title: Phyletic distribution and diversification of the Phage Shock Protein stress response system in bacteria and archaea

abstract: The bacterial cell envelope is an essential structure that protects the cell from environmental threats, while simultaneously serving as communication interface and diffusion barrier. Therefore, maintaining cell envelope integrity is of vital importance for all microorganisms. Not surprisingly, evolution has shaped conserved protection networks that connect stress perception, transmembrane signal transduction and mediation of cellular responses upon cell envelope stress. The phage shock protein (PSP) stress response is one of such conserved protection networks. Most of the knowledge about the Psp response comes from studies in the Gram-negative model bacterium, Escherichia coli where the Psp system consists of several well-defined protein components. Homologous systems were identified in representatives of Proteobacteria, Actinobacteria, and Firmicutes; however, the Psp system distribution in the microbial world remains largely unknown. By carrying out a large-scale, unbiased comparative genomics analysis, we found components of the Psp system in many bacterial and archaeal phyla and demonstrated that the PSP system deviates dramatically from the proteobacterial prototype. Two of its core proteins, PspA and PspC, have been integrated in various (often phylum-specifically) conserved protein networks during evolution. Based on protein sequence and gene neighborhood analyses of pspA and pspC homologs, we built a natural classification system of PSP networks in bacteria and archaea. We performed a comprehensive in vivo protein interaction screen for the PSP network newly identified in the Gram-positive model organism Bacillus subtilis and found a strong interconnected PSP response system, illustrating the validity of our approach. Our study highlights the diversity of PSP organization and function across many bacterial and archaeal phyla and will serve as foundation for future studies of this envelope stress response beyond model organisms.


title: SARS CoV-2 nucleoprotein enhances the infectivity of lentiviral spike particles

abstract: The establishment of SARS CoV-2 spike-pseudotyped lentiviral (LV) systems has enabled the rapid identification of entry inhibitors and neutralizing agents, alongside allowing for the study of this emerging pathogen in BSL-2 level facilities. While such frameworks recapitulate the cellular entry process in ACE2+ cells, they are largely unable to factor in supplemental contributions by other SARS CoV-2 genes. To address this, we performed an unbiased ORF screen and identified the nucleoprotein (N) as a potent enhancer of spike-pseudotyped LV particle infectivity. We further demonstrate that this augmentation by N renders LV spike particles less vulnerable to the neutralizing effects of a human IgG-Fc fused ACE2 microbody. Biochemical analysis revealed that the spike protein is better enriched in virions when the particles are produced in the presence of SARS CoV-2 nucleoprotein. Importantly, this improvement in infectivity is achieved without a concomitant increase in sensitivity towards RBD binding-based neutralization. Our results hold important implications for the design and interpretation of similar LV pseudotyping-based studies.

category: microbiology


title: In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

abstract: Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.


title: Coordination between nucleotide excision repair and specialized polymerase DnaE2 action enables DNA damage survival in non-replicating bacteria

abstract: Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicating Caulobacter and observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of the polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in its absence. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.


title: Assessment of the suitability of marker fragments DNA sequences of the internal transcribed spacer region (ITS), beta-tubulin gene (TUB) and elongation factor (EF1) genes for diagnostics of Fusarium tricinctum species complex in Russian in grain products

abstract: By results of laboratory researches from plant samples of grain crops species Fusarium avenaceum, Fusarium tricinctum and Fusarium acuminatum related to Fusarium tricinctum species complex were isolated and identified, based on cultural and morphological characteristics, molecular-genetic analysis of 3 DNA fragments was performed: internal transcribed spacer (ITS) site, beta-tubulin gene site (TUB), elongation factor gene site (EF1) showed insignificant intraspecific and interspecific variability at ITS and EF1 sites, which may negatively affect the reliability of target species identification, TUB site was more effective for distinguishing and identifying the studied species, due to significant intraspecific and interspecific variability

category: molecular biology


title: Parasite co-opts a ubiquitin receptor to induce a plethora of developmental changes

abstract: Obligate parasites can induce complex and substantial phenotypic changes in their hosts in ways that favour their transmission to other trophic levels. However, mechanisms underlying these changes remain largely unknown. Here, we demonstrate how SAP05 protein effectors from insect-vectored plant pathogenic phytoplasmas take control of several plant developmental processes to simultaneously prolong host lifespan and induce witchs broom-like proliferations of leaf and sterile shoots, organs colonized by phytoplasmas and vectors. SAP05 acts by mediating the concurrent degradation of SPL and GATA developmental regulators via a process that uniquely relies on hijacking the plant ubiquitin receptor RPN10 independently of substrate lysine ubiquitination. RPN10 is highly conserved among eukaryotes, but SAP05 does not bind insect vector RPN10. A two-amino-acid substitution within plant RPN10 generates a functional variant that is resistant to SAP05 activities. Therefore, one effector protein enables obligate parasitic phytoplasmas to induce a plethora of developmental phenotypes in their hosts.


title: ToxCast chemical library screen identifies diethanolamine as an activator of Wnt signaling

abstract: Numerous autism spectrum disorder (ASD) risk genes are associated with Wnt signaling, suggesting that brain development may be especially sensitive to genetic perturbation of this pathway. Additionally, valproic acid, which modulates Wnt signaling, increases risk for ASD when taken during pregnancy. We previously found that an autism-linked gain-of-function UBE3AT485A mutant construct hyperactivated canonical Wnt signaling, providing a genetic means to elevate Wnt signaling above baseline levels. To identify environmental use chemicals that enhance or suppress Wnt signaling, we screened the ToxCast Phase I and II libraries in cells expressing this autism linked UBE3AT485 gain-of-function mutant construct. Using structural comparisons, we identify classes of chemicals that stimulated Wnt signaling, including ethanolamines, as well as chemicals that inhibited Wnt signaling, such as agricultural pesticides, and synthetic hormone analogs. To prioritize chemicals for follow-up, we leveraged predicted human exposure data, and identified diethanolamine (DEA) as a chemical that both stimulates Wnt signaling in UBE3AT485A-transfected cells and has a high potential for prenatal exposure in humans. DEA also enhanced proliferation in two primary human neural progenitor cell lines. Overall, this study identifies chemicals with the potential for human exposure that influence Wnt signaling in human cells.


title: SARS-CoV2 envelop proteins reshape the serological responses of COVID-19 patients

abstract: The SARS-CoV-2 pandemic has elicited a unique international mobilization of the scientific community to better understand this coronavirus and its associated disease and to develop efficient tools to combat infection. Similar to other coronavirae, SARS-CoV-2 hijacks the host cell complex secretory machinery to produce properly folded viral proteins that will compose the nascent virions; including Spike, Envelope and Membrane proteins, the most exposed membrane viral proteins to the host immune system. Antibody response is part of the anti-viral immune arsenal that infected patients develop to fight viral particles in the body. Herein, we investigate the immunogenic potential of Spike (S), Envelope (E) and Membrane (M) proteins using a human cell-based system to mimic membrane insertion and N-glycosylation. We show that both S and M proteins elicit the production of specific IgG, IgM and IgA in SARS-CoV-2 infected patients. Elevated Ig responses were observed in COVID+ patients with moderate and severe forms of the disease. Finally, when SARS-CoV-2 Spike D614 and G614 variants were compared, reduced Ig binding was observed with the Spike G614 variant. Altogether, this study underlines the needs for including topological features in envelop proteins to better characterize the serological status of COVID+ patients, points towards an unexpected immune response against the M protein and shows that our assay could represent a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness.

category: cell biology


title: Emerin oligomerization and nucleoskeletal coupling at the nuclear envelope regulate nuclear mechanics against stress

abstract: Emerin is an integral nuclear envelope protein participating in the maintenance of nuclear shape. When mutated or absent, emerin causes X-linked Emery-Dreifuss muscular dystrophy (EDMD). To define how emerin takes parts in molecular scaffolding at the nuclear envelope and helps protect the nucleus against mechanical stress, we established its nanoscale organization using single molecule tracking and super-resolution microscopy. We show that emerin monomers form localized oligomeric nanoclusters stabilized by both lamin A/C and SUN1 at the LINC complex. Interactions of emerin with nuclear actin and BAF additionally modulate its membrane mobility and its ability to oligomerize. In nuclei subjected to mechanical challenges, the mechanotransducing functions of emerin are coupled to changes in its oligomeric state, and the incremental self-assembly of emerin determines nuclear shape adaptation against forces. We also show that the abnormal nuclear envelope deformations induced by EDMD emerin mutants stem from an improper formation of lamin A/C and LINC complex-stabilized emerin oligomers. These findings place emerin at the center of the molecular processes that regulate nuclear shape remodeling in response to mechanical challenges.


title: Gene co-expression network reveals highly conserved, well-regulated anti-ageing mechanisms in old ant queens.

abstract:
Evolutionary theories of ageing predict a reduction in selection efficiency with age, a so-called  selection shadow, due to extrinsic mortality decreasing effective population size with age. Classic symptoms of ageing include a deterioration in transcriptional regulation and protein homeostasis. Understanding how ant queens defy the trade-off between fecundity and lifespan remains a major challenge for the evolutionary theory of ageing. It has often been discussed that the low extrinsic mortality of ant queens, that are generally well protected within the nest by workers and soldiers, should reduce the selection shadow acting on old queens. We tested this by comparing strength of selection acting on genes upregulated in young and old queens of the ant, Cardiocondyla obscurior. In support of a reduced selection shadow, we find old-biased genes to be under strong purifying selection. We also analysed a gene co-expression network (GCN) with the aim to detect signs of ageing in the form of deteriorating regulation and proteostasis. We find no evidence for ageing. In fact, we detect higher connectivity in old queens indicating increased transcriptional regulation with age. Within the GCN, we discover five highly correlated modules that are upregulated with age. These old-biased modules regulate several anti-ageing mechanisms such as maintenance of proteostasis, transcriptional regulation and stress response. We observe stronger purifying selection on central hub genes of these old-biased modules compared to young-biased modules. These results indicate a lack of transcriptional ageing in old C. obscurior queens possibly facilitated by strong selection at old age and well-regulated anti-ageing mechanisms.

Significance StatementUnderstanding the exceptional longevity of ant queens and how they defy the trade-off between fecundity and lifespan remains a major challenge for the evolutionary theory and molecular biology of ageing. In this study we offer several clues as to how this occurs on a molecular level in C. obscurior queens. Specifically, we believe a reduction in the selection shadow due to low extrinsic mortality, has allowed the evolution of well-regulated anti-ageing mechanisms. Consequently, we suggest several promising starting points for future research into the poorly understood phenomenon of extreme longevity in ant queens. Making progress in this field will not only allow us to better understand longevity and fertility in social insects but may also offer interesting research strategies for human ageing.

category: evolutionary biology


title: Calling differential DNA methylation at cell-type resolution: addressing misconceptions and best practices

abstract: We benchmarked two approaches for the detection of cell-type-specific differential DNA methylation: Tensor Composition Analysis (TCA) and a regression model with interaction terms (CellDMC). Our experiments alongside rigorous mathematical explanations show that TCA is superior over CellDMC, thus resolving recent criticisms suggested by Jing et al. Following misconceptions by Jing and colleagues with modelling cell-type-specificity and the application of TCA, we further discuss best practices for performing association studies at cell-type resolution. The scripts for reproducing all of our results and figures are publicly available at github.com/cozygene/CellTypeSpecificMethylationAnalysis.

category: genomics


title: Different evolutionary trends form the twilight zone of the bacterial pan-genome

abstract: The pan-genome is defined as the combined set of all genes in the gene pool of a species. Pan-genome analyses have been very useful in helping to understand different evolutionary dynamics of bacterial species: an open pan-genome often indicates a free-living lifestyle with metabolic versatility, while closed pan-genomes are linked to host-restricted, ecologically specialised bacteria. A detailed understanding of the species pan-genome has also been instrumental in tracking the phylodynamics of emerging drug resistance mechanisms and drug resistant pathogens. However, current approaches to analyse a species pan-genome do not take the species population structure into account, nor do they account for the uneven sampling of different lineages, as is commonplace due to over-sampling of clinically relevant representatives. Here we present the application of a population structure-aware approach for classifying genes in a pan-genome based on within-species distribution. We demonstrate our approach on a collection of 7,500 E. coli genomes, one of the most-studied bacterial species used as a model for an open pan-genome. We reveal clearly distinct groups of genes, clustered by different underlying evolutionary dynamics, and provide a more biologically informed and accurate description of the species pan-genome.


title: Functional Near Infrared Spectroscopy (fNIRS) based Odor Detection and Classification using Functional Data Analysis

abstract:
An objective approach for odor detection is to analyze the brain activity using imaging techniques during the odor stimulation. In this study, Functional Near Infrared Spectroscopy (fNIRS) is used to record hemodynamic response from the frontal region of the brain by using a 4-channel fNIRS system. The fNIRs data is collected during the odor detection task in which the subjects were asked to press a button when they detect the given odor. Functional Data Analysis (FDA) was applied on fNIRs data to convert discrete measured samples of data to continuous smooth curves. The FDA method enables us to use the bases coefficients of fNIRS smoothed curves for features that represent the shape of the raw fNIRS signal. With the learning algorithm that we proposed, these features were used to train the support vector machine classifier. We evaluated the odor detection problem, in two binary classification cases: odorant vs. non-odorant and odorant vs. fingertapping. The model achieved a classification accuracy of 94.12% and 97.06% over the stimulus condition in the two cases, respectively. Moreover to find the actual predictors we used the extracted defined features (slope, standard deviation, and delta) to train our classifier. We achieved an average accuracy of 91.18 % on classifying odorant vs. non-odorant and an accuracy of 94.12% for odorant vs. fingertapping on the stimulus condition. The results determined that fNIRs signals of odorant and non-odorant are distinguishable without being affected by the motor activity during the experiment.

These findings suggest that fNIRs measurement on the forehead could be potentially used for objective and comparably inexpensive assessment of odor detection in cases that the subjective report is unreliable.

category: bioinformatics


title: Spatially Interacting Phosphorylation Sites and Mutations in Cancer

abstract: Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1,255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1,000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance.


title: Genetic and gene expression analysis of flowering time regulation by light quality in lentil

abstract:
Flowering time is important due to its roles in adaptation to different environments and subsequent formation of crop yield. Changes in light quality affect a range of developmental processes including flowering time, however little is known about light quality induced flowering time control in lentil. This study aims to investigate the genetic basis for differences in flowering response to light quality in lentil.

We explored variation in flowering time caused by changes in red/far-red related light quality environments of a lentil interspecific recombinant inbred line population developed from a cross between Lens culinaris cv. Lupa and L. orientalis accession BGE 016880. A genetic linkage map was constructed and then used for identifying QTL associated with flowering time regulation under different light quality environments. Differential gene expression analysis through transcriptomic study and RT-qPCR were used to identify potential candidate genes.

QTL mapping located 13 QTLs controlling flower time under different light quality environments, with phenotypic variance explained ranging from 1.7 to 62.9%. Transcriptomic profiling and gene expression analysis for both parents of this interspecific RIL population identified flowering-related genes showing environment-specific differential expression (flowering DEGs). One of these, a member of the florigen gene family FTa1 (LcFTa1) was located close to 3 major QTLs. Furthermore, gene expression results suggests two other florigen genes (LcFTb1 and LcFTb2), MADS-box transcription factors like LcAGL6/13d, LcSVPb, LcSOC1b and LcFULb, as well as bHLH transcription factor LcPIF6 and Gibberellin 20 oxidase LcGA20oxC,G, may be involved in the light quality response as well.

Our results show that a major component of flowering time sensitivity to light quality is tightly linked to LcFTa1 and associated with changes in its expression. This work provides a foundation for crop improvement of lentil with better adaptation to variable light environments.

category: plant biology


title: Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1

abstract:
Post tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1.

Significance StatementA leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

category: neuroscience


title: c-Rel is required for IL-33-dependent activation of ILC2s

abstract: Group 2 innate lymphoid cells (ILC2s) are emerging as important cellular regulators of homeostatic and disease-associated immune processes. The cytokine interleukin-33 (IL-33) promotes ILC2-dependent inflammation and immunity, with IL-33 having been shown to activate NF-{kappa}B in a wide variety of cell types. However, it is currently unclear which NF-{kappa}B members play an important role in IL-33-dependent ILC2 biology. Here, we identify the NF-{kappa}B family member c-Rel as a critical component of the IL-33-dependent activation of ILC2s. Although c-Rel is dispensable for ILC2 development, it is critical for ILC2 function in the lung, with c-Rel-deficient (c-Rel-/-) mice resistant to papain- and IL-33-induced lung inflammation. We also show that the absence of c-Rel reduces the IL-33-dependent expansion of ILC2 precursors and lower levels of IL-5 and IL-13 cytokine production by mature ILC2s in the lung. Together, these results identify the IL-33-c-Rel axis as a central control point of ILC2 activation and function.

category: immunology


title: AAV-Mediated In Vivo CAR Gene Therapy for Targeting Human T Cell Leukemia

abstract:
Chimeric antigen receptor (CAR) T cell therapy is the most active field in immuno-oncology and brings substantial benefit to patients with B cell malignancies. However, the complex procedure for CAR T cell generation hampers its widespread applications. Here, we describe a novel approach in which human CAR T cells can be generated within the host upon injecting an Adeno-associated virus (AAV)vector carrying the CAR gene, which we call AAV delivering CAR gene therapy (ACG). Upon single infusion into a humanized NCG tumor mouse model of human T cell leukemia, AAV generates sufficient numbers of potent in vivo CAR cells, resulting in tumor regression; these in vivo generated CAR cells produce antitumor immunological characteristics. This instantaneous generation of in vivo CAR T cells may bypass the need for patient lymphodepletion, as well as the ex vivo processes of traditional CAR T cell production, which may make CAR therapy simpler and less expensive. It may allow the development of intricate, individualized treatments in the form of on-demand and diverse therapies.

Significance StatementAAV can generate enough CAR cells within the host. That act as a living drug, distributed throughout the body, and persist for weeks, with the ability to recognize and destroy tumor cells.


title: Assessment of the reproducibility and inter-site transferability of the murine direct splenocyte mycobacterial growth inhibition assay (MGIA)

abstract: Tuberculosis (TB) vaccine candidates must be tested for safety and efficacy using preclinical challenge models prior to advancement to human trials, because of the lack of a validated immune correlate or biomarker of protection. New, unbiased tools are urgently needed to expedite the selection of vaccine candidates at an early stage of development and reduce the number of animals experimentally infected with virulent Mycobacterium tuberculosis (M.tb). In recent years, there has been a concerted effort to develop standardised functional ex vivo mycobacterial growth inhibition assays (MGIAs) as a potential surrogate read-out of vaccine efficacy. We have previously described a direct MGIA for use with mouse splenocytes. In the current study, we set out to systematically compare co-culture conditions for the murine direct splenocyte MGIA with respect to both intra-assay repeatability and inter-site reproducibility. Common sample sets were shared between laboratory sites and reproducibility and sensitivity to detect a BCG-vaccine induced response were assessed. Co-culturing 5x106 splenocytes in 48-well plates resulted in improved reproducibility and superior sensitivity to detect a vaccine response compared with standing or rotating sealed 2ml screw-cap tubes. As the difference between naive and BCG vaccinated mice was not consistently detected across both sample sets at both sites, we sought to further improve assay sensitivity by altering the multiplicity of infection (MOI). Cell viability at the end of the co-culture period was improved when splenocyte input number was reduced, with the highest viability for the condition of 3x106 splenocytes in 48-well plates. This cell input was also associated with the greatest sensitivity to detect a BCG vaccine-mediated MGIA response using an M.tb inoculum. Based on our findings, we recommend optimal co-culture conditions in a move towards aligning direct MGIA protocols and generating a cross-species consensus for early evaluation of TB vaccine candidates and biomarker studies.


title: Trade-offs between antiseptic cytotoxicity and efficacy in a human ex vivo wound contamination model

abstract: Wound cleansing agents are routine in wound care, even in the absence of signs of infection. Antiseptic activity prevents contaminating microbes from establishing an infection while also raising concerns of cytotoxicity and delayed wound healing. Here, we used an ex vivo human skin excisional wound model to evaluate the cytotoxicity of five clinically-used wound cleaning agents (saline, povidone iodine, Dove(R) soap, Dial(R) soap, and chlorhexidine gluconate). We established a wound contamination model using [~]100 cells of Pseudomonas aeruginosa per wound to evaluate antiseptic efficacy and microbial biofilm spatial organization. We found that Dial(R) soap and chlorhexidine gluconate significantly reduced metabolic activity of the biopsies, while all treatments except saline affected local cellular viability. Within the contamination model, only chlorhexidine gluconate treatment resulted in significantly lower P. aeruginosa counts at 24 hours post-treatment, driven by sub-limit-of-detection counts immediately post-treatment. Later applications of chlorhexidine gluconate had no effects on microbial growth, with microscopy showing extensive surface colonization of the wound bed. We present a clinically-relevant model for evaluating antiseptic cytotoxicity and efficacy, with the ability to resolve spatial localization and temporal dynamics of tissue viability and microbial growth.


title: Microbiota-derived metabolites inhibit Salmonella virulent subpopulation development by acting on single-cell behaviors

abstract:
Salmonella spp. express Salmonella pathogenicity island 1 (SPI-1) genes to mediate the initial phase of interaction with host cells. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit SPI-1 gene expression. A number of reports show only a subset of Salmonella cells in a population express these genes, suggesting short-chain fatty acids could decrease SPI-1 population-level expression by acting on per-cell expression and/or the proportion of expressing cells. Here, we combine single-cell, theoretical, and molecular approaches to address the effect of short-chain fatty acids on SPI-1 expression. Our results show short-chain fatty acids do not repress SPI-1 expression by individual cells. Rather, these compounds act to selectively slow the growth of SPI-1 expressing cells, ultimately decreasing their frequency in the population. Further experiments indicate slowed growth arises from short-chain fatty acid-mediated depletion of the proton motive force. By influencing the SPI-1 cell-type proportions, our findings imply gut microbial metabolites act on cooperation between the two cell-types and ultimately influence Salmonellas capacity to establish within a host.

Significance StatementEmergence of distinct cell-types in populations of genetically identical bacteria is common. Furthermore, it is becoming increasingly clear that cooperation between cell-types can be beneficial. This is the case during Salmonella infection, in which cooperation between inflammation-inducing virulent and fast-growing avirulent cell-types occurs during infection to aid in colonization of the host gut. Here, we show gut microbiota-derived metabolites slow growth by the virulent cell-type. Our study implies microbial metabolites shape cooperative interactions between the virulent and avirulent cell types, a finding that can help explain the wide array of clinical manifestations of Salmonella infection.


title: Multispecies site occupancy modeling and study design for spatially replicated environmental DNA metabarcoding

abstract:
O_LIEnvironmental DNA (eDNA) metabarcoding has become widely applied to gauge biodiversity in a noninvasive and cost-efficient manner. The detection of species using eDNA metabarcoding is, however, imperfect owing to various factors that can cause false negatives in the inherent multi-stage workflow.
C_LIO_LIImperfect detection in the multi-stage workflow of eDNA metabarcoding also raises an issue of study design: namely, how available resources should be allocated among the different stages to optimize survey efficiency.
C_LIO_LIHere, we propose a variant of the multispecies site occupancy model for eDNA metabar-coding studies where samples are collected at multiple sites within a region of interest. This model describes the variation in sequence reads, the unique output of the high-throughput sequencers, in terms of the hierarchical workflow of eDNA metabarcoding and interspecific heterogeneity, allowing the decomposition of the sources of variation in the detectability of species throughout the different stages of the workflow. We also introduced a Bayesian decision analysis framework to identify the study design that optimizes the efficiency of species detection with a limited budget.
C_LIO_LIAn application of the model to freshwater fish communities in the Lake Kasumigaura watershed, in Japan, highlighted a remarkable inhomogeneity in the detectability of species, indicating a potential risk of the biased detection of specific species. Species with lower site occupancy probabilities tended to be difficult to detect as they had lower capture probabilities and lower dominance of the sequences. The expected abundance of sequence reads was predicted to vary by up to 23.5 times between species.
C_LIO_LIAn analysis of the study design suggested that ensuring multiple within-site replications of the environmental samples is preferred in order to achieve better species detection efficiency, provided that a throughput of tens of thousands of sequence reads was secured.
C_LIO_LIThe proposed framework makes the application of eDNA metabarcoding more error-tolerant, allowing ecologists to monitor ecological communities more efficiently.
C_LI

category: ecology


title: Long-reads are revolutionizing 20 years of insect genome sequencing

abstract:
The first insect genome (Drosophila melanogaster) was published two decades ago. Today, nuclear genome assemblies are available for a staggering 601 insect species representing 20 orders. In this study, we analyzed the most-contiguous assembly for each species and provide a "state of the field" perspective, emphasizing taxonomic representation, assembly quality, gene completeness, and sequencing technologies. Relative to species richness, genomic efforts have been biased towards four orders (Diptera, Hymenoptera, Collembola, and Phasmatodea), Coleoptera are underrepresented, and 11 orders still lack a publicly available genome assembly. The average insect genome assembly is 439.2 megabases in length with 87.5% of single-copy benchmarking genes intact. Most notable has been the impact of long-read sequencing; assemblies that incorporate long-reads are ~48x more contiguous than those that do not. We offer four recommendations as we collectively continue building insect genome resources: (1) seek better integration between independent research groups and consortia, (2) balance future sampling between filling taxonomic gaps and generating data for targeted questions, (3) take advantage of long read sequencing technologies, and (4) expand and improve gene annotations.

Significance statementSince the first insect genome was sequenced ~20 years ago, sequencing technologies and the availability of insect genome assemblies have both advanced dramatically. In this study, we curated, analyzed, and summarized the field of insect genomics in terms of taxonomic representation, assembly quality, gene completeness, and sequencing technology. We show that 601 insect species have genome assemblies available, with some groups heavily overrepresented (e.g., Diptera) relative to others (e.g., Coleoptera). The major takeaway of our study is that genome assemblies produced with long reads are ~48x more contiguous than short read assemblies.


title: Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

abstract:
Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appear to act on Nuclear Factor Kappa B (NF-{kappa}B) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

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org.highwire.dtl.DTLVardef@1d7e0f8org.highwire.dtl.DTLVardef@1f2c602org.highwire.dtl.DTLVardef@1a5dd7dorg.highwire.dtl.DTLVardef@7071c8_HPS_FORMAT_FIGEXP  M_FIG C_FIG


title: Soluble guanylate cyclase stimulation mitigates skeletal and cardiac muscle dysfunction in a mdx model of Duchenne muscular dystrophy

abstract: The impairment of neuronal nitric oxide synthase (nNOS) signaling contributes to disease pathology in the muscle wasting disorder Duchenne muscular dystrophy (DMD). nNOS signal propagation occurs through nitric oxide sensitive soluble guanylate cyclase (sGC), a critical source of cyclic guanosine monophosphate (cGMP) in muscle. Although both nNOS and sGC activity are impaired in DMD patients, little is known about sGC as a therapeutic target. In this study, we tested the hypothesis that stimulating sGC activity with the allosteric agonist BAY41-8543 mitigates striated muscle pathology in the mdx4cv mouse model of DMD. In contrast to DMD patients, mdx mice exhibited greater basal sGC activity than wild type controls with preservation of cGMP levels due partly to upregulation of sGC in some muscles. Stimulating sGC activity in mdx mice with BAY41-8543 substantially reduced skeletal muscle damage, macrophage densities and inflammation and significantly increased resistance to contraction-induced fatigue. BAY41-8543 also enhanced in vivo diaphragm function while reducing breathing irregularities suggesting improved respiratory function. BAY41-8543 attenuated cardiac hypertrophic remodeling, fibrosis and diastolic dysfunction including left atrium enlargement in aged mdx mice. Overall, sGC stimulation significantly mitigated skeletal and cardio-respiratory dysfunction in mdx4cv mice. Importantly, this study provides compelling pre-clinical evidence supporting sGC as a novel target in DMD and the repurposing of FDA-approved sGC stimulators, such as riociguat and veraciguat, as a novel therapeutic approach for DMD.

category: physiology


title: Mapping language and non-language cognitive deficits in post-stroke anomic aphasia

abstract:
While language impairment is the defining symptom of aphasia, the co-occurrence of non-language cognitive deficits and their importance in predicting rehabilitation and recovery outcomes is well documented. Despite this, people with aphasia (PWA) are rarely tested on assessments of higher order cognitive functions, making it difficult for studies to associate these functions with a consistent lesion correlate. Contrary to classic models of speech and language, cumulative evidence shows that Brocas area and surrounding regions in the left inferior frontal cortex (LIFC) are involved in, but not specific to, speech production - suggesting that these regions may be involved in higher-level cognitive functions that support language production. A better understanding of language processing in the context of other domain general cognitive functions is essential for improving aphasia treatments.

This study aimed to explore the brain-behaviour relationships between tests of individual cognitive skill and language abilities in people with post-stroke aphasia, with a focus on language production deficits and their associated lesion correlates. We predicted our analysis would reveal a latent (non-language specific) cognitive component, that would be driven by damage to LIFC.

We analysed the behavioural and neural correlates of an extensive battery of language and non-language cognitive tests in a sample of thirty-six adults with long-term speech production deficits from post-stroke aphasia. All participants were anomic, with relatively intact speech comprehension and no apraxia of speech. The behavioural variables were analysed using Principal Component Analysis and their neural correlates were estimated using Voxel-Based Correlational Morphology. A significant number of anomic adults showed impaired performance on tests of non-language specific cognitive function. The variance underlying behavioural performance was best captured by four orthogonal components, two higher-order cognitive components (executive functions and verbal working memory) and two linguistic processing components (phonology and semantics). Brain-behaviour relationships revealed separable neural correlates for each component in line with previous studies and an executive functions correlate in the left inferior frontal cortex (LIFC).

Our findings suggest that in adults with chronic post-stroke language production deficits (anomia), higher-level cognitive functions explain more of the variance in language function than classical models of the condition imply. Additionally, lesions to the LIFC, including Brocas area, were associated with executive (dys)function, independent of language abilities, suggesting that lesions to this area are associated with non-language specific higher-level cognitive functions that support speech production. These findings support contemporary models of speech production that place language processing within the context of domain-general perception, action and conceptual knowledge.


title: Clinical and Genetic insights in a tertiary care center cohort of patients with bicuspid aortic valve

abstract:
BACKGROUNDto describe spectrum of valve function in bicuspid aortic valve (BAV) patients referred to a tertiary care center and to investigate genetic pathways associated with valve degeneration.

METHODSAll consecutive patients with BAV were prospectively included from 2014 to 2018. BAV was defined according to embryologic and Sievers classifications. Clinical and echo variables were compared according to aortic valve function. Aortic valve tissues were collected from BAV patients (n=15) operated for severe aortic stenosis (AS-BAV, n=7) or aortic regurgitation (AR-BAV, n=8). RT-qPCR was performed to compare gene expression level in AS-BAV, AR-BAV and controls corresponding to healthy tricuspid aortic valves collected on human heart explant immediately after transplantation (n=5).

RESULTSOut of 223 adults with BAV, mean age 53{+/-}17 years, 83% had left-right coronary cusps fusion, 80% Sievers type 1 BAV and 49% aortopathy. Twenty-four patients had normal valve function, 66 patients had AS-BAV, 91 patients had AR-BAV and 40 patient had AR+AS BAV. BAV phenotype did not predict neither AS-BAV nor AR-BAV (all p>0.1). By multivariable analysis, age >50 (41.6[10.3-248.2],p<0.001) and presence of raphe(12.8[2.4-87.4],p<0.001) were significantly associated with AS-BAV and male gender of AR-BAV(5[1.6-16.4], p=0.005). RT-qPCR revealed overexpression of RUNX2 in AS-BAV (17.67{+/-}1.83 vs 3.25{+/-}0.93, p=0.04), and overexpression of COL1A1 (4.01{+/-}0.6vs2.25{+/-}0.5,p=0.03) and FLNA (23.31{+/-}7.5vs1.97{+/-}0.3,p=0.03) in AR-BAV.

CONCLUSIONSThis prospective study confirmed high prevalence of valve dysfunction at first diagnosis of BAV in a referred population. Clinical and echo variables are poorly associated with BAV dysfunction. The leaking or stenotic processes could be both supported by dysregulation of specific genetic pathways

category: genetics


title: A farewell to EQ: A new brain size measure for comparative primate cognition

abstract: Both absolute and relative brain size vary greatly among and within the major vertebrate lineages. Scientists have long debated how larger brains in primates and hominins translate into greater cognitive performance, and in particular how to control for the relationship between the non-cognitive functions of the brain and body size. One solution to this problem is to establish the slope of cognitive equivalence, that is the line connecting organisms with an identical bauplan but different body sizes. Here, we suggest that intraspecific slopes provide the best available estimate of this measure. This approach was abandoned because slopes were too low by an unknown margin due to estimation error. We control for the error problem by focusing on highly dimorphic primate species with large sample sizes and fitting a line through the mean values for adult females and males. We obtain the best estimate for the slope of ca 0.27, a value much lower than those constructed using all mammal species, and close to the value expected based on the genetic correlation between brain size and body size. We also find that the estimate of cognitive brain size based on cognitive equivalence fits empirical cognitive studies better than the encephalization quotient (EQ), which should therefore be avoided in future studies on primates, and presumably mammals and birds in general. The use of residuals from the line of cognitive equivalence may change conclusions concerning the cognitive abilities of extant and extinct primate species, including hominins.

category: animal behavior and cognition


title: Region-specific maladaptive gray matter myelination is associated with differential susceptibility to stress-induced behavior in male rodents and humans

abstract: Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter myelin contributes to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin content in multiple brain areas. We found that oligodendrocyte cell density and myelin content were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and myelin. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with myelin in the amygdala and spatial processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species- independent relationship between region-specific, gray matter oligodendrocytes and myelin and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.


title: Region-specific, maladaptive, gray matter myelination is associated with differential susceptibility to stress-induced behavior in rats and humans


title: Shared genetic influences on resting-state functional networks of the brain

abstract: The amplitude of activation in brain resting state networks (RSNs), measured with resting-state functional MRI, is heritable and genetically correlated across RSNs, indicating pleiotropy. Recent univariate genome-wide association studies (GWAS) explored the genetic underpinnings of individual variation in RSN activity. Yet univariate genomic analyses do not describe the pleiotropic nature of RSNs. In this study we used a novel multivariate method called genomic SEM to model latent factors that capture the shared genomic influence on RSNs and to identify SNPs and genes driving this pleiotropy. Using summary statistics from GWAS of 21 RSNs reported in UK Biobank (N = 31,688), the genomic latent factor analysis was first conducted in a discovery sample (N = 21,081), and then tested in an independent sample from the same cohort (N = 10,607). In the discovery sample, we show that the genetic organization of RSNs can be best explained by two distinct but correlated genetic factors that divide multimodal association networks and sensory networks. Eleven of the 17 factor loadings were replicated in the independent sample. With the multivariate GWAS, we found and replicated nine independent SNPs associated with the joint architecture of RSNs. Further, by combining the discovery and replication samples, we discovered additional SNP and gene associations with the two factors of RSN amplitude. We conclude that modelling the genetic effects on brain function in a multivariate way is a powerful approach to learn more about the biological mechanisms involved in brain function.


title: A deep learning model for fish classification base on DNA barcode

abstract: Fish is one of the most extensive distributed organisms in the world, fish taxonomy is an important part of biodiversity and is also the basis of fishery resources management. However, the morphological characters are so subtle to identify and intact specimens are not available sometimes, making the research and application of morphological method laborious and time-consuming. DNA barcoding based on a fragment of the cytochrome c oxidase subunit I (COI) gene is a valuable molecular tool for species identification and biodiversity studies. In this paper, a novel deep learning classification approach that fuses Elastic Net-Stacked Autoencoder (EN-SAE) with Kernel Density Estimation (KDE), named ESK-model, is proposed bases on DNA barcode. In stage one, ESK-model preprocesses the original data from COI fragments. In stage two, EN-SAE is used to learn the deep features and obtain the outgroup score of each fish. In stage three, KDE is used to select the threshold base on the outgroup scores and classify fish from different families. The effectiveness and superiority of ESK-model have been validated by experiment on three dominant fish families and comparisons with state-of-the-art methods. Those findings confirm that the ESK-model can accurately classify fish from different family base on DNA barcode.


title: Hybrid Support Vector Regression Model and K-Fold Cross Validation for Water Quality Index Prediction in Langat River, Malaysia

abstract: Water quality analysis is an important step in water resources management and needs to be managed efficiently to control any pollution that may affect the ecosystem and to ensure the environmental standards are being met. The development of water quality prediction model is an important step towards better water quality management of rivers. The objective of this work is to utilize a hybrid of Support Vector Regression (SVR) modelling and K-fold cross-validation as a tool for WQI prediction. According to Department of Environment (DOE) Malaysia, a standard Water Quality Index (WQI) is a function of six water quality parameters, namely Ammoniacal Nitrogen (AN), Biochemical Oxygen Demand (BOD), Chemical Oxygen Demand (COD), Dissolved Oxygen (DO), pH, and Suspended Solids (SS). In this research, Support Vector Regression (SVR) model is combined with K-fold Cross Validation (CV) method to predict WQI in Langat River, Kajang. Two monitoring stations i.e., L15 and L04 have been monitored monthly for ten years as a case study. A series of results were produced to select the final model namely Kernel Function performance, Hyperparameter Kernel value, K-fold CV value and sets of prediction model value, considering all of them undergone training and testing phases. It is found that SVR model i.e., Nu-RBF combined with K-fold CV i.e., 5-fold has successfully predicted WQI with efficient cost and timely manner. As a conclusion, SVR model and K-fold CV method are very powerful tools in statistical analysis and can be used not limited in water quality application only but in any engineering application.


title: A conserved role of the duplicated Masculinizer gene in sex determination of the Mediterranean flour moth, Ephestia kuehniella

abstract:
Sex determination in the silkworm, Bombyx mori, is based on Feminizer (Fem), a W-linked Fem piRNA that triggers female development in WZ individuals, and the Z-linked Masculinizer (Masc), which initiates male development and dosage compensation in ZZ individuals. While Fem piRNA is missing in a close relative of B. mori, Masc determines sex in several representatives of distant lepidopteran lineages. We studied the molecular mechanisms of sex determination in the Mediterranean flour moth, Ephestia kuehniella (Pyralidae). We identified an E. kuehniella Masc ortholog, EkMasc, and its paralog resulting from a recent duplication, EkMascB. Both genes are located on the Z chromosome and encode a similar Masc protein that contains two conserved domains but has lost the conserved double zinc finger domain. We developed PCR-based genetic sexing and demonstrated a peak in the expression of EkMasc and EkMascB genes only in early male embryos. Simultaneous knock-down experiments of both EkMasc and EkMascB using RNAi during early embryogenesis led to a shift from male- to female-specific splicing of the E. kuehniella doublesex gene (Ekdsx), their downstream effector, in ZZ embryos and resulted in a strong female-biased sex-ratio. Our results thus confirmed the conserved role of both EkMasc and EkMascB genes in masculinization. We suggest that the C-terminal proline-rich domain, we have identified in all functionally confirmed Masc proteins, in conjunction with the masculinizing domain, is important for transcriptional regulation of sex determination in Lepidoptera. The function of the Masc double zinc finger domain is still unknown, but appears to have been lost in E. kuehniella.

Author summaryThe sex-determining cascade in the silkworm, Bombyx mori, differs greatly from those of other insects. In B. mori, female development is initiated by Fem piRNA expressed from the W chromosome during early embryogenesis. Fem piRNA silences Masculinizer (Masc) thereby blocking the male pathway resulting in female development. It is currently unknown whether this cascade is conserved across Lepidoptera. In the Mediterranean flour moth, Ephestia kuehniella, we identified an ortholog of Masc and discovered its functional duplication on the Z chromosome, which has not yet been found in any other lepidopteran species. We provide two lines of evidence that both the EkMasc and EkMascB genes play an essential role in masculinization: (i) they show a peak of expression during early embryogenesis in ZZ but not in WZ embryos and (ii) their silencing by RNAi results in female-specific splicing of the E. kuehniella doublesex gene (Ekdsx) in ZZ embryos and in a female-biased sex ratio. Our results suggest a conserved role of the duplicated Masc gene in sex determination of E. kuehniella.


title: Saccharomyces cerevisiae deficient in the early anaphase release of Cdc14 can traverse anaphase I without ribosomal DNA disjunction and successfully complete meiosis

abstract: Eukaryotic meiosis is a specialized cell cycle involving two successive nuclear divisions that lead to the formation of haploid gametes. The phosphatase Cdc14 plays an essential role in meiosis as revealed in studies of the yeast Saccharomyces cerevisiae. Cdc14 is stored in the nucleolus, a sub-nuclear domain containing the ribosomal DNA, and its release is regulated by two distinct pathways, one acting in early anaphase I of meiosis and a second at the exit from meiosis II. The early anaphase release is thought to be important for disjunction of the ribosomal DNA, disassembly of the anaphase I spindle, spindle pole re-duplication and the counteraction of CDK, all of which are required for progression into meiosis II. The release of Cdc14 from its nucleolar binding partner Net1 is stimulated by phosphorylation of cyclin-dependent kinase sites in Net1, but the importance of that phospho-regulation in meiosis is not well understood. We induced net1-6cdk mutant cells to enter meiosis and examined the localization of Cdc14 and various indicators of meiotic progression. The net1-6cdk mutations inhibit, but dont fully prevent Cdc14 release, and they almost completely prevent disjunction of the ribosomal DNA during meiosis I. Failure to disjoin the ribosomal DNA is lethal in mitosis, and we expected the same to be true in meiosis. However, the cells were able to complete meiosis II, yielding the expected four meiotic products as viable spores. Therefore, all ribosomal DNA disjunction required for meiosis can occur in meiosis II. We discuss the implications of these findings for our understanding of meiotic chromosome segregation.


title: Comparative genome analysis revealed gene inversions, boundary expansion and contraction, and gene loss in Stemona sessilifolia (Miq.) Miq. chloroplast genome

abstract: Stemona sessilifolia (Miq.) Miq., commonly known as Baibu, is one of the most popular herbal medicines in Asia. In Chinese Pharmacopoeia, Baibu has multiple authentic sources, and there are many homonym herbs sold as Baibu in the herbal medicine market. The existence of the counterfeits of Baibu brings challenges to its identification. To assist the accurate identification of Baibu, we sequenced and analyzed the complete chloroplast genome of Stemona sessilifolia using next-generation sequencing technology. The genome was 154,039 bp in length, possessing a typical quadripartite structure consisting of a pair of inverted repeats (IRs: 27,094 bp) separating by a large single copy (LSC: 81,950 bp) and a small single copy (SSC: 17,901 bp). A total of 112 unique genes were identified, including 80 protein-coding, 28 transfer RNA, and four ribosomal RNA genes. Besides, 45 tandem, 27 forward, 23 palindromic, and 72 simple sequence repeats were detected in the genome by repeat analysis. Compared with its counterfeits (Asparagus officinalis and Carludovica palmate), we found that IR expansion and SSC contraction events of Stemona sessilifolia resulted in two copies of the rpl22 gene in the IR regions and partial duplication of the ndhF gene in the SSC region. Secondly, an approximately 3-kb-long inversion was identified in the LSC region, leading to the petA and cemA gene presented in the complementary strand of the chloroplast DNA molecule. Comparative analysis revealed some highly variable regions, including trnF-GAA_ndhJ, atpB_rbcL, rps15_ycf1, trnG-UCC_trnR-UCU, ndhF_rpl32. Finally, gene loss events were investigated in the context of phylogenetic relationships. In summary, the complete plastome of Stemona sessilifolia will provide valuable information for the molecular identification of Baibu and assist in elucidating the evolution of Stemona sessilifolia.


title: Consumer risk perception towards pesticides stained tomatoes in Uganda.

abstract:
BackgroundTomatoes are consumeddaily. Unfortunately, abuse of pesticides application by vegetable growers in Uganda increases risks of exposing consumers through the pesticide residues, as it may be above European Union Maximum Residue Limits (used as a standard in Uganda). This study is aimed to determine consumer attitudes and risk perception towards pesticide stained tomatoes available on the Ugandan local markets.

MethodsA cross-sectional study sampled 468 household consumers in four districts one from each region of Uganda. In each district, 60 household members from three randomly selected Sub Counties were interviewed. In addition, in each district 9 tomato handlers (3 tomato farmers, 3 tomato retailers and 3 tomato wholesalers) participated in Focus Group Discussion (FGDs) perdistrict. Collected data was entered into MS-Excel 13 and exported into STATA SE 14.0 for cleaning and analysis at below a 5% level of significance and 95% Confidence Intervals (CI). Proportion of risk perceptions and attitudes were computed and presented as percentages while factors associated with risk perception were determined using Fisher exact test. Qualitative data was analyzed using deductive and inductive approaches under thematic content analysis.

ResultsMore than half, 54.2% (253/468), of the respondents were females, mean age was 37 years (SD=13.13, ranging from 18 to 88 years). Half of the respondents, 50.9% (238/467), were farmers by occupation and 40.3% (188/468) had completed upper primary education. Only 5.0% (20/396) of consumers reported a high risk perception towards tomatoes stained with pesticide residues, the rest, 95.0% (376/396), were buying pesticide stained tomatoes despite their awareness about the possible health effects. The main reason for buying the pesticide stained tomatoes was that a majority, 59.0% (230/390), lacked an alternative to stained tomatoes. However, consumers generally had a negative attitude towards pesticide stained tomatoes, with 67.0% (313/468) of the consumers disagreeing to a statement that tomatoes sold on the market are safe. Consumer risk perception was significantly associated with consumer awareness about residues in the tomatoes; where the proportino of consumers who were aware of the risk of pesticide stained tomatoes were 42.8 times more likely not to buy stained tomatoes compared to the proportion of those who were not aware. OR, 42.8 (95% CI: 10.76-170.28). However, level of education P(0.975), gender P(0.581) and age-group P(0.680) were not associated with consumer risk perception after Fisher-Exact tests analysis. (95% CI and 5% level of significance).

ConclusionConsumer risk perception on pesticide stained tomatoes among Ugandan consumers ranked low with a majority of consumers buying tomatoes stained with pesticide residuesdue to lack of an alternative, except for a few who had a high risk perception about the pesticide health effects.


title: Consumer risk perception towards pesticide stained tomatoes in Uganda.


title: Metaplasia of respiratory and digestive tissues in the Eastern oyster Crassostrea virginica associated with the Deepwater Horizon oil spill

abstract: Metaplasia is a well documented and deleterious effect of crude oil components on bivalved molluscs, including oysters. This reversible transformation of one cell type to another, is a common response to petroleum-product exposure in molluscs. It has been shown experimentally in previous work that eastern oysters (Crassostrea virginica) exposed to petroleum products will exhibit metaplasia of digestive tissues. Here we document for the first time that wild adult oysters inhabiting coastal waters in the northern Gulf of Mexico during and in the aftermath of the Deepwater Horizon oil spill (2010) exhibited metaplasia in both ctenidia and digestive epithelia at significantly higher levels than geographic controls of C. virginica from Chesapeake Bay. Both ctenidial (respiratory and suspension feeding) and digestive tract tissues exhibited significantly higher frequencies of metaplasia in specimens from the Gulf of Mexico compared to those from Chesapeake Bay. Metaplasia included the loss of epithelial cilia, transformations of columnar epithelia, hyperplasia and reduction of ctenidial branches, and vacuolization of digestive tissues. Evidence for a reduction of metaplasia following the oil spill (2010-2013) is suggestive but equivocal.

category: zoology


title: Automated in vivo tracking of cortical oligodendrocytes

abstract: Oligodendrocytes exert a profound influence on neural circuits by accelerating axon potential conduction, altering excitability and providing metabolic support. As oligodendrogenesis continues in the adult brain and is essential for myelin repair, uncovering the factors that control their dynamics is necessary to understand the consequences of adaptive myelination and develop new strategies to enhance remyelination in diseases such as multiple sclerosis. Unfortunately, few methods exist for analysis of oligodendrocyte dynamics, and even fewer are suitable for in vivo investigation. Here, we describe the development of a fully automated cell tracking pipeline using convolutional neural networks (Oligo-Track) that provides rapid volumetric segmentation and tracking of thousands of cells over weeks in vivo. This system reliably replicated human analysis, outperformed traditional analytic approaches, and extracted injury and repair dynamics at multiple cortical depths, establishing that oligodendrogenesis after cuprizone-mediated demyelination is suppressed in deeper cortical layers. Volumetric data provided by this analysis revealed that oligodendrocyte soma size progressively decreases after their generation, and declines further prior to death, providing a means to predict cell age and eventual cell death from individual time points. This new CNN-based analysis pipeline offers a rapid, robust method to quantitatively analyze oligodendrocyte dynamics in vivo, which will aid in understanding how changes in these myelinating cells influence circuit function and recovery from injury and disease.


title: Impaired clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimers disease

abstract: Patients with Alzheimers disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). Here, we report that Tg-SwDI mice failed to show day-night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimers disease symptoms or delay pathological onset.


title: Burst Control

abstract: The output of neocortical layer 5 pyramidal cells (L5PCs) is expressed by a train of single spikes with intermittent bursts of multiple spikes at high frequencies. The bursts are the result of nonlinear dendritic properties, including Na+, Ca2+, and NMDA spikes, that interact with the [~]10,000 synapses impinging on the neurons dendrites. Output spike bursts are thought to implement key dendritic computations, such as coincidence detection of bottom-up inputs (arriving mostly at the basal tree) and top-down inputs (arriving mostly at the apical tree). In this study we used a detailed nonlinear model of L5PC receiving excitatory and inhibitory synaptic inputs to explore the conditions for generating bursts and for modulating their properties. We established the excitatory input conditions on the basal versus the apical tree that favor burst and show that there are two distinct types of bursts. Bursts consisting of 3 or more spikes firing at < 200 Hz, which are generated by stronger excitatory input to the basal versus the apical tree, and bursts of [~]2-spikes at [~]250 Hz, generated by prominent apical tuft excitation. Localized and well-timed dendritic inhibition on the apical tree differentially modulates Na+, Ca2+, and NMDA spikes and, consequently, finely controls the burst output. Finally, we explored the implications of different burst classes and respective dendritic inhibition for regulating synaptic plasticity.


title: Molecular epidemiology of human respiratory syncytial virus with severe acute respiratory infection in Huzhou from 2016 to 2019

abstract:
BackgroundHuman respiratory syncytial virus (HRSV) is one of the major cause of acute lower respiratory infection in infants, the elderly and people with low immunity worldwide. Based on antigenic and genetic variations, Human respiratory syncytial virus is divided into two subgroups (A and B). Each of the subgroups is further categorized into genotypes based on the phylogenetic analyses of the sequences of the second hypervariable region.

MethodsNasopharyngeal swabs (NPSs) were collected from patients of the First Peoples Hospital in Huzhou from January 2016 to December 2019. Real-time RT-PCR (qPCR) was performed using double nucleic acid detection kit for respiratory syncytial virus (A\B) (Shenzhen shengkeyuan) with the ABI Q7 (Applied Biosystems). For genotyping, the primer set A-F/A-R was used to amplify the G protein of HRSV-A. Primer set B-F/B-R was used to amplify the G protein of HRSV-B. The phylogenetic analysis was constructed using the neighbor-joining algorithm with the Kimura two-parameter model and supported statistically by bootstrapping with 1000 replicates with MEGA software (version 7.0) with 1000 bootstrap replicates.

ResultsA total of 973 nasopharyngeal swab samples were collected from January 2016 to December 2019, and 63 samples were positive for RSV nucleic acid, with the detection rate of 6.47%. Of the positive specimens, 28 were belonged to HRSV-A, and 35 were belonged to HRSV-B. Infection with RSV was found in all age groups tested, with the 0-1 year age group having the highest detection rate 15.2%. The detection rate was high from November to next March. Phylogenetic analysis clustered HRSV-A strains identified in Huzhou into ON1genotype. All 17 of the HRSV-B strains belonged to BA9 genotype.

ConclusionsWe analyzed the HRSV strains circulation in Huzhou from January 2016 to December 2019 in Huzhou, China. This is the first molecular analysis on HRSV in Huzhou. We found Subgroup A and B of RSV were co-circulating and the 0-1 year age group having the highest infection rate.


title: Simultaneous estimation of per cell division mutation rate and turnover rate from bulk tumour sequence data

abstract:
Tumors often harbor orders of magnitude more mutations than healthy tissues. The increased number of mutations may be due to an elevated mutation rate or frequent cell death and correspondingly rapid cell turnover, or a combination of the two. It is difficult to disentangle these two mechanisms based on widely available bulk sequencing data, where sequences from individual cells are intermixed and, thus, the cell lineage tree of the tumor cannot be resolved. Here we present a method that can simultaneously estimate the cell turnover rate and the rate of mutations from bulk sequencing data. Our method works by simulating tumor growth and finding the parameters with which the observed data can be reproduced with maximum likelihood. Applying this method to a real tumor sample, we find that both the mutation rate and the frequency of death may be high.

Author SummaryTumors frequently harbor an elevated number of mutations, compared to healthy tissue. These extra mutations may be generated either by an increased mutation rate or the presence of cell death resulting in increased cellular turnover and additional cell divisions for tumor growth. Separating the effects of these two factors is a nontrivial problem. Here we present a method which can simultaneously estimate cell turnover rate and genomic mutation rate from bulk sequencing data. Our method is based on the estimation of the parameters of a generative model of tumor growth and mutations. Applying our method to a human hepatocellular carcinoma sample reveals an elevated per cell division mutation rate and high cell turnover.


title: Distinguishing excess mutations and increased cell death based on variant allele frequencies


title: RAS specific protease Induces Irreversible Growth Arrest via p27 in several KRAS Mutant Colorectal Cancer cell lines

abstract: Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. In the course of studies developing RRSP as an anti-cancer therapeutic, it was shown that cleavage of total RAS by RRSP results in a range of cell fates from cytotoxicity to moderate growth inhibition. Despite the considerable amount of evidence demonstrating RRSP anti-tumor effects in vivo, our understanding of the mechanisms involved are unknown. Here, we first demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. The cleavage of RAS inhibited phosphorylation of ERK and cell proliferation regardless of the RAS isoform. To investigate further how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo cytotoxic death, RRSP treatment of GP5d cells induces G1 cell cycle arrest, and SW620 cells instead induces growth inhibition through cell senescence. In three of four cell lines tested, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to inactivate all RAS and inhibit cancer cell growth through a variety of mechanisms highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.

category: cancer biology


title: The Future is Less Concrete than the Present: A Neural Signature of the Concreteness of Prospective Thought Is Modulated by Temporal Proximity during Intertemporal Decision-Making

abstract:
Why do people discount future rewards? Multiple theories in psychology argue that future events are imagined less concretely than immediate events, thereby diminishing their perceived value. Here we provide neuroscientific evidence for this proposal. First, we construct a neural signature of the concreteness of prospective thought, using an fMRI dataset where the concreteness of imagined future events is orthogonal to their valence by design. Then, we apply this neural signature in two additional fMRI datasets, each using a different delay discounting task, to show that neural measures of concreteness decline as rewards are delayed farther into the future.

Significance StatementPeople tend to devalue, or discount, outcomes in the future relative to those that are more immediate. This tendency is evident in peoples difficulty in making healthy food choices or saving money for retirement. Several psychological theories propose that discounting occurs because delayed outcomes are perceived less concretely that more immediate ones. Here we build a brain decoder for the concreteness of future thought and use this unobtrusive measure to show that outcomes are processed less concretely as they occur farther into the future.


title: A brain-based universal measure of attention: predicting task-general and task-specific attention performance and their underlying neural mechanisms from task and resting state fMRI

abstract: Attention is central for many aspects of cognitive performance, but there is no singular measure of a persons overall attentional functioning across tasks. To develop a universal measure that integrates multiple components of attention, we collected data from more than 90 participants performing three different attention-demanding tasks during fMRI. We constructed a suite of whole-brain models that can predict a profile of multiple attentional components - sustained attention, divided attention and tracking, and working memory capacity - from a single fMRI scan type within novel individuals. Multiple brain regions across the frontoparietal, salience, and subcortical networks drive accurate predictions, supporting a universal (general) attention factor across tasks, which can be distinguished from task-specific attention factors and their neural mechanisms. Furthermore, connectome-to-connectome transformation modeling enhanced predictions of an individuals attention-task connectomes and behavioral performance from their rest connectomes. These models were integrated to produce a new universal attention measure that generalizes best across multiple, independent datasets, and which should have broad utility for both research and clinical applications.


title: Triku: a feature selection method based on nearest neighbors for single-cell data

abstract: Feature selection is a relevant step in the analysis of single-cell RNA sequencing datasets. Triku is a feature selection method that favours genes defining the main cell populations. It does so by selecting genes expressed by groups of cells that are close in the nearest neighbor graph. Triku efficiently recovers cell populations present in artificial and biological benchmarking datasets, based on mutual information and silhouette coefficient measurements. Additionally, gene sets selected by triku are more likely to be related to relevant Gene Ontology terms, and contain fewer ribosomal and mitochondrial genes. Triku is available at https://gitlab.com/alexmascension/triku.


title: Dynamic Representation of the Subjective Value of Information

abstract: To improve future decisions, people should seek information based on the value of information (VOI), which depends on the current evidence and the reward structure of the upcoming decision. When additional evidence is supplied, people should update VOI to adjust subsequent information seeking, but the neurocognitive mechanisms of this updating process remain unknown. We used a modified beads task to examine how the VOI is represented and updated in the human brain. We theoretically derived, and empirically verified, a normative prediction that the VOI depends on decision evidence and is biased by reward asymmetry. Using fMRI, we found that the subjective VOI is represented in right dorsolateral prefrontal cortex (DLPFC). Critically, this VOI representation was updated when additional evidence was supplied, showing that DLPFC dynamically tracks the up-to-date VOI over time. These results provide new insights into how humans adaptively seek information in the service of decision making.


title: Effect of ozone exposure on Amyotrophic Lateral Sclerosis (ALS) pathology using a mice model of TDP-43 proteinopathy

abstract:
BackgroundOzone (O3), one of the main photochemical pollutants in the atmosphere today, is a serious health risk factor. Although the effects of O3 exposure have been documented on many diseases, they have not yet been examined on Amyotrophic Lateral Sclerosis (ALS)- a fatal progressive and neurodegenerative disease.

ObjectivesTo investigate the effect of the O3 exposure in a mice model of TDP-43 proteinopathy, exploring a possible association between the O3 exposure and the ALS pathogenesis.

MethodsTDP-43A315T and wild-type (WT) mice were exposed to O3 (0.25 ppm) or filtered air (FA) for 15 days (4 hours/day). We assessed (1) weight loss (2) motor performance (3) plasma glucose content and (4) metabolic markers from plasma samples of the animals.

ResultsThroughout the experiment, we observed a progressive decline in body weight and the motor coordination in TDP-43A315T mice compared to WT controls. Although there was a trend, there were no significant differences in the decline of body weight of TDP-43A315T mice when exposed to either FA or O3. In O3-TDP-43A315T mice, the disease duration lasted longer. In addition, O3-TDP-43A315T mice showed improvements in motor performance as well TDP-43A315T mice were hypoglycemic compared to WT mice. However, FA-TDP-43A315T mice showed lower plasma glucose levels at the disease end-stage. We found altered levels of adipokines and metabolic proteins in TDP-43A315T mice compared to WT controls. A positive correlation was found among GIP and glucagon compared to insulin concentrations in control mice. Interestingly, resistin, Gastric Inhibitory Peptide (GIP), Glucagon Like Peptide 1 (GIP-1) and insulin levels were higher in O3-TDP-43A315T mice.

DiscussionWe provide new evidence about a mechanistic link between O3 exposure and the improvement of the metabolic disturbances present in TDP-43A315T mice. Further studies are needed to corroborate the obtained results as they warrant to understanding the underlying mechanisms.


title: Developmental change in prefrontal cortex recruitment supports the emergence of value-guided memory

abstract: Prioritizing memory for valuable information can promote adaptive behavior across the lifespan, but it is unclear how the neurocognitive mechanisms that enable the selective acquisition of useful knowledge develop. Here, using a novel task coupled with functional magnetic resonance imaging, we examined how children, adolescents, and adults (N = 90) learn from experience what information is likely to be rewarding, and modulate encoding and retrieval processes accordingly. We found that the ability to use learned value signals to selectively enhance memory for useful information strengthened throughout childhood and into adolescence. Encoding and retrieval of high- vs. low-value information was associated with increased activation in striatal and prefrontal regions implicated in value processing and cognitive control. Age-related increases in value-based lateral prefrontal cortex modulation mediated the relation between age and memory selectivity. Our findings demonstrate that developmental increases in the strategic engagement of the prefrontal cortex support the emergence of adaptive memory.


title: DLAB - Deep learning methods for structure-based virtual screening of antibodies

abstract:
Antibodies are one of the most important classes of pharmaceuticals, with over 80 approved molecules currently in use against a wide variety of diseases. The drug discovery process for antibody therapeutic candidates however is time-and cost-intensive and heavily reliant on in-vivo and in-vitro high throughput screens. Here, we introduce a framework for structure-based deep learning for antibodies (DLAB) which can virtually screen putative binding antibodies against antigen targets of interest. DLAB is built to be able to predict antibody-antigen binding for antigens with no known antibody binders.

We demonstrate that DLAB can be used both to improve antibody-antigen docking and structure-based virtual screening of antibody drug candidates. DLAB enables improved pose ranking for antibody docking experiments as well as selection of antibody-antigen pairings for which accurate poses are generated and correctly ranked. We also show that DLAB can identify binding antibodies against specific antigens in a case study. Our results demonstrate the promise of deep learning methods for structure-based virtual screening of antibodies.


title: PolyA: a tool for adjudicating competing annotations of biological sequences

abstract: Annotation of a biological sequence is usually performed by aligning that sequence to a database of known sequence elements. When that database contains elements that are highly similar to each other, the proper annotation may be ambiguous, because several entries in the database produce high-scoring alignments. Typical annotation methods work by assigning a label based on the candidate annotation with the highest alignment score; this can overstate annotation certainty, mislabel boundaries, and fails to identify large scale rearrangements or insertions within the annotated sequence. Here, we present a new software tool, PolyA, that adjudicates between competing alignment-based annotations by computing estimates of annotation confidence, identifying a trace with maximal confidence, and recursively splicing/stitching inserted elements. PolyA communicates annotation certainty, identifies large scale rearrangements, and detects boundaries between neighboring elements.


title: Characterizing white matter alterations in drug-naïve de novo Parkinsons disease with diffusion MRI

abstract: Parkinsons disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and non-motor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease-related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel-based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel-based analysis (FBA) is a recent framework that offers tract-specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug-naive de novo PD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to both functional degeneration and the creation of compensatory networks in the early stage.


title: Revealing the Physiological Origin of Event-Related Potentials using Electrocorticography in Humans

abstract: The scientific and clinical value of event-related potentials (ERPs) depends on understanding the contributions to them of three possible mechanisms: (1) additivity of time-locked voltage changes; (2) phase resetting of ongoing oscillations; (3) asymmetrical oscillatory activity. Their relative contributions are currently uncertain. This study uses analysis of human electrocorticographic activity to quantify the origins of movement-related potentials (MRPs) and auditory evoked potentials (AEPs). The results show that MRPs are generated primarily by endogenous additivity (88%). In contrast, P1 and N1 components of AEPs are generated almost entirely by exogenous phase reset (93%). Oscillatory asymmetry contributes very little. By clarifying ERP mechanisms, these results enable creation of ERP models; and they enhance the value of ERPs for understanding the genesis of normal and abnormal auditory or sensorimotor behaviors.


title: Rapid processing and quantitative evaluation of multicontrast EPImix scans for adaptive multimodal imaging

abstract:
Current neuroimaging acquisition and processing approaches tend to be optimised for quality rather than speed. However, rapid acquisition and processing of neuroimaging data can lead to novel neuroimaging paradigms, such as adaptive acquisition, where rapidly processed data is used to inform subsequent image acquisition steps. Here we first evaluate the impact of several processing steps on the processing time and quality of registration of manually labelled T1-weighted MRI scans. Subsequently, we apply the selected rapid processing pipeline both to rapidly acquired multicontrast EPImix scans of 95 participants (which include T1-FLAIR, T2, T2*, T2-FLAIR, DWI & ADC contrasts, acquired in [~]1 minute), as well as to slower, more standard single-contrast T1-weighted scans of a subset of 66 participants. We quantify the correspondence between EPImix and single-contrast T1-weighted scans, using correlations between voxels and regions of interest across participants, measures of within- and between-participant identifiability as well as regional structural covariance networks. Furthermore, we explore the use of EPImix for the rapid construction of morphometric similarity networks. Finally, we quantify the reliability of EPImix-derived data using test-retest scans of 10 participants. Our results demonstrate that quantitative information can be derived from a neuroimaging scan acquired and processed within minutes, which could further be used to implement adaptive multimodal imaging and tailor neuroimaging examinations to individual patients.

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title: Rheb-mTOR Activation Rescues Amyloid Beta-Induced Cognitive Impairment and Memory Function by Restoring miR-146 Activity in Glial Cells

abstract: Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimers disease patients brain suggests ineffective target cytokine mRNA suppression by existing microRNPs in diseased brain. Exploring the mechanism of amyloid beta induced cytokine expression, we have identified how the inactivation of the repressive miR-146 microRNPs causes increased production of cytokines in amyloid beta exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer induced sequestration of mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling and retarded Ago2-cytokine mRNA interaction in rat astrocyte cells. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 microRNPs in amyloid beta exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimers disease.


title: FORUM: Building a Knowledge Graph from public databases and scientific literature to extract associations between chemicals and diseases

abstract:
Metabolomics studies aim at reporting a metabolic signature (list of metabolites) related to a particular experimental condition. These signatures are instrumental in the identification of biomarkers or classification of individuals, however their biological and physiological interpretation remains a challenge. Overcoming this challenge is critical when aiming to associate metabolic signatures with potential pathological outcomes. To support this task, we introduce FORUM: a Knowledge Graph (KG) providing a semantic representation of relations between chemicals and biomedical concepts, built from a federation of life science databases and scientific literature repositories. An important number of scientific articles discuss relations between chemical compounds and biomedical concepts in various contexts, from biomarkers to therapeutic uses. The extraction of these statements and their interconnection in a graph structure can thus allow us to identify and explore relations strongly supported in the scientific literature.

The use of a Semantic Web framework on biological data allows us to apply ontological based reasoning to infer new relations between entities. We show that these new relations provide different levels of abstraction and could open the path to new hypotheses. We estimate the statistical relevance of each extracted relation, explicit or inferred, using an enrichment analysis, and instantiate them as new knowledge in the KG to support results interpretation/further inquiries. Beyond this result, FORUM can also provide insights into complex biological questions and the extracted information could then be used for further developments.

Containing more than 8 billion triples and providing more than 8 million relations, FORUM leverages the increasing availability of linked datasets in life science and is built in agreement with FAIR principles. A web interface to browse and download the extracted relations, as well as a SPARQL endpoint to directly probe the whole FORUM knowledge graph, are available at https://forum-webapp.semantic-metabolomics.fr. The code needed to reproduce the triplestore is available at https://github.com/eMetaboHUB/Forum-DiseasesChem.


title: COMPMAP: an allele-specific expression read-counter based on competitive mapping

abstract:
SummaryChanges to regulatory sequences account for important phenotypic differences between species and populations. In heterozygote individuals, regulatory polymorphism typically manifests as allele-specific expression (ASE) of transcripts. ASE data from inter-species and inter-population hybrids, in conjunction with expression data from the parents, can be used to infer regulatory changes in cis and trans throughout the genome. Improper data handling, however, can create problems of mapping bias and excessive loss of information, which are prone to arise unintentionally from the cumbersome pipelines with multiple dependencies that are common among current methods. Here, we introduce a new, selfcontained method implemented in Python that generates allele-specific expression counts from genotype-specific map alignments. Rather than assessing individual SNPs, our approach sorts and counts reads within a given homologous region by comparing individual read-mapping statistics from each parental alignment. Reads that are aligned ambiguously to both references are resolved proportionally to the allele-specific matching read counts or statistically using a binomial distribution. Using simulations, we show CompMap has low error rates in assessing regulatory divergence.

AvailabilityThe Python code with examples and installation instructions is available on the GitHub repository https://github.com/santiagosnchez/CompMap

Contactsantiago.snchez@gmail.com

Supplementary information


title: StrainGE: A toolkit to track and characterize low-abundance strains in complex microbial communities

abstract: Human-associated microbial communities comprise not only complex mixtures of bacterial species, but also mixtures of conspecific strains, the implications of which are mostly unknown since strain level dynamics are underexplored due to the difficulties of studying them. We introduce the Strain Genome Explorer (StrainGE) toolkit, which deconvolves strain mixtures and characterizes component strains at the nucleotide level from short-read metagenomic sequencing with higher sensitivity and resolution than other tools. StrainGE is able to identify nearest known references and find variants for multiple conspecific strains within a sample at relative abundances below 0.1% in typical metagenomic datasets.