolic level of calcium (in particular, the repeated calcium increases called 'calcium oscillations' in mammals) is required for these events.
Researchers have focused on identifying the factor(s) that can induce calcium oscillations during fertilization.
Sperm-specific phospholipase C, i.e., PLC zeta (PLCζ), is a strong candidate of the factor(s), and several research groups using different species obtained evidence that PLCζ is a sperm factor that can induce calcium oscillations during fertilization.
However, postacrosomal sheath Tryptophan-Tryptophan (WW)-domain-binding protein (PAWP) was recently shown to have a pivotal role in inducing calcium oscillations in some species.
In this review, we focus on PLCζ and PAWP as sperm factors, and we discuss this controversy: Which of these two molecules survives as a sperm factor? | 214,420,589 |
Title:
Surgical fixation of rib fractures decreases intensive care length of stay in flail chest patients
Abstract:
Background: Nonoperative treatment is currently the standard therapy for rib fractures.
However, there is a trend towards surgical fixation from conservative management over the last decade.
While surgical fixation of rib fractures has shown promising results, its impact on the clinical results remains unclear based on the current literature.
As such, the present study aims to compare the short-term outcomes of multiple rib fracture patients treated by surgical fixation with traditional conservative management.
::: Methods: Data for patients with multiple (three or more) rib fractures admitted to our department between January 2012 and January 2019 were retrospectively collected and analyzed.
Propensity score matched patients were compared between those treated with surgical rib fixation and those of nonoperatively treated.
Primary outcomes were hospital length of stay for multiple rib fracture patients, and intensive care unit (ICU) length of stay for flail chest patients.
Secondary outcomes included in hospital mortality, ICU usage rate, duration of ventilator support, ventilator usage rate, and pneumonia. ::: Results: The study included 1,201 patients with mean age of 50.1±12.7 years, of whom 954 (79.4%) were male.
The average number of rib fractures was 6.3±2.4, with a mean injury severity score of 20.5±7.3.
Among them, 563 (46.9%) patients had surgical rib fixation and 638 (53.1%) patients received nonoperative treatment.
There were 191 patients with a flail chest, 133 (69.6%) had operative rib fixation and 58 (30.4%) were nonoperatively treated.
After propensity score match, the hospital length of stay was not significantly differed between surgery and conservative management in multiple rib fracture patients (10.7±3.4 vs .
10.2±3.8 day, P=0.067), nor were the secondary outcomes, in terms of in hospital mortality (0.9% vs .
1.1%, P=0.704), ICU usage rate (12.3% vs .
12.9%, P=0.820), duration of ventilator support (100.1±13.9 vs .
99.8±20.7 hours, P=0.822), ventilator usage rate (12.0% vs .
12.9%, P=0.732), and pneumonia (24.3% vs .
24.9%, P=0.861).
For patients with a flail chest, shorter ICU length of stay was found to be associated with surgical rib fixation comparing with nonoperative treatment (5.5±1.9 vs .
6.7±2.1 days, P=0.011).
No secondary outcomes such as in hospital mortality (4.4% vs .
4.4%, P=1.000), ICU usage rate (20.0% vs .
22.2%, P=0.796), duration of ventilator support (113.1±20.4 vs .
131.2±19.5 hours, P=0.535), ventilator usage rate (20.0% vs .
20.0%, P=1.000), pneumonia (28.9% vs .
31.1%, P=0.818) were significant different between the operative and nonoperative groups. ::: Conclusions: Surgical rib fixation results in a shorter ICU length of stay in patients with a flail chest, and a comparable outcome for patients with multiple rib fractures when compared with nonoperative treatment. | 214,435,324 |
Title:
Recently expanded clonal lineages of the rice blast fungus display distinct patterns of presence/absence of effector genes
Abstract:
Background Understanding the mechanisms and timescales of plant pathogen outbreaks requires a detailed genome-scale analysis of their population history.
The fungus Magnaporthe (Syn.
Pyricularia) oryzae —the causal agent of blast disease of cereals— is among the most destructive plant pathogens to world agriculture and a major threat to the production of rice, wheat and other cereals.
Although M. oryzae is a multihost pathogen that infects more than 50 species of cereals and grasses, all rice-infecting isolates belong to a single genetically defined lineage.
Here, we combined multiple genomics datasets to reconstruct the genetic history of the rice-infecting lineage of M. oryzae based on 131 isolates from 21 countries.
Results The global population of the rice blast fungus consists of a diverse set of individuals and three well-defined genetic groups.
Multiple population genetic tests revealed that the rice-infecting lineage of the blast fungus probably originated from a recombining diverse group in South East Asia followed by three independent clonal expansions that took place over the last ∼200 years.
Patterns of allele sharing identified a subpopulation from the recombining diverse group that introgressed with one of the clonal lineages before its global expansion.
Remarkably, the four genetic lineages of the rice blast fungus vary in the number and patterns of presence/absence of candidate effector genes.
In particular, clonal lineages carry a reduced repertoire of effector genes compared with the diverse group, and specific combinations of effector presence/absence define each of the pandemic clonal lineages.
Conclusions Our analyses reconstruct the genetic history of the rice-infecting lineage of M. oryzae revealing three clonal lineages associated with rice blast pandemics.
Each of these lineages displays a specific pattern of presence/absence of effector genes that may have shaped their adaptation to the rice host and their evolutionary history. | 214,444,093 |
Title:
Hollow fiber vitrification allows cryopreservation of embryos with compromised cryotolerance
Abstract:
Purpose ::: This study aims to demonstrate vitrification methods that provide reliable cryopreservation for embryos with compromised cryotolerance. ::: ::: ::: Methods ::: Two-cell stage mouse embryos and in vitro produced porcine embryos were vitrified using the hollow fiber vitrification (HFV) and Cryotop (CT) methods.
The performance of these two methods was compared by the viability of the vitrified-rewarmed embryos.
::: ::: ::: Results ::: Regardless of the method used, 100% of the mouse 2-cell embryos developed successfully after vitrification-rewarming into the blastocyst stage, whereas vitrification tests using porcine morulae with the HFV method produced significantly better results.
The developmental rates of vitrified porcine morula into the blastocyst stage, as well as blastocyst cell number, were 90.3% and 112.3 ± 6.9 in the HFV group compared with 63.4% and 89.5 ± 8.1 in the CT group (P < .05).
Vitrification tests using 4- to 8-cell porcine embryos resulted in development into the blastocyst stage (45.5%) in the HFV group alone, demonstrating its better efficacy.
The HFV method did not impair embryo viability, even after spontaneous rewarming at room temperature for vitrified embryos, which is generally considered a contraindication. ::: ::: ::: Conclusion ::: Vitrification test using embryos with compromised cryotolerance allows for more precise determining of effective cryopreservation methods and devices. | 214,448,347 |
Title:
Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
Abstract:
SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.
There are currently no registered therapies for treating coronavirus infections.
Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases.
We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling.
By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products.
Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail.
In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.
Possible targets of these compounds and potential drugs acting on a certain target were predicted.
This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections. | 214,495,563 |
Title:
Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Abstract:
Since December 2019, a novel coronavirus named 2019 coronavirus (2019-nCoV) has emerged in Wuhan of China and spread to several countries worldwide within just one month.
Apart from fever and respiratory complications, acute kidney injury has been observed in some patients with 2019-nCoV. In a short period of time, angiotensin converting enzyme II (ACE2), have been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same for severe acute respiratory syndrome coronavirus (SARS).
To investigate the possible cause of kidney damage in 2019-nCoV patients, we used both published kidney and bladder cell atlas data and an independent unpublished kidney single cell RNA-Seq data generated in-house to evaluate ACE2 gene expressions in all cell types in healthy kidneys and bladders. ::: ::: Our results showed the enriched expression of all subtypes of proximal tubule cells of kidney and low but detectable levels of expression in bladder epithelial cells.
These results indicated the urinary system is a potential route for 2019-nCoV infection, along with the respiratory system and digestion system.
Our findings suggested the kidney abnormalities of SARS and 2019-nCoV patients may be due to proximal tubule cells damage and subsequent systematic inflammatory response induced kidney injury.
Beyond that, laboratory tests of viruses and related indicators in urine may be needed in some special patients of 2019-nCoV. | 214,548,115 |
Title:
CT manifestations of coronavirus disease-2019: A retrospective analysis of 73 cases by disease severity
Abstract:
Purpose To report CT features of coronavirus disease-2019 (COVID-19) in patients with various disease severity.
Methods The CT manifestations and clinical data of 73 patients with COVID-19 were retrospectively collected in 6 hospitals 10 from Jan 21 to Feb 3, 2020.
We analyzed the initial and follow-up CT features of patients with disease severity, according to the Guidelines for the Diagnosis and Treatment of New Coronavirus Pneumonia.
Results Six patients (8%) were diagnosed as mild type pneumonia; these patients had no obvious abnormal CT findings or manifested mild changes of lung infection.
All 43 patients (59%) with common type presented unique or multiple ground-glass opacities (GGO) in the periphery of the lungs, with or without interlobular septal thickening.
In the 21 patients (29%) with severe type, extensive GGO and pulmonary consolidation were found in 16 cases (16/21, 76%) and 5 cases (24%), respectively.
An extensive "white lung", with atelectasis and pleural effusion were found in critical type patients (3, 4%).
On the resolutive phase of the disease, CT abnormalities showed complete resolution, or demonstrated residual linear opacities.
Conclusions Different CT features are seen according to disease severity, which can help COVID-19 stratification. | 214,591,161 |
Title:
Simple semi-high throughput determination of activity signatures of key antioxidant enzymes for physiological phenotyping
Abstract:
Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide anions significantly accumulate during biotic and abiotic stress and cause oxidative damage and eventually cell death.
There is accumulating evidence that ROS are also involved in regulating beneficial plant–microbe interactions, signal transduction and plant growth and development.
Due to the relevance of ROS throughout the life cycle and for interaction with the multifactorial environment, the physiological phenotyping of the mechanisms controlling ROS homeostasis is of general importance.
In this study, we have developed a robust and resource-efficient experimental platform that allows the determination of the activities of the nine key ROS scavenging enzymes from a single extraction that integrates posttranscriptional and posttranslational regulations.
The assays were optimized and adapted for a semi-high throughput 96-well assay format.
In a case study, we have analyzed tobacco leaves challenged by pathogen infection, drought and salt stress.
The three stress factors resulted in distinct activity signatures with differential temporal dynamics.
This experimental platform proved to be suitable to determine the antioxidant enzyme activity signature in different tissues of monocotyledonous and dicotyledonous model and crop plants.
The universal enzymatic extraction procedure combined with the 96-well assay format demonstrated to be a simple, fast and semi-high throughput experimental platform for the precise and robust fingerprinting of nine key antioxidant enzymatic activities in plants. | 214,599,685 |
Title:
Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status
Abstract:
The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status.
The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon.
This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation.
To address this problem, we sought to compare p53 IHC patterns with TP53 mutation status.
We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]).
IHC for p16 and p53, and sequencing of TP53 exons 4-9 were performed.
HPV in situ hybridization (ISH) was performed in selected cases.
We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression.
These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions.
Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused.
The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH.
This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53 mutational status in both VSCC and vulvar in situ lesions. | 214,599,802 |
Title:
Facing up to why the wandering mind: Patterns of off-task laboratory thought are associated with stronger neural recruitment of right fusiform cortex while processing facial stimuli
Abstract:
Human cognition is not always tethered to events in the external world.
Laboratory and real world experience sampling studies reveal that attention is often devoted to self-generated mental content rather than to events taking place in the immediate environment.
Recent studies have begun to explicitly examine the consistency between states of off-task thought in the laboratory and in daily life, highlighting differences in the psychological correlates of these states across the two contexts.
Our study used neuroimaging to further understand the generalizability of off-task thought across laboratory and daily life contexts.
We examined (1) whether context (daily life versus laboratory) impacts on individuals' off-task thought patterns and whether individual variations in these patterns are correlated across contexts; (2) whether neural correlates for the patterns of off-task thoughts in the laboratory show similarities with those thoughts in daily life, in particular, whether differences in cortical grey matter associated with detail and off-task thoughts in the para-hippocampus, identified in a prior study on laboratory thoughts, were apparent in real life thought patterns.
We also measured neural responses to common real-world stimuli (faces and scenes) and examined how neural responses to these stimuli were related to experiences in the laboratory and in daily life - finding evidence of both similarities and differences.
There were consistent patterns of off-task thoughts reported across the two contexts, and both patterns had a commensurate relationship with medial temporal lobe architecture.
However, compared to real world off-task thoughts, those in the laboratory focused more on social content and showed a stronger correlation with neural activity when viewing faces compared to scenes.
Overall our results show that off-task thought patterns have broad similarities in the laboratory and in daily life, and the apparent differences may be, in part, driven by the richer environmental context in the real world.
More generally, our findings are broadly consistent with emerging evidence that shows off-task thoughts emerge through the prioritisation of information that has greater personal relevance than events in the here and now. | 214,603,133 |
Title:
Hybrid-ALPPS followed by Ante Situm with Cardiopulmonary Bypass: Rapid Liver Augmentation and Complex Surgery
Abstract:
BACKGROUND ::: Tumors invading the inferior vena cava (IVC) and hepatic veins pose a challenge for surgeons.
Hannoun et al.1 were able to show that the resection of these tumors can be done under hypothermia in the Ante-Situm position.
Additionally, not only the localization of the tumor but the remaining volume of the remnant liver (FLR) needs to be considered.
Schnitzbauer et al.2 were able to induce massive liver hypertrophy in a short period, combining an in-situ split with a portal vein ligation (ALPPS).
As this controversial technique has evolved, a safe ALPPS can be performed nowadays.3 To our knowledge, this is the first case that combines a laparoscopic partial ALPPS with an extended resection requiring cardiopulmonary bypass (CPB). ::: ::: ::: METHODS ::: A 58-year-old female presented with a known chronic hepatitis C suffered from a pulmonary embolism, caused by a large, central hepatocellular carcinoma (HCC) with invasion of the suprahepatic IVC and continuous growth into the right atrium (RA).
Due to the small FLR, we performed a laparoscopic hybrid-partial-ALPPS with an embolization of the right portal vein.
We were able to remove the mass with an Ante-Situm position and resection of the RA under CPB. ::: ::: ::: RESULTS ::: The postoperative course was complicated by posthepatic liver failure and bleeding.
However, after 28 days the patient was discharged in a good medical condition. ::: ::: ::: CONCLUSIONS ::: Although tumors invading the suprahepatic IVC and RA pose a surgical challenge, patients can be treated adequately with multidisciplinary management.
Advanced HCCs have high recurrence rates; however, a R0 resection might improve overall survival.
Wakayma et al. showed in their retrospective study with 13 patients a median survival of 30.8 months when a complete resection was performed.4 Our patient had a disease-free survival of 11 months and is still alive after 24 months.
Taking the complexity of the operation and the oncological prospect with a probable recurrence into account, indication for surgery needs to be considered on an individual basis. | 214,606,738 |
Title:
Eliminating COVID-19: A Community-based Analysis
Abstract:
We analyze the spread of COVID-19 by considering the transmission of the disease among individuals both within and between communities.
A set of communities can be defined as any partition of a population such that travel/social contact within each community far exceeds that between them (e.g. the U.S. could be partitioned by state or commuting zone boundaries).
COVID-19 can be eliminated if the community-to-community reproductive number---i.e.
the expected/average number of other communities to which a single infected community will transmit the virus---is reduced to less than one.
We find that this community-to-community reproductive number is proportional to the travel rate between communities and exponential in the length of the time-delay before community-level action is taken.
Thus, reductions in travel and the speed at which communities take action can play decisive roles in stopping the outbreak.
The analysis suggests that for the coronavirus to be eliminated, it is not necessary to impose aggressive social distancing measures all over the world at once, but rather only in communities in which active spreading is detected.
The sooner such measures are imposed, the shorter the duration they must remain in place.
If infected communities (including those that become re-infected in the future) are quick enough to act, the number of actively infected communities (and thus the number of communities in which such measures are required) will exponentially decrease over time. | 214,612,018 |
Title:
Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection
Abstract:
SARS-CoV-2 causes the recent global COVID-19 public health emergency.
ACE2 is the receptor for both SARS-CoV-2 and SARS-CoV. To predict the potential host range of SARS-CoV-2, we analyzed the key residues of ACE2 for recognizing S protein.
We found that most of the selected mammals including pets (dog and cat), pangolin and Circetidae mammals remained the most of key residues for association with S protein from SARS-CoV and SARS-CoV-2.
The interaction interface between cat/dog/pangolin/Chinese hamster ACE2 and SARS-CoV/SARS-CoV-2 S protein was simulated through homology modeling.
We identified that N82 in ACE2 showed a closer contact with SARS-CoV-2 S protein than M82 in human ACE2.
Our finding will provide important insights into the host range of SARS-CoV-2 and a new strategy to design an optimized ACE2 for SARS-CoV-2 infection. | 214,616,384 |
Title:
Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS): a validation study in Italian population.
Abstract:
BACKGROUND ::: Although cognitive deficit in persons with schizophrenia is well documented, the assessment of the patient's perception of its own cognitive functioning is a relevant issue not adequately studied.
Several evaluation tools have been elaborated, however none has been validated in Italian.
The aim of the study is the validation of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), a rating scale designed to measure subjective cognitive deficits complaints in persons with schizophrenia.
< span class="text116">Method.
146 persons meeting the DSM-5 diagnostic criteria for schizophrenia have been recruited.
The SSTICS was translated in Italian in accordance with international standard methods.
Subjects were also evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Subjective Well-being under Neuroleptic scale (SWN).
Cronbach's alpha coefficient was used to assess internal consistency.
Constructs were examined using exploratory factor analysis (principal component with varimax rotation).
The factorial model was then tested via confirmatory factor analysis.
::: ::: ::: RESULTS ::: The factorial analysis revealed a 4-factor structure, which is more parsimonious than those obtained in previous studies.
Correlations between STICSS and the other rating scales were significant for several domains.
::: ::: ::: CONCLUSIONS ::: The Italian version of the SSTICS showed good psychometric properties and is suitable to measure the patients' subjective perception of cognitive impairment.
Subjective evaluation can integrate objective measures of cognitive performances, supporting a multidimensional model of functional impairment in schizophrenia. | 214,617,725 |
Title:
A metabolic network-based approach for developing feeding strategies for CHO cells to increase monoclonal antibody production
Abstract:
Chinese hamster ovary (CHO) cells are the main workhorse in the biopharmaceutical industry for the production of recombinant proteins, such as monoclonal antibodies.
To date, a variety of metabolic engineering approaches have been used to improve the productivity of CHO cells.
While genetic manipulations are potentially laborious in mammalian cells, rational design of CHO cell culture medium or efficient fed-batch strategies are more popular approaches for bioprocess optimization.
In this study, a genome-scale metabolic network model of CHO cells was used to design feeding strategies for CHO cells to improve monoclonal antibody (mAb) production.
A number of metabolites, including threonine and arachidonate, were suggested by the model to be added into cell culture medium.
The designed composition has been experimentally validated, and then optimized, using design of experiment methods.
About a two-fold increase in the total mAb expression has been observed using this strategy.
Our approach can be used in similar bioprocess optimization problems, to suggest new ways of increasing production in different cell factories. | 214,618,322 |
Title:
Breast Cancer Presentation, Surgical Management and Mortality Across the Rural–Urban Continuum in the National Cancer Database
Abstract:
OBJECTIVE ::: The purpose of this study was to examine differences in presentation, surgical management, and mortality among breast cancer patients in the National Cancer Database (NCDB) based on area of residence. ::: ::: ::: METHODS ::: The NCDB was queried for women with a diagnosis of breast cancer from 1 January 2004-31 December 2015.
The data were divided by metropolitan (large, medium, small) and non-metropolitan (urban, rural) status. ::: ::: ::: RESULTS ::: Cancer stage increased with rurality (p < 0.0001).
Residency in a large metropolitan area was associated with increased breast reconstruction rates (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.19-1.30) and reduced overall mortality (hazard ratio 0.92, 95% CI 0.89-0.95) compared with rural areas.
There was no difference in mastectomy use among small metropolitan (OR 1.03, 95% CI 1.01-1.04), urban (OR 0.99, 95% CI 0.98-1), and rural areas (OR 1.05, 95% CI 1.01-1.07) compared with large metropolitan areas. ::: ::: ::: CONCLUSIONS ::: Across the rural-urban continuum in the NCDB, stage of cancer presentation increased with rurality.
Conversely, residency in a large metropolitan area was associated with higher reconstruction rates and a reduction in overall mortality.
Future studies should evaluate factors contributing to advanced disease presentation and lower reconstruction rates among rural breast cancer patients. | 214,618,390 |
Title:
Seasonal Occurrence and Relative Abundance of Fishes and Macroinvertebrates in Pleasant Bay (Massachusetts)
Abstract:
Abstract Pleasant Bay, MA, is a coastal lagoon system featuring diverse habitats that support a variety of commercially, recreationally, and ecologically important marine species.
In response to ecosystem changes noted by natural resource managers, we conducted an inventory of commercially and recreationally important shellfish and finfish in the bay from 2014 to 2017, the first such survey to be conducted since 1966.
Fish and macroinvertebrate community composition and seasonal patterns of abundance during this study were broadly similar to those observed during other recent studies along the eastern shore of Cape Cod.
This comprehensive inventory indicated that Pleasant Bay is home to a diverse and changing assemblage of marine species, some of which utilize the bay as spawning or nursery habitat.
Long-term monitoring is necessary to place our observations in the broader contexts of short-term variability and long-term change. | 214,624,812 |
Title:
A brief history of CAR-T cells: from laboratory to the bedside
Abstract:
Abstract Chimeric antigen receptors (CARs) are genetically engineered receptors that provide specific properties to an immune effector cell and these receptors gain the specificity of a monoclonal antibody targeted against specific tumor cells.
T cells with engineered CARs acquire potent immunological properties and redirect the immune system in order to eliminate malignant cells.
First-engineered T cells with chimeric molecule (CAR-T cells) were developed in 1989–1993 by Israeli immunologists Zelig Eshhar and Gideon Gross.
The first clinical application of CAR-T cells was done in the University of Pennsylvania and Children’s Hospital in Philadelphia by the immunologist Carl June and hematologist David Porter to patients with chronic lymphocytic leukemia in 2011 and together with the pediatrician Stephan Grupp to patients with acute lymphoblastic leukemia (ALL) in 2012.
The US Food and Drug Administration Agency (FDA) in 2017 and the European Medicines Agency (EMA) in 2018 have licensed two products of CAR-T cells: tisagenlecleucel for the use in children and young adults up to 25 years of age with B-cell ALL who do not respond to treatment or have relapsed two or more times and tisagenlecleucel and axicabtagene ciloleucel for the use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Current progress in CAR technology includes the use in other hematological malignancies, solid tumors, the use of dual CAR-T cells and chimeric antigen receptor natural killer cells (CAR-NK cells). | 214,625,177 |
Title:
Coronavirus disease 2019: initial chest CT findings
Abstract:
OBJECTIVES: To systematically analyze CT findings during the early and progressive stages of natural course of coronavirus disease 2019 and also to explore possible changes in pulmonary parenchymal abnormalities during these two stages.
METHODS: We retrospectively reviewed the initial chest CT data of 62 confirmed coronavirus disease 2019 patients (34 men, 28 women; age range 20-91 years old) who did not receive any antiviral treatment between January 21 and February 4, 2020, in Chongqing, China.
Patients were assigned to the early-stage group (onset of symptoms within 4 days) or progressive-stage group (onset of symptoms within 4-7 days) for analysis.
CT characteristics and the distribution, size, and CT score of pulmonary parenchymal abnormalities were assessed.
RESULTS: In our study, the major characteristic of coronavirus disease 2019 was ground-glass opacity (61.3%), followed by ground-glass opacity with consolidation (35.5%), rounded opacities (25.8%), a crazy-paving pattern (25.8%), and an air bronchogram (22.6%).
No patient presented cavitation, a reticular pattern, or bronchial wall thickening.
The CT scores of the progressive-stage group were significantly greater than those of the early-stage group (p = 0.004).
CONCLUSIONS: Multiple ground-glass opacities with consolidations in the periphery of the lungs were the primary CT characteristic of coronavirus disease 2019.
CT score can be used to evaluate the severity of the disease.
If these typical alterations are found, then the differential diagnosis of coronavirus disease 2019 must be considered.
KEY POINTS: • Multiple GGOs with consolidations in the periphery of the lungs were the primary CT characteristic of COVID-19.
• The halo sign may be a special CT feature in the early-stage COVID-19 patients.
• Significantly increased CT score may indicate the aggravation of COVID-19 in the progressive stage. | 214,632,840 |
Title:
Factors affecting serum lactate in patients with intracranial tumors – A report of our series and review of the literature
Abstract:
Background ::: A hyperlactemia may occur in the presence of tissue hypoperfusion, in diseases affecting metabolism and in cases of malignant neoplasm.
However, the factors affecting the serum lactate levels in patients submitted to craniotomy for the resection of an intracranial tumor have been investigated only marginally.
Here, we assessed the factors possibly affecting the levels of serum lactate in intracranial tumors and carried out a thorough literature review on this topic. ::: ::: ::: Methods ::: All patients submitted to elective craniotomy from January 2017 to August 2018 for the resection of a glioblastoma (GBM; 101 cases) and a benign meningioma (WHO I; 105 cases) were included in this study.
The sex, age, histological diagnosis, body mass index (BMI), and diabetes were assessed as possible factors affecting the level of the preoperative and postoperative serum lactate in these patients.
::: ::: ::: Results ::: We found that preoperative hyperlactemia (> 2 mmol/l) was more frequent in patients with GBM than in patients with meningioma (P = 0.0003).
Moreover, a strong correlation between a preoperative lactemia and postoperative lactemia (P < 0.0001) was observed.
On univariate analysis, we found increased preoperative serum lactate levels in GBM patients (P = 0.0022) and in patients with a BMI ≥30 (P = 0.0068).
Postoperative serum lactate levels were significantly higher in GBM patients (P = 0.0003).
On multivariate logistic regression analysis, a diagnosis of GBM was an independent factor for higher level of preoperative (P = 0.0005) and postoperative (P < 0.0001) serum lactate. ::: ::: ::: Conclusion ::: The malignant phenotype of GBM is the strongest factor associated with a pre- and postoperative hyperlactemia in patients submitted to craniotomy for the resection of an intracranial tumor. | 214,639,081 |
Title:
Herd immunity – estimating the level required to halt the COVID-19 epidemics in affected countries
Abstract:
Previous workers have attempted to predict the cumulative number of cases of Coronavirus Disease 2019 (COVID-19) in China.1 However, since then, the epidemic has rapidly evolved into a pandemic affecting multiple countries worlwide.2 There have been serious debates about how to react to the spread of this disease, particularly by European countries, such as Italy, Spain, Germany, France and the UK, e.g. from closing schools and universities to locking down entire cities and countries.
An alternative strategy would be to allow the causal virus (SARS-CoV-2) to spread to increase the population herd immunity, but at the same time protecting the elderly and those with multiple comorbidities, who are the most vulnerable to this virus.3 Before initiating either of these strategies, we need to estimate the basic reproductive number (R0), or the more ‘real-life’ effective reproductive number (Rt) for a given population.
R0 is the number of secondary cases generated by the presence of one infected individual in an otherwise fully susceptible, well-mixed population.
Rt is a more practical real-life version of this, which uses real-life data (from diagnostic testing and/or clinical surveillance) to estimate the reproductive number for an ongoing epidemic.
For this anaylsis, we will estimate Rt, and we can do this by applying the exponential growth method,4 using data on the daily number of new COVID-19 cases, together with a recent estimate of the serial interval (mean=4.7 days, standard deviation=2.9 days),5 at a 0.05 significance level, with the mathematical software R (v3.6.1.).
Using these values of Rt, we can then calculate the minimum (‘critical’) level of population immunity, Pcrit, acquired via vaccination or naturally-induced (i.e. after recovery from COVID-19), to halt the spread of infection in that population, using the formula: Pcrit=1-(1/Rt).
So, for example, if the value of Rt=3 then Pcrit=0.67, i.e. at least two-thirds of the population need to be immune.6 As of 13 March 2020, there were 32 countries outside China with over 100 COVID-19 cases.7 The seven countries with the highest number of infections were: the United States (n=2294), France (n=3671), Germany (n=3675), Spain (n=5232), Korea (n=8086), Iran (n=11364) and Italy (n=17660).
The number of confirmed cases in the other 25 countries were less than 1200 (Table 1).[Truncated] | 214,644,723 |
Title:
DeepMILO: a deep learning approach to predict the impact of non-coding sequence variants on 3D chromatin structure
Abstract:
Non-coding variants have been shown to be related to disease by alteration of 3D genome structures.
We propose a deep learning method, DeepMILO, to predict the effects of variants on CTCF/cohesin-mediated insulator loops.
Application of DeepMILO on variants from whole-genome sequences of 1834 patients of twelve cancer types revealed 672 insulator loops disrupted in at least 10% of patients.
Our results show mutations at loop anchors are associated with upregulation of the cancer driver genes BCL2 and MYC in malignant lymphoma thus pointing to a possible new mechanism for their dysregulation via alteration of insulator loops. | 214,648,225 |
Title:
How decisions and the desire for coherency shape subjective preferences over time
Abstract:
Recent findings suggest a bidirectional relationship between preferences and choices such that what is chosen can become preferred.
Yet, it is still commonly held that preferences for individual items are maintained, such as caching a separate value estimate for each experienced option.
Instead, we propose that all possible choice options and preferences are represented in a shared, continuous, multidimensional space that supports generalization.
Decision making is cast as a learning process that seeks to align choices and preferences to maintain coherency.
We formalized an error-driven learning model that updates preferences to align with past choices, which makes repeating those and related choices more likely in the future.
The model correctly predicts that making a free choice increases preferences along related attributes.
For example, after choosing a political candidate based on trivial information (e.g., they like cats), voters' views on abortion, immigration, and trade subsequently shifted to match their chosen candidate. | 214,659,256 |
Title:
Covid-19: Automatic detection from X-Ray images utilizing Transfer Learning with Convolutional Neural Networks
Abstract:
In this study, a dataset of X-ray images from patients with common bacterial pneumonia, confirmed Covid-19 disease, and normal incidents, was utilized for the automatic detection of the Coronavirus disease.
The aim of the study is to evaluate the performance of state-of-the-art convolutional neural network architectures proposed over the recent years for medical image classification.
Specifically, the procedure called Transfer Learning was adopted.
With transfer learning, the detection of various abnormalities in small medical image datasets is an achievable target, often yielding remarkable results.
The datasets utilized in this experiment are two.
Firstly, a collection of 1427 X-ray images including 224 images with confirmed Covid-19 disease, 700 images with confirmed common bacterial pneumonia, and 504 images of normal conditions.
Secondly, a dataset including 224 images with confirmed Covid-19 disease, 714 images with confirmed bacterial and viral pneumonia, and 504 images of normal conditions.
The data was collected from the available X-ray images on public medical repositories.
The results suggest that Deep Learning with X-ray imaging may extract significant biomarkers related to the Covid-19 disease, while the best accuracy, sensitivity, and specificity obtained is 96.78%, 98.66%, and 96.46% respectively.
Since by now, all diagnostic tests show failure rates such as to raise concerns, the probability of incorporating X-rays into the diagnosis of the disease could be assessed by the medical community, based on the findings, while more research to evaluate the X-ray approach from different aspects may be conducted. | 214,667,149 |
Title:
An update on COVID-19 for the radiologist - A British society of Thoracic Imaging statement
Abstract:
In December 2019, Wuhan City (Hubei Province, China) reported a febrile respiratory tract illness of unknown origin in a cluster of patients.
Bronchoalveolar lavage of the patients isolated a novel strain of coronavirus (SARS-coronavirus-2 [SARS-CoV-2]) as the pathogen.1 The pulmonary infection caused by SARS-CoV-2 was named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO).
As of 14 March 2020, the WHO reported 142,651 worldwide cases with 5,393 deaths.2 Despite the imposition of strict quarantine rules and restricted travel within and from China, the infection has spread rapidly affecting countries worldwide.
It continues to escalate.
As of 14 March 2020, 797 UK cases have been confirmed, with 10 deaths.3 Testing currently involves a laboratory test from swab samples obtained from the respiratory tract (most commonly a single nose and throat swab).
The WHO currently classifies cases into three potential categories: (1) suspected, (2) probable, and (3) confirmed.
Suspected cases are primarily those with a febrile respiratory illness and history of travel to a country or region reporting local transmission of COVID-19 disease during the 14 days prior to symptom onset.
In the past few weeks, changes to diagnostic criteria (using imaging as an adjunct to real-time transcriptase polymerase chain reaction [RT-PCR]) has led to an increase in reported cases.
Clinical presentation of COVID-19 The majority of patients present with a lower respiratory tract infection comprising fever, cough, dyspnoea, and myalgia.
Although most patients have a mild illness, 17–29% of patients are reported to develop acute respiratory distress syndrome (ARDS).4,5 Mortality rates are estimated at 3.6%.6 An elevated C-reactive protein (CRP) and lymphopenia (<1,100 μ/L) are characteristic7 Radiology departments should be prepared for an increase in the number of cases of COVID-19 and new diagnoses or risk stratification may be imaging based.
As such, it is important for radiologists to be familiar with the potential spectrum of imaging findings, as well as set out protocols to limit contamination and spread.
Chest imaging findings in COVID-19 Initial findings Initial imaging with chest radiograph (CXR) and computed tomography (CT) may be normal in COVID-19.
Disease severity and timing of imaging appear to impact on the rates of normal baseline imaging.
In non-severe disease, up to 18% of patients have a normal initial CXR or CT, but only 3% in severe disease.8 In a series of 121 symptomatic patients, a normal CT was found in 56% of patients scanned within 2 days of symptom onset, whereas normal scans were observed in only 9% and 4% of patients if imaged 3–5 days or 6–12 days from symptoms, respectively.9 Therefore, radiographic abnormalities are almost certain to be present on CT following 6 days of symptoms.
Furthermore, Shi et al. have reported radiological abnormality, predominantly ground-glass opacity (GGO), in subclinical disease, where 15 patients were imaged using CT before symptom onset.10 As such, the precise time when imaging becomes abnormal is heterogeneous and the disease should not be excluded based on a normal CT examination acquired early after symptom onset.
When imaging is abnormal, there are some common features.
CXR typically shows patchy or diffuse asymmetric airspace opacities, similar to other causes of coronavirus pneumonias.4 The most common initial CT findings of COVID-19 pneumonia are bilateral, subpleural GGO, ill-defined margins, and a slight right lower lobe predilection10; however, the initial imaging findings are not organism specific and can overlap with H1N1 influenza, cytomegalovirus pneumonia, and other atypical pneumonias11 Temporal evolution of findings With increased time between symptom onset and imaging, the pattern of radiological findings progresses from focal unilateral abnormality to diffuse bilateral opacities with evolution to consolidation, reticulation, and mixed-pattern disease involving more lung segments.10 The pattern of CT disease may have prognostic implications, with consolidation being reported in nearly all patients requiring intensive care unit (ICU) support and GGO in those not requiring ICU.5 “Crazy-paving” pattern and the “atoll” sign is also reported with greater time from symptom onset.9 In a cohort of 21 patients with COVID-19 who recovered, late-stage CT findings (14 days or longer) showed varying degrees of clearing but signs may persist for more than 1 month after initial detection.12 Uncommon imaging findings Imaging features that are only rarely encountered include pneumothorax, cavitation, or lymphadenopathy.13 Features such as pleural effusion, extensive tiny lung nodules, tree in bud, and lymphadenopathy may well suggest bacterial superinfection or an alternative diagnosis.14 | 214,683,286 |
Title:
Feasibility of autologous fibrin glue in general thoracic surgery.
Abstract:
Background ::: Fibrin glue effectively controls air leakage in lung surgery; however, allogenic fibrin glue cannot eliminate the risks of infection and allergy despite current sterilization methods.
Autologous fibrin glue (AFG) could be a good alternative, but is not commonly used worldwide because of its limited availability and lack of evidence.
Herein, we report clinical outcomes of AFG in thoracic surgery. ::: ::: ::: Methods ::: We retrospectively analyzed patients who underwent lobectomies or segmentectomies between November 2016 and September 2017 in our institution.
We used two types of AFGs.
One was a partially-autologous fibrin glue (PAFG), the components of which are largely autologous but which contains allogenic thrombin.
The other was a completely-autologous fibrin glue (CAFG) which has no allogenic components.
PAFG was used in the first half of the study period, after which CAFG was used from March 2017 onward.
Patients who did not undergo AFG generation were categorized as the non-AFG group.
The perioperative outcomes of the three groups were evaluated.
::: ::: ::: Results ::: A total of 207 patients underwent lung surgery, including 118 lobectomies and 89 segmentectomies.
Among them, 83 patients received PAFG, 94 received CAFG, and 30 received non-AFG.
The mean postoperative drainage period was within a few days in each group (PAFG vs. CAFG vs. non-AFG: 3.23±3.91 vs. 3.16±4.04 vs. 3.17±4.16 days, respectively; P=0.405), and the incidence of postoperative prolonged air leakage was within an acceptable range (PAFG vs. CAFG vs. non-AFG: 13.3% vs. 12.8% vs. 16.7%, respectively; P=0.821). ::: ::: ::: Conclusions ::: The use of AFG is clinically feasible for patients who undergo lobectomies or segmentectomies.
AFGs could be a viable alternative to conventional allogenic fibrin glues. | 214,685,928 |
Title:
Formulation of moment equations for rarefied gases within two frameworks of non-equilibrium thermodynamics: RET and GENERIC
Abstract:
In this work, we make a further step in bringing together different approaches to non-equilibrium thermodynamics.
The structure of the moment hierarchy derived from the Boltzmann equation is at the heart of rational extended thermodynamics (RET, developed by Ingo Müller and Tommaso Ruggeri).
Whereas the full moment hierarchy has the structure expressed in the general equation for the nonequilibrium reversible–irreversible coup- ling (GENERIC), the Poisson bracket structure of reversible dynamics postulated in that approach is a major obstacle for truncating moment hierarchies, which seems to work only in exceptional cases (most importantly, for the five moments associated with conservation laws).
The practical importance of truncated moment hierarchies in rarefied gas dynamics and microfluidics motivates us to develop a new strategy for establishing the full GENERIC structure of truncated moment equations, based on non-entropy-producing irreversible processes associated with Casimir symmetry.
Detailed results are given for the special case of 10 moments.
This article is part of the theme issue ‘Fundamental aspects of nonequilibrium thermodynamics’. | 214,693,449 |
Title:
Continuum thermomechanics of nonlinear micromorphic, strain and stress gradient media
Abstract:
A comprehensive constitutive theory for the thermo-mechanical behaviour of generalized continua is established within the framework of continuum thermodynamics of irreversible processes.
It represents an extension of the class of generalized standard materials to higher order and higher grade continuum theories.
It reconciles most existing frameworks and proposes some new extensions for micromorphic and strain gradient media.
The special case of strain gradient plasticity is also included as a contribution to the current debate on the consideration of energetic and dissipative mechanisms.
Finally, the stress gradient continuum theory emerges as a new research field for which an elastic-viscoplastic theory at finite deformations is provided for the first time.
This article is part of the theme issue ‘Fundamental aspects of nonequilibrium thermodynamics’. | 214,693,455 |
Title:
Time–energy uncertainty principle for irreversible heat engines
Abstract:
Even though irreversibility is one of the major hallmarks of any real-life process, an actual understanding of irreversible processes remains still mostly semi-empirical.
In this paper, we formulate a thermodynamic uncertainty principle for irreversible heat engines operating with an ideal gas as a working medium.
In particular, we show that the time needed to run through such an irreversible cycle multiplied by the irreversible work lost in the cycle is bounded from below by an irreducible and process-dependent constant that has the dimension of an action.
The constant in question depends on a typical scale of the process and becomes comparable to Planck’s constant at the length scale of the order Bohr radius, i.e. the scale that corresponds to the smallest distance on which the ideal gas paradigm realistically applies.
This article is part of the theme issue ‘Fundamental aspects of nonequilibrium thermodynamics’. | 214,693,465 |
Title:
Nonlinear Luttinger liquid plasmons in semiconducting single-walled carbon nanotubes
Abstract:
Interacting electrons confined in one dimension are generally described by the Luttinger liquid formalism, where the low-energy electronic dispersion is assumed to be linear and the resulting plasmonic excitations are non-interacting.
Instead, a Luttinger liquid in one-dimensional materials with nonlinear electronic bands is expected to show strong plasmon-plasmon interactions, but an experimental demonstration of this behaviour has been lacking.
Here, we combine infrared nano-imaging and electronic transport to investigate the behaviour of plasmonic excitations in semiconducting single-walled carbon nanotubes with carrier density controlled by electrostatic gating.
We show that both the propagation velocity and the dynamic damping of plasmons can be tuned continuously, which is well captured by the nonlinear Luttinger liquid theory.
These results contrast with the gate-independent plasmons observed in metallic nanotubes, as expected for a linear Luttinger liquid.
Our findings provide an experimental demonstration of one-dimensional electron dynamics beyond the conventional linear Luttinger liquid paradigm and are important for understanding excited-state properties in one dimension. | 214,704,521 |
Title:
On the Evolution of Covid-19 in Italy: a Follow up Note
Abstract:
In a previous note we made an analysis of the spreading of the COVID disease in Italy.
We used a model based on the logistic and Hubbert functions, the analysis we exploited has shown limited usefulness in terms of predictions and failed in fixing fundamental indications like the point of inflection of the disease growth.
In this note we elaborate on the previous model, using multi-logistic models and attempt a more realistic analysis. | 214,714,093 |
Title:
Analysis of Surgical Trends for Axillary Lymph Node Management in Patients with Ductal Carcinoma In Situ Using the NSQIP Database: Are We Following National Guidelines?
Abstract:
BACKGROUND ::: For patients with ductal carcinoma in situ (DCIS), multiple national cancer organizations recommend that sentinel lymph node biopsy (SLNB) be offered when treated with mastectomy, but not when treated with breast-conserving surgery (BCS).
This study analyzes national surgical trends of SLNB and axillary lymph node dissection (ALND) in DCIS patients undergoing breast surgery with the aim to quantify deviations from national guidelines.
::: ::: ::: METHODS ::: A retrospective cohort analysis of the American College of Surgeons' National Surgical Quality Improvement Program (ACS NSQIP) database from 2005 to 2017 identified patients with DCIS.
Patients were categorized by their primary method of breast surgery, i.e. mastectomy or BCS, then further categorized by their axillary lymph node (ALN) management, i.e. no intervention, SLNB, or ALND.
Data analysis was conducted via linear regression and a non-parametric Mann-Kendall test to assess a temporal trend and Sen's slope. ::: ::: ::: RESULTS ::: Overall, 43,448 patients with DCIS met the inclusion criteria: 20,504 underwent mastectomy and 22,944 underwent BCS.
Analysis of DCIS patients from 2005 to 2017 revealed that ALND decreased and SLNB increased in every subgroup, regardless of surgical treatment modality.
Evaluation in the mastectomy group increased overall: mastectomy alone increased from 57.1 to 65.8% (p < 0.01) and mastectomy with immediate reconstruction increased from 58.5 to 72.1% (p < 0.01).
Increases also occurred in the total BCS population: partial mastectomy increased from 14.0 to 21.1% and oncoplastic surgery increased from 10.5 to 23.0% (both p < 0.01). ::: ::: ::: CONCLUSIONS ::: Despite national guideline recommendations for the management of ALN surgery in DCIS patients, approximately 20-30% of cases continue to not follow these guidelines.
This warrants further education for surgeons and patients. | 214,715,201 |
Title:
On the impact of the pangenome and annotation discrepancies while building protein sequence databases for bacteria proteogenomics
Abstract:
In proteomics, peptide information within mass spectrometry data from a specific organism sample is routinely challenged against a protein sequence database that best represent such organism.
However, if the species/strain in the sample is unknown or poorly genetically characterized, it becomes challenging to determine a database which can represent such sample.
Building customized protein sequence databases merging multiple strains for a given species has become a strategy to overcome such restrictions.
However, as more genetic information is publicly available and interesting genetic features such as the existence of pan- and core genes within a species are revealed, we questioned how efficient such merging strategies are to report relevant information.
To test this assumption, we constructed databases containing conserved and unique sequences for ten different species.
Features that are relevant for probabilistic-based protein identification by proteomics were then monitored.
As expected, increase in database complexity correlates with pangenomic complexity.
However, Mycobacterium tuberculosis and Bortedella pertusis generated very complex databases even having low pangenomic complexity or no pangenome at all.
This suggests that discrepancies in gene annotation is higher than average between strains of those species.
We further tested database performance by using mass spectrometry data from eight clinical strains from Mycobacterium tuberculosis, and from two published datasets from Staphylococcus aureus.
We show that by using an approach where database size is controlled by removing repeated identical tryptic sequences across strains/species, computational time can be reduced drastically as database complexity increases. | 214,722,042 |
Title:
A hierarchical watershed model of fluid intelligence in childhood and adolescence
Abstract:
Fluid intelligence is the capacity to solve novel problems in the absence of task-specific knowledge, and is highly predictive of outcomes like educational attainment and psychopathology.
Here, we modelled the neurocognitive architecture of fluid intelligence in two cohorts: CALM (N = 551, aged 5 - 17 years) and NKI-RS (N = 335, aged 6 - 17 years).
We used multivariate Structural Equation Modelling to test a preregistered watershed model of fluid intelligence.
This model predicts that white matter contributes to intermediate cognitive phenotypes, like working memory and processing speed, which, in turn, contribute to fluid intelligence.
We found that this model performed well for both samples and explained large amounts of variance in fluid intelligence (R2CALM = 51.2%, R2NKI-RS = 78.3%).
The relationship between cognitive abilities and white matter differed with age, showing a dip in strength around ages 7 - 12 years.
This age-effect may reflect a reorganization of the neurocognitive architecture around pre- and early puberty.
Overall, these findings highlight that intelligence is part of a complex hierarchical system of partially independent effects. | 214,722,395 |
Title:
Genome structure predicts modular transcriptome responses to genetic and environmental conditions
Abstract:
Understanding the plasticity, robustness, and modularity of transcriptome expression to genetic and environmental conditions is crucial to deciphering how organisms adapt in nature.
To test how genome architecture influences transcriptome profiles, we quantified expression responses for distinct temperature-adapted genotypes of the nematode Caenorhabditis briggsae when exposed to chronic temperature stresses throughout development.
We found that 56% of the 8795 differentially-expressed genes show genotype-specific changes in expression in response to temperature (genotype-by-environment interactions, GxE).
Most genotype-specific responses occur under heat stress, indicating that cold versus heat stress responses involve distinct genomic architectures.
The 22 co-expression modules that we identified differ in their enrichment of genes with genetic versus environmental versus interaction effects, as well as their genomic spatial distributions, functional attributes, and rates of molecular evolution at the sequence level.
Genes in modules enriched for simple effects of either genotype or temperature alone tend to evolve especially rapidly, consistent with disproportionate influence of adaptation or weaker constraint on these subsets of loci.
Chromosome scale heterogeneity in nucleotide polymorphism, however, rather than the scale of individual genes, predominate as the source of genetic differences among expression profiles, and natural selection regimes are largely decoupled between coding sequences and non-coding flanking sequences that contain cis-regulatory elements.
These results illustrate how the form of transcriptome modularity and genome structure contribute to predictable profiles of evolutionary change. | 214,722,490 |
Title:
Strong selective sweeps on the X chromosome in the human-chimpanzee ancestor explain its low divergence
Abstract:
The human and chimpanzee X chromosomes are less divergent than expected based on autosomal divergence.
This has led to a controversial hypothesis proposing a unique role of the X chromosome in human-chimpanzee speciation.
We study incomplete lineage sorting patterns between humans, chimpanzees and gorillas to show that this low divergence is entirely due to megabase-sized regions comprising one-third of the X chromosome, where polymorphism in the human-chimpanzee ancestral species was severely reduced.
Background selection can explain 10% of this reduction at most.
Instead, we show that several strong selective sweeps in the ancestral species can explain this reduction of diversity in the ancestor.
We also report evidence of population specific sweeps in extant humans that overlap the regions of low diversity in the ancestral species.
These regions further correspond to chromosomal sections shown to be devoid of Neanderthal introgression into modern humans.
This suggests that the same X-linked regions that undergo selective sweeps are among the first to form reproductive barriers between diverging species.
We hypothesize that meiotic drive is the underlying mechanism causing these two observations.
Authors' Summary Because the speciation events that leads to human, chimpanzee and gorilla were close in time, their genetic relationship of these species varies along the genome.
While human and chimpanzee species are most closely related, 15% of the human genome is more closely related to the gorilla genome than the chimpanzee genome, a phenomenon called incomplete lineage sorting (ILS).
The amount and distribution of ILS can be predicted using population genetics theory, and is affected by demography and selection in the ancestral populations.
It was previously reported that the X chromosome, in contrast to autosomes, is deprived of ILS, and this givies rise to controversial theories about the speciation event that splits humans and chimpanzees.
Using a full genome alignment of the X chromosome, we show that this deprivation of ILS affects only one third of the chromosome.
These regions also show reduced diversity in the extant populations of human and great apes, and coincide with regions devoid of Neanderthal introgression.
We propose that these regions are targets of selection and that they played a role in the formation of reproductive barriers. | 214,723,019 |
Title:
Position information encoded by population activity in hierarchical visual areas
Abstract:
Neurons in high-level visual areas respond to more complex visual features with broader receptive fields (RFs) compared to those in low-level visual areas.
Thus, high-level visual areas are generally considered to carry less information regarding the position of seen objects in the visual field.
However, larger RFs may not imply loss of position information at the population level.
Here, we evaluated how accurately the position of a seen object could be predicted (decoded) from activity patterns in each of six representative visual areas with different RF sizes (V1–V4, LOC, and FFA).
We collected fMRI responses while human subjects viewed a ball randomly moving in a two-dimensional field.
To estimate population RF sizes of individual fMRI voxels, RF models were fitted for individual voxels in each brain area.
The voxels in higher visual areas showed larger estimated RFs than those in lower visual areas.
Then, the ball’s position in a separate session was predicted by maximum likelihood regression (support vector regression, SVR) to predict the position.
We found that regardless of the difference in RF size, all visual areas showed similar prediction accuracies, especially on the horizontal dimension.
Higher areas showed slightly lower accuracies on the vertical dimension, which appears to be attributed to the narrower spatial distributions of the RFs centers.
The results suggest that much of position information is preserved in population activity through the hierarchical visual pathway regardless of RF sizes, and is potentially available in later processing for recognition and behavior.
Significance statement High-level ventral visual areas are thought to achieve position invariance with larger receptive fields at the cost of the loss of precise position information.
However, larger receptive fields may not imply loss of position information at the population level.
Here, multivoxel fMRI decoding reveals that high-level visual areas are predictive of an object’s position with similar accuracies to low-level visual areas, especially on the horizontal dimension, preserving the information potentially available for later processing. | 214,723,097 |
Title:
Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hypocretin/Orexin receptor 1-KO mice
Abstract:
Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities.
Salient stimuli activate spiking of locus coeruleus noradrenergic (NALC) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response.
Hypothalamic HCRT neurons provide one of the densest input to NALC cells.
To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1Dbh-CKO) mice’, and their control littermates’ electrocortical response in several contexts of enhanced arousal.
Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1Dbh-CKO mice exhibited a weakened ability to lower infra-θ frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz).
A fast-γ (55-80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15-45 Hz) increased.
Furthermore, EW-associated locomotion was lower.
Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ activities.
Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors.
Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-δ waves (0.75-2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal. | 214,723,241 |
Title:
Wild-type U2AF1 antagonizes the splicing program characteristic of U2AF1-mutant tumors and is required for cell survival
Abstract:
We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation.
A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci.
By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor.
Preferential recognition of specific 3′ splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3′ splice sites.
Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo.
In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele.
Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele.
Author Summary Large-scale genomics studies have identified recurrent mutations in many genes that fall outside the conventional domain of proto-oncogenes.
They include genes encoding factors that mediate RNA splicing; mutations affecting four of these genes are present in up to half of proliferative myeloid disorders and in a significant number of solid tumors, including lung adenocarcinoma.
Here we have characterized several properties of a common mutant version of the U2AF1 splicing factor, a component of the U2 auxiliary factor complex, in lung cells.
We have found that mutant-associated changes in splice site selection are primarily influenced by the ratio of mutant and wild-type U2AF1 gene products; thus increasing wild-type U2AF1 levels represses the mutant-induced splicing program.
We show that the altered splice site preferences of mutant U2AF1 can be attributed to changes in its binding to relevant 3′ splice sites.
We also show that mutant U2AF1 is different from some oncogenes: the growth properties of lung cancer cell lines carrying the mutant allele are unaffected by loss of the mutant gene, while the wild-type allele is absolutely required for survival.
These results advance our understanding of the molecular determinants of the mutant-associated splicing program, and they highlight previously unappreciated roles of wild-type U2AF1 in the presence of the recurrent U2AF1S34F mutation. | 214,723,405 |
Title:
Fine-tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides
Abstract:
Determination of RNA structural-dynamic properties is challenging for experimental methods.
Thus atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments.
However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the non-bonded ff terms.
We have recently demonstrated that some improvement of state-of-the-art AMBER RNA ff can be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces the risk of side-effects.
Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs).
TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to over-fitting to A-form RNA.
Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides.
This allows to refine simulations of RNA TNs without affecting simulations of other RNAs.
The approach is in line with adopted strategy of current RNA ffs, where the terminal nucleotides possess different parameters for the terminal atoms than the internal nucleotides.
The combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations.
TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed.
Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with the primary NMR data which suggests that future tuning of some other ff terms might be useful. | 214,723,598 |
Title:
Combining tensor decomposition and time warping models for multi-neuronal spike train analysis
Abstract:
Recordings from large neural populations are becoming an increasingly popular and accessible method in experimental neuroscience.
While the activity of individual neurons is often too stochastic to interrogate circuit function on a moment-by-moment basis, multi-neuronal recordings enable us to do so by pooling statistical power across many cells.
For example, groups of neurons often exhibit correlated gain or amplitude modulation across trials, which can be statistically formalized in a tensor decomposition framework (Williams et al. 2018).
Additionally, the time course of neural population dynamics can be shifted or stretched/compressed, which can be modeled by time warping methods (Williams et al. 2019).
Here, we compare and contrast these two modeling frameworks and demonstrate how they can be combined.
We demonstrate that combining these methods may be highly advantageous—for example, the presence of random time shifts hampers the performance and interpretability of tensor decomposition, while a time-shifted variant of this model corrects for these disruptions and uncovers ground truth structure in simulated data. | 214,724,447 |
Title:
Molecular phylogenetics supports a clade of red algal parasites retaining native plastids: taxonomy and terminology revised
Abstract:
Parasitism is a life strategy that has repeatedly evolved within the Florideophyceae.
Historically, the terms adelphoparasite and alloparasite have been used to distinguish parasites based on the relative phylogenetic relationship of host and parasite.
However, analyses using molecular phylogenetics indicate that nearly all red algal parasites infect within their taxonomic family, and a range of relationships exist between host and parasite.
To date, all investigated adelphoparasites have lost their plastid, and instead, incorporate a host derived plastid when packaging spores.
In contrast, a highly reduced plastid lacking photosynthesis genes was sequenced from the alloparasite Choreocolax polysiphoniae.
Here we present the complete Harveyella mirabilis plastid genome, which has also lost genes involved in photosynthesis, and a partial plastid genome from Leachiella pacifica.
The H. mirabilis plastid shares more synteny with free-living red algal plastids than that of C. polysiphoniae.
Phylogenetic analysis demonstrates that C. polysiphoniae, H. mirabilis, and L. pacifica form a robustly supported clade of parasites, which retain their own plastid genomes, within the Rhodomelaceae.
We therefore transfer all three genera from the exclusively parasitic family, Choreocolacaceae, to the Rhodomelaceae.
Additionally, we recommend applying the terms archaeplastic parasites (formerly alloparasites), and neoplastic parasites (formerly adelphoparasites) to distinguish red algal parasites using a biological framework rather than taxonomic affiliation with their hosts. | 214,724,814 |
Title:
Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia
Abstract:
The role of the human microbiome in health and disease is increasingly appreciated.
We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis and bipolar disorder.
By using high quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood.
We were able to detect a wide range of bacterial and archaeal phyla in blood.
Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups.
We replicated this finding in an independent schizophrenia case-control cohort.
This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8+ memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia. | 214,724,893 |
Title:
TIMP-1 attenuates the development of cutaneous inflammation-induced evoked and ongoing pain through receptor-mediated cell signaling
Abstract:
Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention.
During inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling through proteolytic maturation of cytokines.
MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs) 1-4. TIMP-1 and −2 have known roles in pain, but only in the context of MMP inhibition.
However, TIMP-1 also has receptor-mediated cell signaling functions that are not well understood.
Here, we examined how TIMP-1-dependent cell signaling impacted inflammatory hypersensitivity and ongoing pain.
We found that hindpaw injection of complete Freund’s adjuvant (CFA) increased keratinocyte-derived TIMP-1 that peaked 3 days following inflammation, when mechanical hypersensitivity began to emerge in WT mice.
These data suggest that TIMP-1 expression inhibits the development of inflammatory hypersensitivity.
To examine this possibility, we injected TIMP-1 knockout (T1KO) mice with a diluted CFA mixture to examine how subtle cutaneous inflammation affected behavioral hypersensitivity.
T1KO mice exhibited rapid onset thermal and mechanical hypersensitivity at the site of inflammation that was absent or attenuated in WT controls.
We also found that T1KO mice exhibited hypersensitivity in adjacent tissues innervated by different sets of afferents, and skin contralateral to the site of inflammation.
Replacement of recombinant murine (rm)TIMP-1 alleviated hypersensitivity when administered at the site and time of inflammation.
To examine the MMP-dependent and -independent mechanisms of rmTIMP-1, T1KO mice were administered full-length rmTIMP-1, the N-terminal region (TIMP-1(N)) with MMP-inhibitory properties, or the C-terminal region (TIMP-1(C)) that retains receptor signaling function.
Each of the peptides prevented inflammatory hypersensitivity, suggesting that rmTIMP-1 acts through mechanisms that also include receptor-mediated cell signaling.
We also found that hypersensitivity was neither due to genotype-specific differences in MMP-9 activity or expression, nor to differences in cytokine expression.
Finally, to evaluate the potential clinical utility of TIMP-1, we administered rmTIMP-1 to WT mice and found that rmTIMP-1 prevented clonidine-induced conditioned place preference (e.g., ongoing pain) and inflammatory mechanical hypersensitivity.
Collectively, our data suggest a novel role for TIMP-1 in the attenuation of inflammatory pain that occurs through previously uncharacterized cell signaling mechanisms. | 214,724,972 |
Title:
Spontaneous retinal waves generate long-range horizontal connectivity in visual cortex
Abstract:
In the primary visual cortex (V1) of higher mammals, long-range horizontal connections (LHCs) are observed to develop, linking iso-orientation domains of cortical tuning.
It is unknown how this feature-specific wiring of circuitry develops before eye opening.
Here, we show that LHCs in V1 may originate from spatio-temporally structured feedforward activities generated from spontaneous retinal waves.
Using model simulations based on the anatomy and observed activity patterns of the retina, we show that waves propagating in retinal mosaics can initialize the wiring of LHCs by co-activating neurons of similar tuning, whereas equivalent random activities cannot induce such organizations.
Simulations showed that emerged LHCs can produce the patterned activities observed in V1, matching topography of the underlying orientation map.
We also confirmed that the model can also reproduce orientation-specific microcircuits in salt-and-pepper organizations in rodents.
Our results imply that early peripheral activities contribute significantly to cortical development of functional circuits.
Highlights Developmental model of long-range horizontal connections (LHCs) in V1 is simulated Spontaneous retinal waves generate feature-specific wiring of LHCs in visual cortex Emerged LHCs induce orientation-matching patterns of spontaneous cortical activity Retinal waves induce orientation-specific microcircuits of visual cortex in rodents Significance statement Long-range horizontal connections (LHCs) in the primary visual cortex (V1) are observed to emerge before the onset of visual experience, selectively connecting iso-domains of orientation maps.
However, it is unknown how such tuning-specific wirings develop before eye-opening.
Here, we show that LHCs in V1 originate from the tuning-specific activation of cortical neurons by spontaneous retinal waves during early developmental stages.
Our simulations of a visual cortex model show that feedforward activities from the retina initialize the spatial organization of activity patterns in V1, which induces visual feature-specific wirings of V1 neurons.
Our model also explains the origin of cortical microcircuits observed in rodents, suggesting that the proposed developmental mechanism is applicable universally to circuits of various mammalian species. | 214,725,043 |
Title:
Holsteins Favor Heifers, Not Bulls: Biased Milk Production Programmed during Pregnancy as a Function of Fetal Sex
Abstract:
Mammalian females pay high energetic costs for reproduction, the greatest of which is imposed by lactation.
The synthesis of milk requires, in part, the mobilization of bodily reserves to nourish developing young.
Numerous hypotheses have been advanced to predict how mothers will differentially invest in sons and daughters, however few studies have addressed sex-biased milk synthesis.
Here we leverage the dairy cow model to investigate such phenomena.
Using 2.39 million lactation records from 1.49 million dairy cows, we demonstrate that the sex of the fetus influences the capacity of the mammary gland to synthesize milk during lactation.
Cows favor daughters, producing significantly more milk for daughters than for sons across lactation.
Using a sub-sample of this dataset (N = 113,750 subjects) we further demonstrate that the effects of fetal sex interact dynamically across parities, whereby the sex of the fetus being gestated can enhance or diminish the production of milk during an established lactation.
Moreover the sex of the fetus gestated on the first parity has persistent consequences for milk synthesis on the subsequent parity.
Specifically, gestation of a daughter on the first parity increases milk production by ∼445 kg over the first two lactations.
Our results identify a dramatic and sustained programming of mammary function by offspring in utero.
Nutritional and endocrine conditions in utero are known to have pronounced and long-term effects on progeny, but the ways in which the progeny has sustained physiological effects on the dam have received little attention to date. | 214,725,044 |
Title:
Reactive oxygen species are major contributors to SOS-mediated mutagenesis induced by fluoroquinolones
Abstract:
Certain antibiotics, particularly fluoroquinolones, induce the mutagenic SOS response and increase the levels of intracellular reactive oxygen species (ROS), which have been correlated with antibiotic lethality.
Both SOS and ROS increase mutagenesis in treated bacteria, likely resulting in the appearance of resistant mutants during antibiotic treatments.
However, the relative contribution of ROS and SOS on this antibiotic-mediated mutagenesis is currently unknown.
We used the antioxidant molecule N-acetylcysteine (NAC) to study the contribution of ROS on the SOS response and mutagenesis mediated by the fluoroquinolone antibiotic ciprofloxacin (CIP).
We show that NAC is able to reduce intracellular ROS levels, mitigating as well the SOS response caused by treatment with subinhibitory concentrations of CIP.
This effect leads to the reduction of antibiotic-induced mutagenesis to levels comparable to a translesion DNA-polymerases (TLS) deficient strain, suggesting that ROS play a major role in SOS-induced mutagenesis.
Collectively, our results shed light on the mechanisms underlying antibiotic-induced mutagenesis and pave the way for the use of NAC as a safe adjuvant in antibiotic therapy to inhibit antibiotic-induced mutagenesis, hence augmenting our capacity to fight against threatening bacterial infections. | 214,725,140 |
Title:
Weak spatiotemporal response of prey to predation risk in a freely interacting system
Abstract:
The extent to which prey space use actively minimises predation risk continues to ignite controversy.
Methodological reasons that have hindered consensus include inconsistent measurements of predation risk, biased spatiotemporal scales at which responses are measured, and lack of robust null expectations.
We addressed all three challenges in a comprehensive analysis of the spatiotemporal responses of adult female elk (Cervus elaphus) to the risk of predation by grey wolves (Canis lupus) during winter in northern Yellowstone, USA.
We quantified spatial overlap between the winter home ranges of GPS-collared elk and three measures of predation risk: the intensity of wolf space use, the distribution of wolf-killed elk and vegetation openness.
We also assessed whether elk varied their use of areas characterised by more or less predation risk across hours of the day, and estimated encounter rates between simultaneous elk and wolf pack trajectories.
We determined whether observed values were significantly lower than expected if elk movements were random with reference to predation risk using a null model approach.
Although a small proportion of elk did show a tendency to minimise use of open vegetation at specific times of the day, overall we highlight a notable absence of spatiotemporal response by female elk to the risk of predation posed by wolves in northern Yellowstone.
Our results suggest that predator-prey interactions may not always result in strong spatiotemporal patterns of avoidance. | 214,725,289 |
Title:
Wide field-of-view, multi-region two-photon imaging of neuronal activity in vivo
Abstract:
We demonstrate a two-photon imaging system with corrected optics including a custom objective that provides cellular resolution across a 3.5 mm field of view (9.6 mm2).
Temporally multiplexed excitation pathways can be independently repositioned in XY and Z to simultaneously image regions within the expanded field of view.
We used this new imaging system to measure activity correlations between neurons in different cortical areas in awake mice. | 214,725,507 |
Title:
Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation
Abstract:
The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer’s disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages.
Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons.
This study tested the hypothesis that entorhinal-dependent navigation is impaired in pre-dementia Alzheimer’s disease.
Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer’s disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-dependent navigation.
Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer’s Disease.
Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants.
Path-integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision.
The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57).
This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer’s disease.
This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer’s disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer’s drugs. | 214,725,576 |
Title:
Normative age modelling of cortical thickness in autistic males
Abstract:
Understanding heterogeneity in neural phenotypes is an important goal on the path to precision medicine for autism spectrum disorders (ASD).
Age is a critically important variable in normal structural brain development and examining structural features with respect to age-related norms could help to explain ASD heterogeneity in neural phenotypes.
Here we examined how cortical thickness (CT) in ASD can be parameterized as an individualized metric of deviance relative to typically-developing (TD) age-related norms.
Across a large sample (n=870 per group) and wide age range (5-40 years), we applied a normative modelling approach that provides individualized whole-brain maps of age-related CT deviance in ASD.
This approach isolates a subgroup of ASD individuals with highly age-deviant CT.
The median prevalence of this ASD subgroup across all brain regions is 7.6%, and can reach as high as 10% for some brain regions.
This work showcases an individualized approach for understanding ASD heterogeneity that could potentially further prioritize work on a subset of individuals with significant cortical pathophysiology represented in age-related CT deviance.
Rather than cortical thickness pathology being a widespread characteristic of most ASD patients, only a small subset of ASD individuals are actually highly deviant relative to age-norms.
These individuals drive small on-average effects from case-control comparisons.
Rather than sticking to the diagnostic label of autism, future research should pivot to focus on isolating subsets of autism patients with highly deviant phenotypes and better understand the underlying mechanisms that drive those phenotypes. | 214,725,582 |
Title:
Ecological Representations
Abstract:
Cognitive science has three main motivations for claiming that cognition requires representation; the need for intentional access to the world, poverty of perceptual access to that world, and the need to support ‘higher-order’ cognition.
In addition to these motivations, all representational systems must address two major problems: symbol grounding and system-detectable error.
Here we argue that James J Gibson’s ecological information fits the basic definition of a representation, solves both problems and immediately addresses the first two motivations.
We then develop an argument (begun in Golonka, 2015) that informational representations and the resulting neural representations can also support ‘higher-order’ cognition and provides an ecological framework for understanding neural activity.
Ecological psychology can be a complete theory of cognition, and the key is the way that information represents the world. | 214,725,627 |
Title:
Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk
Abstract:
We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls.
We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci.
These variants explained 26-36% of the heritable risk of PD.
Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals.
Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data.
We found significant genetic correlations with brain volumes, smoking status, and educational attainment.
In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. | 214,725,776 |
Title:
Continent-scale phenotype mapping using citizen scientists’ photographs
Abstract:
Field investigations of phenotypic variation in free living organisms are often limited in scope owing to time and funding constraints.
By collaborating with online communities of amateur naturalists, investigators can greatly increase the amount and diversity of phenotypic data in their analyses while simultaneously engaging with a public audience.
Here, we present a method for quantifying phenotypes of individual organisms in citizen scientists’ photographs.
We then show that our protocol for measuring wing phenotypes from photographs yields accurate measurements in two species of Calopterygid damselflies.
Finally, we present results from two case studies: (1) an analysis of wing pigmentation in male smoky rubyspots (Hetaerina titia) showing previously undocumented geographical variation in a seasonal polyphenism, and (2) an analysis of variation in the relative size of the wing spots of male banded demoiselles (Calopteryx splendens) in Great Britain questioning previously documented evidence for character displacement.
Additionally, we show that, while most observations of our target species were made by members of the large and established community of amateur naturalists at iNaturalist.org, our efforts to increase recruitment through various outreach initiatives were successful.
Our results demonstrate that our protocol can be used to create high quality phenotypic datasets using citizen scientists’ photographs, and, when combined with metadata (e.g., date and location), can greatly broaden the scope of studies of geographical and temporal variation in phenotypes.
Our analyses of the recruitment and engagement process also demonstrate that collaborating with an online community of amateur naturalists can be a powerful way to conduct hypothesis-driven research aiming to elucidate the processes that impact trait evolution at landscape scales. | 214,726,335 |
Title:
Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
Abstract:
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2.
Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks.
Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously.
Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2.
Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells.
We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals.
Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far.
This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not. | 214,727,006 |
Title:
CAPRI: Efficient Inference of Cancer Progression Models from Cross-sectional Data
Abstract:
We devise a novel inference algorithm to effectively solve the cancer progression model reconstruction problem.
Our empirical analysis of the accuracy and convergence rate of our algorithm, CAncer PRogression Inference (CAPRI), shows that it outperforms the state-of-the-art algorithms addressing similar problems.
Motivation Several cancer-related genomic data have become available (e.g., The Cancer Genome Atlas, TCGA) typically involving hundreds of patients.
At present, most of these data are aggregated in a cross-sectional fashion providing all measurements at the time of diagnosis.
Our goal is to infer cancer “progression” models from such data.
These models are represented as directed acyclic graphs (DAGs) of collections of “selectivity” relations, where a mutation in a gene A “selects” for a later mutation in a gene B. Gaining insight into the structure of such progressions has the potential to improve both the stratification of patients and personalized therapy choices.
Results The CAPRI algorithm relies on a scoring method based on a probabilistic theory developed by Suppes, coupled with bootstrap and maximum likelihood inference.
The resulting algorithm is efficient, achieves high accuracy, and has good complexity, also, in terms of convergence properties.
CAPRI performs especially well in the presence of noise in the data, and with limited sample sizes.
Moreover CAPRI, in contrast to other approaches, robustly reconstructs different types of confluent trajectories despite irregularities in the data.
We also report on an ongoing investigation using CAPRI to study atypical Chronic Myeloid Leukemia, in which we uncovered non trivial selectivity relations and exclusivity patterns among key genomic events.
Availability CAPRI is part of the TRanslational ONCOlogy R package and is freely available on the web at: http://bimib.disco.unimib.it/index.php/Tronco Contact [email protected] | 214,727,256 |
Title:
Rising out of the ashes: additive genetic variation for susceptibility to Hymenoscyphus fraxineus in Fraxinus excelsior
Abstract:
Since the early 1990s, ash dieback due to the invasive ascomycete Hymenoscyphus fraxineus is threatening Fraxinus excelsior in most of its natural range.
Previous studies reported significant levels of genetic variability for susceptibility in F. excelsior either in field or inoculation experiments.
The present study was based on a field experiment planted in 1995, fifteen years before onset of the disease.
Crown and collar status were monitored on 788 trees from 23 open-pollinated progenies originating from 3 French provenances.
Susceptibility was modeled using a Bayesian approach where spatio-temporal effects were explicitly taken into account.
Moderate narrow-sense heritability was found for Crown Dieback (CD, h2=0.42).
This study is first to show that Collar Lesions are also heritable (h2=0.49 for prevalence and h2=0.42 for severity) and that there is significant genetic correlation (r=0.40) between the severities of both symptoms.
There was no evidence for differences between Provenances.
Family effects were detected, but computing Individual Breeding Values (IBV) showed that most of the genetic variation lies within families.
In agreement with previous reports, early flushing correlates with better crown status.
Consequences of these results in terms of management and breeding are discussed. | 214,727,268 |
Title:
Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2
Abstract:
17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic.
COVID-19 is caused by a coronavirus named SARS-CoV-2.
Given the most optimistic projections estimating that it will take more than a year to develop a vaccine, our best short term strategy may lie in identifying virus-specific targets for small molecule interventions.
All coronaviruses utilize a molecular mechanism called -1 PRF to control the relative expression of their proteins.
Prior analyses of SARS-CoV revealed that it utilizes a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of -1 PRF, that it also harbors a -1 PRF attenuation element.
Altering -1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted.
Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals.
Structural analyses reveal that the core -1 PRF signal, composed of the U UUA AAC slippery site and three-stemmed mRNA pseudoknot is highly conserved.
In contrast, the upstream attenuator hairpin is less well conserved.
Functional assays revealed that both elements promote similar rates of -1 PRF and that silent coding mutations in the slippery site strongly ablate -1 PRF activity.
We suggest that molecules that were previously identified as inhibiting SARS-CoV mediated -1 PRF may serve as lead compounds to counter the current pandemic. | 214,727,298 |
Title:
Quantifying the potential for future gene therapy to lower lifetime risk of polygenic late-onset diseases
Abstract:
Background Within the next few decades, gene therapy techniques and genetic knowledge may sufficiently advance to support prophylactic gene therapy to prevent polygenic late-onset diseases.
A combination of a large number of common low effect gene variants offers the most likely explanation for the heritability of the majority of these diseases, and their risk may be lowered by correcting the effect of a subset of such gene variants.
Methods Computer simulations quantified the correlation between the aging process, polygenic risk score, and hazard ratio change with age, using as inputs clinical incidence rates and familial heritability, and estimated the outcomes of hypothetical future prophylactic gene therapy on the lifetime risk and age of onset for eight highly prevalent late-onset diseases.
Results The simulation results confirmed that gene therapy would be beneficial in both delaying the age of onset and lowering the lifetime risk of the analyzed lateonset diseases.
Longer life expectancy is associated with a higher lifetime risk of these diseases, and this tendency, while delayed, will continue after the therapy.
Conclusions When the gene therapy as hypothesized here becomes possible, and if the incidences of the treated diseases follow the proportional hazards model with multiplicative genetic architecture composed of a sufficient number of common small effect gene variants, then (a) late-onset diseases with the highest familial heritability will have the largest number of variants available for editing, (b) diseases that currently have the highest lifetime risk, and particularly those with the highest incidence rate continuing into older ages, will prove the most challenging cases in which to lower lifetime risk and delay the age of onset at the populational level, and (c) diseases that are characterized by the lowest lifetime risk will show the strongest and longest-lasting response to such therapy. | 214,727,384 |
Title:
Role of serotonin in development of esophageal and gastric fundal varices
Abstract:
Objective The aim was to determine the role of plasma free serotonin concentrations on the development of esophageal and gastric fundal varices.
Background Esophageal and gastric varices are a serious consequence of portal hypertension in patients with the chronic liver disease.
Several studies have evaluated possible noninvasive predictors for the presence of varices including plasma serotonin level.
Materials and methods This study was conducted on 100 patients: 60 hepatic patients with esophageal and/or gastric varices, 20 hepatic patients without varices, and 20 nonhepatic patients who were admitted to Tropical Medicine Department in Menoufia University Hospitals.
Patients and control were subjected to laboratory investigations, abdominal ultrasound, upper endoscopy, and quantitative measurement of plasma free serotonin using enzyme-linked immunosorbent assay technique.
Results The plasma free serotonin levels were much higher in patients with liver cirrhosis with varices than in nonhepatic patients (mean: 92.240 ± 18.534 vs. 20.015 ± 3.042 ng/ml; P < 0.0001).
Moreover, plasma serotonin level was much higher in patients with varices than patients without varices (mean: 92.240 ± 18.534 vs. 42.220 ± 9.891 ng/ml; P < 0.0001).
The best cutoff value of free serotonin in the prediction of esophageal and gastric varices was greater than or equal to 25.3 ng/ml, with sensitivity of 98.75%, specificity of 100%, positive predictive value of 100.0%, and negative predictive value of 95.2%.
Conclusion Free serotonin is significant in the development of esophageal and fundal varices, indicating the clinical value of serotonergic receptor blockers in these patients. | 214,729,677 |
Title:
Why is it difficult to accurately predict the COVID-19 epidemic?
Abstract:
Since the COVID-19 outbreak in Wuhan City in December of 2019, numerous model predictions on the COVID-19 epidemics in Wuhan and other parts of China have been reported.
These model predictions have shown a wide range of variations.
In our study, we demonstrate that nonidentifiability in model calibrations using the confirmed-case data is the main reason for such wide variations.
Using the Akaike Information Criterion (AIC) for model selection, we show that an SIR model performs much better than an SEIR model in representing the information contained in the confirmed-case data.
This indicates that predictions using more complex models may not be more reliable compared to using a simpler model.
We present our model predictions for the COVID-19 epidemic in Wuhan after the lockdown and quarantine of the city on January 23, 2020.
We also report our results of modeling the impacts of the strict quarantine measures undertaken in the city after February 7 on the time course of the epidemic, and modeling the potential of a second outbreak after the return-to-work in the city. | 214,729,892 |
Title:
Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China
Abstract:
Background Cancer patients are regarded as a highly vulnerable group in the current Coronavirus Disease 2019 (COVID-19) pandemic.
To date, the clinical characteristics of COVID-19-infected cancer patients are largely unknown.
Patients and methods In this retrospective cohort study, we included cancer patients with laboratory confirmed COVID-19 from three designated hospitals in Wuhan, China.
The clinical data were collected from medical records from Jan 13, 2020, to Feb 26, 2020.
Univariate and multivariate analyses were performed to assess the risk factors associated with severe events defined as a condition requiring admission to an intensive care unit, the use of mechanical ventilation, or death.
Results 28 COVID-19-infected cancer patients were included; 17 (60.7%) patients were male.
Median age was 65.0 years (IQR:56.0-70.0).
Lung cancer was the most frequent cancer type (7, 25.0%).
8 (28.6%) patients were suspected to be from hospital-associated transmission.
The following clinical features were shown in our cohort: fever (23, 82.1%), dry cough (22, 81%) and dyspnoea (14, 50.0%), along with lymphopaenia (23, 82.1%), high level of high-sensitivity C-reactive protein (23, 82.1%), anaemia (21, 75.0%) and hypoproteinaemia (25, 89.3%).
The common chest CT findings were ground-glass opacity (21, 75.0%) and patchy consolidation (13, 46.3%).
15 (53.6%) patients had severe events and mortality was 28.6%.
If the last anti-tumour treatment was within 14 days, it significantly increased the risk of developing severe events (HR=4.079, 95%CI 1.086-15.322, P=0.037).
Furthermore, patchy consolidation on CT on admission was associated with a higher risk for developing severe events (HR=5.438, 95%CI 1.498-19.748, P=0.010).
Conclusions Cancer patients show deteriorating conditions and poor outcomes from the COVID-19 infection.
It is recommended that cancer patients receiving anti-tumour treatments should have vigorous screening for COVID-19 infection and should avoid treatments causing immunosuppression or have their dosages decreased in case of COVID-19 co-infection. | 214,734,459 |
Title:
Strong correlations between power-law growth of COVID-19 in four continents and the inefficiency of soft quarantine strategies
Abstract:
In this work we analyse the growth of the cumulative number of confirmed infected cases by the COVID-19 until March 27th, 2020, from countries of Asia, Europe, North and South America.
Our results show (i) that power-law growth is observed for all countries; (ii) by using the distance correlation, that the power-law curves between countries are statistically highly correlated, suggesting the universality of such curves around the World; and (iii) that soft quarantine strategies are inefficient to flatten the growth curves.
Furthermore, we present a model and strategies which allow the government to reach the flattening of the power-law curves.
We found that, besides the social distance of individuals, of well known relevance, the strategy of identifying and isolating infected individuals in a large daily rate can help to flatten the power-laws.
These are essentially the strategies used in the Republic of Korea.
The high correlation between the power-law curves of different countries strongly indicate that the government containment measures can be applied with success around the whole World.
These measures must be scathing and applied as soon as possible. | 214,743,064 |
Title:
AHA/ACCF Scientific Statement on the Evaluation of Syncope
Abstract:
Introduction… 316 ::: ::: General Evaluation… 316 ::: ::: Syncope in the Patient With a Normal Evaluation… 318 ::: ::: Syncope in the Patient With Coronary Artery Disease… 319 ::: ::: Nonischemic Dilated Cardiomyopathy… 320 ::: ::: Syncope in Other Forms of Structural Heart Disease… 320 ::: ::: Syncope Resulting From Inherited Cardiac Ion Channel Abnormalities… 321 ::: ::: Evaluation of the Pediatric Patient With Syncope… 321 ::: ::: Special Considerations in the Elderly… 323 ::: ::: Neurological Evaluation… 323 ::: ::: Conclusions… 324 ::: ::: Syncope, a transient loss of consciousness, is a common clinical problem.
The most common causes of syncope are cardiovascular in origin and are associated with a high rate of mortality in patients with underlying heart disease, transient myocardial ischemia, and other less common cardiac abnormalities.1 ::: ::: The primary purpose of the evaluation of the patient with syncope is to determine whether the patient is at increased risk for death.
This involves identifying patients with underlying heart disease, myocardial ischemia, Wolff-Parkinson-White syndrome, and potentially life-threatening genetic diseases such as long-QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
If these diagnoses can be excluded, the goal then becomes identification of the cause of syncope in an attempt to improve the quality of the patient’s life and to prevent injury to the patient or others.
The purpose of this statement is to summarize the data that direct the evaluation of the patient with syncope (Figure 1). ::: ::: ::: ::: Figure 1.
Flow chart for the diagnostic approach to the patient with syncope. ::: ::: ::: ::: In the general population, the most common cause of syncope is neurocardiogenic, followed by primary arrhythmias.
Other names for neurocardiogenic syncope include neurally mediated, vasodepressor, and vasovagal syncope.
The causes of syncope are highly age dependent.2 Pediatric and young patients are most likely to have neurocardiogenic syncope, conversion reactions (psychiatric causes), and primary arrhythmic causes such as the LQTS and Wolff-Parkinson-White syndrome.
In middle age, neurocardiogenic syncope … | 214,752,364 |
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