title: The Unique Cytoarchitecture and Wiring of the Human Default Mode Network

abstract: It is challenging to specify the role of the default mode network (DMN) in human behaviour. Contemporary theories, based on functional magnetic resonance imaging (MRI), suggest that the DMN is insulated from the external world, which allows it to support perceptually-decoupled states and to integrate external and internal information in the construction of abstract meanings. To date, the neuronal architecture of the DMN has received relatively little attention. Understanding the cytoarchitectural composition and connectional layout of the DMN will provide novel insights into its role in brain function. We mapped cytoarchitectural variation within the DMN using a cortical type atlas and a histological model of the entire human brain. Next, we used MRI acquired in healthy young adults to explicate structural wiring and effective connectivity. We discovered profound diversity of DMN cytoarchitecture. Connectivity is organised along the most dominant cytoarchitectural axis. One side of the axis is the prominent receiver, whereas the other side remains more insulated, especially from sensory areas. The structural heterogeneity of the DMN engenders a network-level balance in communication with external and internal sources, which is distinctive, relative to other functional communities. The neuronal architecture of the DMN suggests it is a protuberance from the core cortical processing hierarchy and holds a unique role in information integration.


title: Causal contributions of neural noise to left frontal networks subtending the modulation of conscious visual perception in the human brain

abstract: For several decades, the field of human neurophysiology has focused on the role played by cortical oscillations in enabling brain function underpinning behaviors. In parallel, a less visible but robust body of work on the stochastic resonance phenomenon has also theorized contributions of neural noise - hence more heterogeneous, complex and less predictable activity - in brain coding. The latter notion has received indirect causal support via improvements of visual function during non-regular or random brain stimulation patterns. Nonetheless, direct evidence demonstrating an impact of brain stimulation on direct measures of neural noise is still lacking. Here we evaluated the impact of three non frequency-specific TMS bursts, compared to a control pure high-beta TMS rhythm, delivered to the left FEF during a visual detection task, on the heterogeneity, predictability and complexity of ongoing brain activity recorded with scalp EEG. Our data showed surprisingly that the three non frequency-specific TMS patterns did not prevent a build-up of local high-beta activity. Nonetheless, they increased power across broader or in multiple frequency bands compared to control purely rhythmic high-beta bursts tested along. Importantly, non frequency-specific patterns enhanced signal entropy over multiple time-scales, suggesting higher complexity and an overall induction of higher levels of cortical noise than rhythmic TMS bursts. Our outcomes provide indirect evidence on a potential modulatory role played by sources of stochastic noise on brain oscillations and synchronization. Additionally, they pave the way towards the development of novel neurostimulation approaches to manipulate cortical sources of noise and further investigate their causal role in neural coding.

category: neuroscience


title: Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection

abstract: While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF- were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.

category: immunology


title: Comparative genomics and pangenomics of vancomycin resistant and susceptible Enterococcus faecium from Irish hospitals across 20 years

abstract: Enterococcus faecium has emerged as an important nosocomial pathogen, which is increasingly difficult to treat due to the genetic acquisition of vancomycin resistance. Ireland exhibits a recalcitrant vancomycin resistant bloodstream infection rate compared to other developed countries. A set of 28 vancomycin resistant isolates was sequenced to construct a dataset alongside 61 other publicly available Irish genomes. This dataset was extensively analysed using in-silico methodologies and uncovered distinct evolutionary, coevolutionary, and clinically relevant population trends. These results suggest that a stable (in terms of genome size, GC%, and number of genes), yet genetically diverse population (in terms of gene content) of Enterococcus faecium persist in Ireland with acquired resistance arising via plasmid acquisition (vanA) or to a lesser extent, chromosomal recombination (vanB). Population analysis described five clusters with one cluster partitioned into four clades which transcend isolation dates. Pangenomic and recombination analyses revealed an open (whole genome and chromosomal specific) pangenome illustrating a rampant evolutionary pattern. Comparative resistomics and virulomics uncovered distinct chromosomal and mobilomal propensity for multidrug resistance, widespread chromosomal point-mutation mediated resistance, and chromosomal harboured arsenals of virulence factors. Comparative phagomics revealed a core prophagome of three prophages throughout the dataset. Interestingly, a potential difference in biofilm formation strategies was highlighted by coevolutionary analysis, suggesting differential biofilm genotypes between vanA and vanB isolates. These results highlight the evolutionary history of Irish Enterococcus faecium isolates and may provide an insight into underlying infection dynamics in a clinical setting.

category: microbiology


title: The energy requirements of ion homeostasis determine the lifespan of starving bacteria

abstract: The majority of microbes on earth, whether they live in the ocean, the soil or in animals, are not growing, but instead struggling to survive starvation1-6. Some genes and environmental conditions affecting starvation survival have been identified7-13, but despite almost a century of study14-16, we do not know which processes lead to irreversible loss of viability, which maintenance processes counteract them and how lifespan is determined from the balance of these opposing processes. Here, we used time-lapse microscopy to capture and characterize the cell death process of E. coli during carbon starvation for the first time. We found that a lack of nutrients results in the collapse of ion homeostasis, triggering a positive-feedback cascade of osmotic swelling and membrane permeabilization that ultimately results in lysis. Based on these findings, we hypothesized that ion transport is the major energetic requirement for starving cells and the primary determinant of the timing of lysis. We therefore developed a mathematical model that integrates ion homeostasis and  cannibalistic nutrient recycling from perished cells16,17 to predict lifespan changes under diverse conditions, such as changes of cell size, medium composition, and prior growth conditions. Guided by model predictions, we found that cell death during starvation could be dramatically slowed by replacing inorganic ions from the medium with a non-permeating osmoprotectant, removing the cost of ion homeostasis and preventing lysis. Our quantitative and predictive model explains how survival kinetics are determined in starvation and elucidates the mechanistic underpinnings of starvation survival.


title: Genome context influences evolutionary flexibility of nearly identical type III effectors in two phytopathogenic Pseudomonads

abstract: Integrative Conjugative Elements (ICEs) are replicons that can insert and excise from chromosomal locations in a site specific manner, can conjugate across strains, and which often carry a variety of genes useful for bacterial growth and survival under specific conditions. Although ICEs have been identified and vetted within certain clades of the agricultural pathogen Pseudomonas syringae, the impact of ICE carriage and transfer across the entire P. syringae species complex remains underexplored. Here we identify and vet an ICE (PmaICE-DQ) from P. syringae pv. maculicola ES4326, a strain commonly used for laboratory virulence experiments, demonstrate that this element can excise and conjugate across strains, and contains loci encoding multiple type III effector proteins. Moreover, genome context suggests that another ICE (PmaICE-AOAB) is highly similar in comparison with and found immediately adjacent to PmaICE-DQ within the chromosome of strain ES4326, and also contains multiple type III effectors. Lastly, we present passage data from in planta experiments that suggests that genomic plasticity associated with ICEs may enable strains to more rapidly lose type III effectors that trigger R-gene mediated resistance in comparison to strains where nearly isogenic effectors are not present in ICEs. Taken together, our study sheds light on a set of ICE elements from P. syringae pv. maculicola ES4326 and highlights how genomic context may lead to different evolutionary dynamics for shared virulence genes between strains.


title: Mechanically induced nuclear shuttling of β-catenin requires co-transfer of actin

abstract:
Mesenchymal stem cells (MSC) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, {beta}-catenin and Yes-Associated Protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles x 2%) and static (1 x 2% hold) strain on nuclear translocation of {beta}-catenin and YAP1 at 3h after force application. Dynamic strain induced nuclear accumulation of {beta}-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced {beta}-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid (LPA) did not increase nuclear content of {beta}-catenin or actin, but induced robust nuclear increase in YAP1. As actin binds {beta}-catenin, we considered whether {beta}-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both {beta}-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of {beta}-catenin via mechanisms utilized for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, {beta}-catenin and YAP1.

Significance statementCells integrate both static and dynamic mechanical signals through the actin cytoskeleton which is attached to the nuclear envelope, affecting nuclear transport of {beta}-catenin and YAP1. Dynamic strain induces nuclear translocation of {beta}-catenin, but not YAP1, while static strain causes nuclear translocation of YAP1, but not {beta}-catenin. Importantly, nuclear transport of actin is induced by dynamic but not static force. Furthermore, nuclear import of {beta}-catenin depends on cofilin/importin-9 dependent actin transport mechanisms. Thus the presence of {beta}-catenin and YAP1 in the nucleus represent specific responses to regulatory mechanical signals.

category: cell biology


title: Local adaptation mediated niche expansion in correlation with genetic richness

abstract: As a central issue in evolution and ecology, the quantitative relationship among the genome, adaptation and the niche was investigated. Local adaptation of five Escherichia coli strains carrying either the wild-type genome or reduced genomes was achieved by experimental evolution. A high-throughput fitness assay of the ancestor and evolved populations across an environmental gradient of eight niches resulted in a total of 80 fitness curves generated from 2,220 growth curves. Further analyses showed that the increases in both local adaptiveness and niche broadness were negatively correlated with genetic richness. Local adaptation caused common niche expansion, whereas niche expansion for generality or speciality was decided by genetic richness. The order of the mutations accumulated stepwise was correlated with the magnitude of the fitness increase attributed to mutation accumulation. Pre-adaptation probably participated in coordination among genetic richness, local adaptation and niche expansion.

category: evolutionary biology


title: Transcriptional and mutational signatures of the aging germline

abstract: Aging is a complex biological process which is accompanied by changes in gene expression and mutational load. In many species including humans, old fathers pass on more paternally-derived de novo mutations, however, the cellular basis and cell types driving this pattern are still unclear. To understand the root causes of this phenomenon, we performed single-cell RNA-sequencing (scRNA-seq) on testes from young and old male Drosophila, as well as genomic sequencing (DNA-seq) on somatic tissue from the same flies. We found that early germ cells from old and young flies have similar mutational loads, but older flies are less able to remove mutations during spermatogenesis. This indicates that germline mutations arise from primarily non-replicative factors, and that the increased mutational load of older males is due to differences in genome maintenance activities such as repairs to DNA damage. We also found that T>A mutations are enriched in older flies, and transcription-related enrichment terms are depleted in older males. Early spermatogenesis-enriched genes have lower dN/dS than late spermatogenesis-enriched genes, supporting the hypothesis that late spermatogenesis is the source of evolutionary innovation. This transcriptional disruption is reflected in the decreased expression of genome maintenance genes in early germ cells of older flies, as well as potentially aberrant transcription of transposable elements in the aging germline. Our results provide novel insights into the transcriptional and mutational signatures of the male germline.


title: CyanoHABs: inevitable evolutionary ecological consequence for low nutrient-requiring cyanobacteria in water eutrophication

abstract:
The mechanism of cyanobacterial harmful algal blooms (CyanoHABs) is complicated and confusing. One major reason is they are studied primarily from an ecological perspective and on bloom-forming species only. This narrow angle loses a broader evolutionary and ecological context in which CyanoHABs occur and fails to provide information on relevant components to achieve a wholistic understanding.

To derive a comprehensive mechanism of CyanoHABs, we examine CyanoHABs through the overlooked evolutionary and ecological lenses: evolutionary radiation, ecological comparison with co-living algae, and recently identified genomic functional repertoire between blooming and non-blooming species. We found four key factors: (1) elaborate diverse functional repertoire and low nutrient requirement in cyanobacteria molded by early adaptive evolution, (2) cyanobacteria having lower nutrient requirements than co-living algae, (3) there is no directed evolution in biological functions toward water eutrophication in cyanobacteria, (4) the CyanoHAB-associated functional repertoire are more abundant and complete in blooming than non-blooming species. These factors lead us to postulate a preliminary mechanism of CyanoHABs as a synergistic quad: superior functional repertoire, established with long adaptive radiation under nutrient-deficient conditions and not evolved toward eutrophic conditions, enables cyanobacteria to efficiently utilize elevated nutrients under current eutrophic levels for excess growth and CyanoHABs thereof, due to their lower nutrient requirements than co-living algae. This working comprehensive mechanism without doubt needs further empirical testing, which can be undertaken with more comparative studies of multiple species using integrated systems biology approaches.


title: CyanoHABs: unavoidable evolutionary ecological consequence for low nutrient-requiring cyanobacteria in eutrophic water


title: An evolutionary ecological mechanism of CyanoHABs: unavoidable consequences when low nutrient requirements meet eutrophication


title: A flexible workflow for building spectral libraries from narrow window data independent acquisition mass spectrometry data

abstract: Advances in library-based methods for peptide detection from data independent acquisition (DIA) mass spectrometry have made it possible to detect and quantify tens of thousands of peptides in a single mass spectrometry run. However, many of these methods rely on a comprehensive, high quality spectral library containing information about the expected retention time and fragmentation patterns of peptides in the sample. Empirical spectral libraries are often generated through data-dependent acquisition and may suffer from biases as a result. Spectral libraries can be generated in silico but these models are not trained to handle all possible post-translational modifications. Here, we propose a false discovery rate controlled spectrum-centric search workflow to generate spectral libraries directly from gas-phase fractionated DIA tandem mass spectrometry data. We demonstrate that this strategy is able to detect phosphorylated peptides and can be used to generate a spectral library for accurate peptide detection and quantitation in wide window DIA data. We compare the results of this search workflow to other library-free approaches and demonstrate that our search is competitive in terms of accuracy and sensitivity. These results demonstrate that the proposed workflow has the capacity to generate spectral libraries while avoiding the limitations of other methods.

category: bioinformatics


title: ME-ACP: Multi-view Neural Networks with Ensemble Model for Identification of Anticancer Peptides

abstract: Cancer remains one of the most threatening diseases, which kills millions of lives every year. As a promising perspective for cancer treatments, anticancer peptides (ACPs) overcome a lot of disadvantages of traditional treatments. However, it is time-consuming and expensive to identify ACPs through conventional experiments. Hence, it is urgent and necessary to develop highly effective approaches to accurately identify ACPs in large amounts of protein sequences. In this work, we proposed a novel and effective method named ME-ACP which employed multi-view neural networks with ensemble model to identify ACPs. Firstly, we employed residue level and peptide level features preliminarily with ensemble models based on lightGBMs. Then, the outputs of lightGBM classifiers were fed into a hybrid deep neural network (HDNN) to identify ACPs. The experiments on independent test datasets demonstrated that ME-ACP achieved competitive performance on common evaluation metrics.


title: Correlations from structure and phylogeny combine constructively in the inference of protein partners from sequences

abstract:
Inferring protein-protein interactions from sequences is an important task in computational biology. Recent methods based on Direct Coupling Analysis (DCA) or Mutual Information (MI) allow to find interaction partners among paralogs of two protein families. Does successful inference mainly rely on correlations from structural contacts or from phylogeny, or both? Do these two types of signal combine constructively or hinder each other? To address these questions, we generate and analyze synthetic data produced using a minimal model that allows us to control the amounts of structural constraints and phylogeny. We show that correlations from these two sources combine constructively to increase the performance of partner inference by DCA or MI. Furthermore, signal from phylogeny can rescue partner inference when signal from contacts becomes less informative, including in the realistic case where inter-protein contacts are restricted to a small subset of sites. We also demonstrate that DCA-inferred couplings between non-contact pairs of sites improve partner inference in the presence of strong phylogeny, while deteriorating it otherwise. Moreover, restricting to non-contact pairs of sites preserves inference performance in the presence of strong phylogeny. In a natural data set, as well as in realistic synthetic data based on it, we find that non-contact pairs of sites contribute positively to partner inference performance, and that restricting to them preserves performance, evidencing an important role of phylogeny.

Author summaryIn protein sequence data, the amino acid usages at different sites of a protein or of two interacting proteins can be correlated because of functional constraints. For instance, the need to maintain physicochemical complementarity among two sites that are in contact in the three-dimensional structure of a protein complex causes such correlations. However, correlations can also arise due to shared evolutionary history, even in the absence of any functional constraint. While these phylogenetic correlations are known to obscure the inference of structural contacts, we show, using controlled synthetic data, that correlations from structure and phylogeny combine constructively to allow the inference of protein partners among paralogs using just sequences. We also show that pairs of amino acids that are not in contact in the structure have a major impact on partner inference in a natural data set and in realistic synthetic ones. These findings explain the success of methods based on pairwise maximum-entropy models or on information theory at predicting protein partners from sequences among paralogs.


title: Copy number alterations and epithelial-mesenchymal transition genes in diffuse and intestinal gastric cancers in Mexican patients

abstract:
Gastric cancer (GC) is a malignancy with the highest mortality among diseases of the digestive system worldwide. The study of GC-alterations is crucial to understand tumor biology, to establish important aspects of cancer prognosis and treatment response. Here, we purified DNA and performed whole-genome analysis with high-density arrays in samples from Mexican patients diagnosed with GC: diffuse (DGC) or intestinal (IGC), or non-atrophic gastritis (NAG) samples that served as controls. We identified shared and unique copy number alterations (CNA) between these altered tissues involving key genes and signaling pathways associated with cancer, allowing their molecular distinction and identification of the most relevant molecular functions impacted. When focused on epithelial-mesenchymal transition (EMT) genes, our bioinformatic analysis revealed that the altered network associated with chromosomal alterations included 11 genes shared between DGC, IGC, and NAG, as well as 19 DGC- and 7 IGC-exclusive genes, whose main molecular functions included adhesion, angiogenesis, migration, metastasis, morphogenesis, proliferation, and survival. This study presents the first whole-genome high-density array study in GC from Mexican patients and reveals shared and exclusive CNA-genes in DGC and IGC. In addition, we provide a bioinformatically predicted network focused on CNA-altered genes involved in the EMT, associated with the hallmarks of cancer, as well as precancerous alterations that could lead to gastric cancer.

ImplicationsMolecular signatures of diffuse and intestinal GC, predicted bioinformatically, involve common and distinct CNA-EMT genes related to the hallmarks of cancer that are potential candidates for screening GC biomarkers, including early stages.

category: cancer biology


title: Genome-wide association studies and genomic selection assays made in a large sample of cacao (Theobroma cacao L.)  germplasm reveal significant marker-trait associations and good predictive value for improving yield potential

abstract: A genome-wide association study was undertaken to unravel marker-trait associations (MTAs) between SNP markers and yield-related traits. It involved a subset of 421 cacao accessions from the large and diverse collection conserved ex situ at the International Cocoa Genebank Trinidad. An average linkage disequilibrium (r2) of 0.10 at 5.2 Mb was found across several chromosomes. Seventeen significant (P [≤] 8.17 x 10-5 (-log10 (p) = 4.088)) MTAs of interest, which accounted for 5 to 17% of the explained phenotypic variation, were identified using a Mixed Linear Model in TASSEL version 5.2.50. The most significant MTAs identified were related to seed number and seed length on chromosome 7 and seed number on chromosome 1. Other significant MTAs involved seed length to width ratio on chromosomes 3 and 5 and seed length on chromosomes 4 and 9. It was noteworthy that several yield-related traits, viz., seed length, seed length to width ratio and seed number were associated with markers on different chromosomes, indicating their polygenic nature. Approximately 40 candidate genes that encode embryo and seed development, protein synthesis, carbohydrate transport and lipid biosynthesis and transport were identified in this study. A significant association of fruit surface anthocyanin intensity co-localised with MYB-related protein 308 on chromosome 4. Testing of a genomic selection approach revealed good predictive value (GEBV) for economic traits such as seed number (GEBV = 0.611), seed length (0.6199), seed width (0.5435), seed length to width ratio (0.5503), seed/cotyledon mass (0.6014) and ovule number (0.6325). The findings of this study could facilitate genomic selection and marker-assisted breeding of cacao thereby expediting improvement in the yield potential of cacao planting material.

category: genomics


title: Effect of therapeutic ultrasound on the mechanical and biological properties of fibroblasts

abstract: Conventional doses of therapeutic ultrasound alter the mechanical behavior of ligament fibroblasts to improve the regenerative and remodeling stages of the wound healing process. Using a multidisciplinary approach, we applied ultrasound doses of 1.0 and 2.0 W/cm2 at 1 MHz frequency for five days on ligament fibroblasts. Atomic force microscopy showed a decrease in cell elastic modulus for both doses, but the treated cells were still viable based on flow cytometry. Finite element method analysis exhibited visible cytoskeleton displacements and decreased harmonics in treated cells. Colorimetric assay revealed increased cell proliferation, while scratch assay showed increased migration at low doses. An increase in collagen and fibronectin was detected by enzyme-linked immunoassay at high doses, and {beta}-actin expression for both treatments was visualized through immunofluorescence imaging. Both doses of ultrasound altered the fibroblast mechanical properties due to cytoskeletal reorganization and enhanced the early and late stages of cell repair.

category: bioengineering


title: NGSpop: A desktop software that supports population studies by identifying sequence variations from next-generation sequencing data

abstract: Next-generation sequencing (NGS) is widely used in all areas of genetic research, such as for genetic disease diagnosis and breeding, and it can produce massive amounts of data. The identification of sequence variants is an important step when processing large NGS datasets; however, currently, the process is complicated, repetitive, and requires concentration, which can be taxing on the researcher. Therefore, to support researchers who are not familiar with bioinformatics in identifying sequence variations regularly from large datasets, we have developed a fully automated desktop software, NGSpop. NGSpop includes functionalities for all the variant calling and visualization procedures used when processing NGS data, such as quality control, mapping, filtering details, and variant calling. In the variant calling step, the user can select the GATK or DeepVariant algorithm for variant calling. These algorithms can be executed using pre-set pipelines and options or customized with the user-specified options. NGSpop is implemented using JavaFX (version 1.8) and can thus be run on Unix like operating systems such as Ubuntu Linux (version 16.04, 18.0.4). Although there are several pipelines and visualization tools available for NGS data analysis, most integrated environments do not support batch processes; thus, variant detection cannot be automated for population-level studies. The NGSpop software, developed in this study, has an easy-to-use interface and helps in rapid analysis of multiple NGS data from population studies.


title: A computationally efficient clustering linear combination approach to jointly analyze multiple phenotypes for GWAS

abstract: There has been an increasing interest in joint analysis of multiple phenotypes in genome-wide association studies (GWAS) because jointly analyzing multiple phenotypes may increase statistical power to detect genetic variants associated with complex diseases or traits. Recently, many statistical methods have been developed for joint analysis of multiple phenotypes in genetic association studies, including the Clustering Linear Combination (CLC) method. The CLC method works particularly well with phenotypes that have natural groupings, but due to the unknown number of clusters for a given data, the final test statistic of CLC method is the minimum p-value among all p-values of the CLC test statistics obtained from each possible number of clusters. Therefore, a simulation procedure must be used to evaluate the p-value of the final test statistic. This makes the CLC method computationally demanding. We develop a new method called computationally efficient CLC (ceCLC) to test the association between multiple phenotypes and a genetic variant. Instead of using the minimum p-value as the test statistic in the CLC method, ceCLC uses the Cauchy combination test to combine all p-values of the CLC test statistics obtained from each possible number of clusters. The test statistic of ceCLC approximately follows a standard Cauchy distribution, so the p-value can be obtained from the cumulative density function without the need for the simulation procedure. Through extensive simulation studies and application on the COPDGene data, the results demonstrate that the type I error rates of ceCLC are effectively controlled in different simulation settings and ceCLC either outperforms all other methods or has statistical power that is very close to the most powerful method with which it has been compared.


title: Biomechanical  characteristics of scapula and glenohumeral movements during pitching motion in injury-prone college baseball pitchers

abstract: Coordination of glenohumeral and scapular movements plays an important role in the injury prevention of baseball pitchers. However, there is no objective data establishing the direct relationship between pitching injuries and associated glenohumeral and scapular movements. Therefore, the objectives of the present study were to demonstrate biomechanical differences in scapular and glenohumeral movements during pitching between injury-prone pitchers and healthy college baseball pitchers. Thirty collegiate baseball pitchers were classified into two groups according to their injury status: injury-prone group (N=15, 20.7{+/-}1.4 years, 180.1{+/-}6.5 cm, 78.9{+/-}5.4 kg) and control group (N=15, 20.9{+/-}1.1 years, 177.1{+/-}6.6 cm, 72.3{+/-}6.7 kg). We obtained the pitching motion data using the three-dimensional motion analysis technique with four high-speed cameras. The horizontal abduction angles of the glenohumeral joint during cocking and acceleration phases were significantly greater in injury-prone pitchers [19.0{degrees} (95% CI: 14.4-23.6) at foot contact, -4.0{degrees} (95% CI: -7.7 to -0.2) at maximum external rotation (MER), and -0.3{degrees} (95% CI: -4.8 to -4.2) at ball release] than in healthy controls [11.7 {degrees}(95%CI:7.1 to 16.3) at foot contact, -10.0{degrees}(95%CI: -13.7 to -6.3) at MER, and -6.9{degrees}(95%CI: -11.4 to -2.4)](p<0.01). In addition, the external rotation angle (ER) of the scapula at MER was significantly greater in the injury-prone group [-0.1{degrees} (95% CI: -5.0 to 4.8)] than in the control group [-12.3{degrees} (95% CI: -17.2 to -7.4)] (p<0.01), but there was no difference in the scapular ER during foot contact between the two groups. These results suggests that injury-prone pitchers have less internal rotation of the scapula and more horizontal abduction of the glenohumeral joint during cocking and acceleration phases. Therefore, sports medicine practitioners may need to pay more attention to coordination of scapular and glenohumeral movements during the cocking and acceleration phases of pitching for prevention of shoulder injuries.

category: physiology


title: Improving behavior monitoring of free moving dairy cows using noninvasive wireless EEG approach and digital signal processing techniques.

abstract:
BackgroundElectroencephalography (EEG) is the most common method to access brain information. Techniques to monitor and to extract brain signal characteristics in farm animals are not as developed as in humans and laboratory animals.

New methodThe method comprised two steps. In the first step, the signals were acquired after the telemetric equipment was developed, the electrodes were positioned and fixed, the sample frequency was defined, the equipment was positioned, and artifacts and other acquisition problems were dealt with. Brain signals from six Holstein heifers that could move freely in free stalls were acquired. The control group consisted in the same number of bovines, contained in a climatic chamber (restrained group). In the second step, the signals were characterized by Power Spectral Density, Short-Time Fourier Transform, and Lempel-Ziv complexity.

ResultsThe results indicated that there was an ideal position to attach the electrodes to the front of the bovines head, so that longer artifact-free signal sections were acquired. The signals showed typical EEG frequency bands, like the bands found in humans. The Lempel-Ziv complexity values indicated that the bovine brain signals contained random and chaotic components. As expected, the signals acquired from the retained bovine group displayed sections with a larger number of artifacts.

Comparison with existing methodsWe present the first method that helps to monitor and to extract brain signal features in unrestrained bovines.

ConclusionsThe method could be applied to investigate changes in brain electrical activity during animal farming, to monitor brain activity related with animal behavior.

HighlightsO_LIA method that allows brain signals to be monitored in freely moving dairy cows is described
C_LIO_LIThe method uses noninvasive electrodes to minimize stress during EEG monitoring and allows bovines to behave normally during the process
C_LIO_LIThe method establishes the frequency sampling rate, electrodes positioning and fixation, equipment holding, artifact extraction, and signal characterization
C_LIO_LIThe brain signals are characterized by PSD, STFT, and Lempel-Ziv normalized complexity
C_LIO_LIThe method can be applied to relate EEG to animal behavior under normal handling conditions
C_LI

category: animal behavior and cognition


title: Jointly Optimized Spatial Histogram UNET Architecture (JOSHUA) for Adipose Tissue Segmentation

abstract:
ObjectiveWe quantify adipose tissue deposition at surgical sites as a function of biomaterial implantation.

Impact StatementTo our knowledge, this study is the first investigation to apply convolutional neural network (CNN) models to identify and segment adipose tissue in histological images from silk fibroin biomaterial implants.

IntroductionWhen designing biomaterials for the treatment of various soft tissue injuries and diseases, one must consider the extent of adipose tissue deposition. In this work, we implant silk fibroin biomaterials in a rodent subcutaneous injury model. Current strategies for quantifying adipose tissue after biomaterial implantation are often tedious and prone to human bias during analysis.

MethodsWe used CNN models with novel spatial histogram layer(s) that can more accurately identify and segment regions of adipose tissue in hematoxylin and eosin (H&E) and Massons Trichrome stained images, allowing for determination of the optimal biomaterial formulation. We compared the method, Jointly Optimized Spatial Histogram UNET Architecture (JOSHUA), to the baseline UNET model and an extension of the baseline model, Attention UNET, as well as to versions of the models with a supplemental "attention"-inspired mechanism (JOSHUA+ and UNET+).

ResultsThe inclusion of histogram layer(s) in our models shows improved performance through qualitative and quantitative evaluation.

ConclusionOur results demonstrate that the proposed methods, JOSHUA and JOSHUA+, are highly beneficial for adipose tissue identification and localization. The new histological dataset and code for our experiments are publicly available.


title: Analysis of RNA sequence and structure in key genes of Mycobacterium ulcerans reveals conserved structural motifs and regions with apparent pressure to remain unstructured

abstract:
Buruli Ulcer is a neglected tropical disease that results in disfiguring and potentially dangerous lesions in affected persons across a wide geographic area, which includes much of West Africa. The causative agent of Buruli Ulcer is Mycobacterium ulcerans, a relative of the bacterium that causes tuberculosis and leprosy. Few therapeutic options exist for the treatment of this disease beyond the main approach, surgical removal, which is frequently ineffective. In this study we analyze six genes in Mycobacterium ulcerans that have high potential of therapeutic targeting. We focus our analysis on a combined in silico and comparative sequence study of potential RNA secondary structure across these genes. The end result of this work was the comprehensive local RNA structural landscape across each of these significant genes. This revealed multiple sites of ordered and evolved RNA structure interspersed between sequences that either have no bias for structure or, indeed, appear to be ordered to be unstructured and (potentially) accessible. In addition to providing data that could be of interest to basic biology, our results provide guides for efforts aimed at targeting this pathogen at the RNA level. We explore this latter possibility through the in silico analysis of antisense oligonucleotides that could be used to target pathogen RNA.

Author SummaryBuruli Ulcer is a neglected tropical necrotizing skin disease endemic to West Africa and several other developing countries. The disease is known to be caused by Mycobacterium ulcerans, but the mode of transmission is not well understood. Here, we present findings on the RNA secondary structural landscape of key genes found in its genome and virulence plasmid. We also suggest potential therapeutic strategies to treat this disease that leverage a better understanding of RNA secondary structure. In our analysis we have predicted regions within these genes that are potentially ordered by evolution to have unusual structural stability and likely functionality, as well as regions that lack stable structure and may be unordered for accessibility. These structured regions can act as potential targets of both antisense oligonucleotide and small molecule therapeutics, while the unstructured regions may be most advantageous for only antisense oligonucleotides. Both strategies have been proven to be effective in other bacterial and viral pathogens; therefore, adaptation to this neglected disease may prove beneficial to developing more effective and efficient treatment options. Through our analysis of the RNA secondary structure landscape of key genes in M. ulcerans, we hope to provide other researchers with new avenues for development of novel therapeutic strategies to treat this devastating and neglected disease.


title: HybridDTA: Hybrid Data Fusion through Pairwise Training for Drug-Target Affinity Prediction

abstract: Candidate compounds with high binding affinities toward a target protein are likely to be developed as drugs. Deep neural networks (DNNs) have attracted increasing attention for drug-target affinity (DTA) estimation owning to their efficiency. However, the negative impact of batch effects caused by measure metrics, system technologies, and other assay information is seldom discussed when training a DNN model for DTA. Suffering from the data deviation caused by batch effects, the DNN models can only be trained on a small amount of "clean" data. Thus, it is challenging for them to provide precise and consistent estimations. We design a batch-sensitive training framework, namely BatchDTA, to train the DNN models. BatchDTA implicitly aligns multiple batches toward the same protein, alleviating the impact of the batch effects on the DNN models. Extensive experiments demonstrate that BatchDTA facilitates four mainstream DNN models to enhance the ability and robustness on multiple DTA datasets. The average concordance index (CI) of the DNN models achieves a relative improvement of 4.0%. BatchDTA can also be applied to the fused data collected from multiple sources to achieve further improvement.


title: BatchDTA: Implicit batch alignment enhances deep learning-based drug-target affinity estimation


title: iEnhancer-CLA: Self-attention-based interpretable model for enhancers and their strength prediction

abstract:
Enhancer is a class of non-coding DNA cis-acting elements that plays a crucial role in the development of eukaryotes for their transcription. Computational methods for predicting enhancers have been developed and achieve satisfactory performance. However, existing computational methods suffer from experience-based feature engineering and lack of interpretability, which not only limit the representation ability of the models to some extent, but also make it difficult to provide interpretable analysis of the model prediction findings.In this paper, we propose a novel deep-learning-based model, iEnhancer-CLA, for identifying enhancers and their strengths. Specifically, iEnhancer-CLA automatically learns sequence 1D features through multiscale convolutional neural networks (CNN), and employs a self-attention mechanism to represent global features formed by multiple elements (multibody effects). In particular, the model can provide an interpretable analysis of the enhancer motifs and key base signals by decoupling CNN modules and generating self-attention weights. To avoid the bias of setting hyperparameters manually, we construct Bayesian optimization methods to obtain model global optimization hyperparameters. The results demonstrate that our method outperforms existing predictors in terms of accuracy for identifying enhancers and their strengths. Importantly, our analyses found that the distribution of bases in enhancers is uneven and the base G contents are more enriched, while the distribution of bases in non-enhancers is relatively even. This result contributes to the improvement of prediction performance and thus facilitates revealing an in-depth understanding of the potential functional mechanisms of enhancers.

Author summaryThe enhancers contain many subspecies and the accuracy of existing models is difficult to improve due to the small data set. Motivated by the need for accurate and efficient methods to predict enhancer types, we developed a self-attention deep learning model iEnhancer-CLA, the aim is to be able to distinguish effectively and quickly between subspecies of enhancers and whether they are enhancers or not. The model is able to learn sequence features effectively through the combination of multi-scale CNN blocks, BLSTM layers, and self-attention mechanisms, thus improving the accuracy of the model. Encouragingly, by decoupling the CNN layer it was found that the layer was effective in learning the motif of the sequences, which in combination with the self-attention weights could provide interpretability to the model. We further performed sequence analysis in conjunction with the model-generated weights and discovered differences in enhancer and non-enhancer sequence characteristics. This phenomenon can be a guide for the construction of subsequent models for identifying enhancer sequences.


title: Simulation of aerosol dispersion during medical examinations

abstract: The main route of transmission of the SARS-CoV2 virus has been shown to be airborne. The objective of this study is to analyze the aerosol dispersion and potential exposure to medical staff within a typical medical examination room during classical airway procedures. The multiphase simulation of the aerosol particles in the airflow is based on a Lagrangian-Eulerian approach. All simulation cases with surgical mask show partially but significantly reduced maxi-mum dispersion distances of the aerosol particles compared to the cases without surgical mask. The simulations have shown that medical examiner are exposed to large amount of aerosol particles, especially during procedures such as laryngoscopy where the examiners head is directly in front of the the patients face. However, exposure can be drastically reduced if the patient wears a mask which is possible for the most of the procedures studied, such as otoscopy, sonography, or anamnesis.


title: The systematic assessment of completeness of public metadata accompanying omics studies

abstract: The scientific community has accumulated enormous amounts of genomic data stored in specialized public repositories. Genomic data is easily accessible and available from public genomic repositories allowing the biomedical community to effectively share the omics datasets. However, improperly annotated or incomplete metadata accompanying the raw omics data can negatively impact the utility of shared data for secondary analysis. In this study, we perform a comprehensive analysis under 137 studies over 18,559 samples across six therapeutics fields to assess the completeness of metadata accompanying omics studies in both publication and its related online repositories across and make observations about how the process of data sharing could be made reliable. This analysis involved finding studies based on the six therapeutic fields, that are Alzheimers disease, acute myeloid leukemia, cystic fibrosis, cardiovascular diseases, inflammatory bowel disease, sepsis, and tuberculosis. We carefully examined the availability of metadata over nine clinical variables, that included disease condition, age, organism, sex, tissue type, ethnicity, country, mortality, and clinical severity. By comparing the metadata availability in both original publications and online repositories, we observed discrepancies in sharing the metadata. We determine that the overall availability of metadata is 72.8%, where the most complete reported phenotypes are disease condition and organism, and the least is mortality. Additionally, we examined the completeness of metadata reported separately in original publications and online repositories. The completeness of metadata from the original publication across the nine clinical phenotypes is 71.1%. In contrast, the overall completeness of metadata information from the public repositories is 48.6%. Our study is the first one to systematically assess the completeness of metadata accompanying raw data across a large number of studies and phenotypes and opens a crucial discussion about solutions to improve completeness and accessibility of metadata accompanying omics studies.


title: Quantification of alternative 3'UTR isoforms from single cell RNA-seq data with scUTRquant

abstract: Although half of human genes use alternative polyadenylation (APA) to generate mRNA isoforms that encode the same protein but differ in their 3'UTRs, most single cell RNA-sequencing (scRNA-seq) pipelines only measure gene expression. Here, we describe an open-access pipeline, called scUTRquant (https://github.com/Mayrlab/scUTRquant), that measures gene and 3'UTR isoform expression from scRNA-seq data obtained from known cell types in any species. scUTRquant-derived gene and 3'UTR transcript counts were validated against standard methods which demonstrated their accuracy. 3'UTR isoform quantification was substantially more reproducible than previous methods. scUTRquant provides an atlas of high-confidence 3' end cleavage sites at single-nucleotide resolution to allow APA comparison across mouse datasets. Analysis of 120 mouse cell types revealed that during differentiation genes either change their expression or they change their 3'UTR isoform usage. Therefore, we identified thousands of genes with 3'UTR isoform changes that have previously not been implicated in specific biological processes.


title: IReNA: integrated regulatory network analysis of single-cell transcriptomes

abstract: Although single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) have been widely used, few methods can reliably integrate these data to perform regulatory network analysis. Here, we developed IReNA (Integrated Regulatory Network Analysis) for network inference through integrated analysis of scRNA-seq and scATAC-seq data, network modularization, transcription factor enrichment, and construction of simplified intermodular regulatory networks. Using public datasets, we showed that integrated network analysis of scRNA-seq and scATAC-seq data using IReNA outperformed currently available methods in identifying known regulators. IReNA facilitates the systems-level understanding of biological regulatory mechanisms, and is available at https://github.com/jiang-junyao/IReNA.


title: Locally synchronized ciliary domains and tissue-scale cilia alignment underlie global metachronal wave patterns

abstract: Motile cilia are hair-like cell extensions present in multiple organs of the body. How cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine here experiments, novel analysis tools, and theory to address this knowledge gap. We investigate collective dynamics of cilia in the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Despite the fact that synchronization is local only, we observed global patterns of traveling metachronal waves across the multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right nose, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment are sufficient to generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.

category: biophysics


title: Local synchronization of cilia and tissue-scale cilia alignment are sufficient for global metachronal waves


title: FLI1 and FRA1 transcription factors drive the transcriptional regulatory networks characterizing muscle invasive bladder cancer

abstract: Bladder cancer is mostly present in the form of urothelium carcinoma, causing over 150.000 deaths each year. Its histopathological classification as muscle invasive (MIBC) and non-muscle invasive (NMIBC) is the most prominent aspect, affecting the prognosis and progression of this disease. In this study, we defined the active regulatory landscape of MIBC and NMIBC cell lines using H3K27ac-seq and used an integrative data approach to combine our findings with existing data. Our analysis revealed FRA1 and FLI1 as the two critical transcription factors differentially regulating MIBC regulatory landscape. Importantly, we show that FRA1 and FLI1 regulate the genes involved in epithelial cell migration and cell junction organization. Knock-down of FRA1 and FLI1 in MIBC revealed the downregulation of several EMT-related genes such as MAP4K4 and FLOT1. Further, ChIP-SICAP performed for FRA1 and FLI1 enabled us to infer chromatin binding partners of these two transcription factors and link this information with their target genes, providing a comprehensive regulatory circuit for the genes implicated in invasive ability of the bladder cancer cells. Finally, for the first time we show that knock-down of FRA1 and FRA1-FLI1 double knock-down results in significant reduction of invasion capacity of MIBC cells towards muscle microenvironment using IC-CHIP assays. Our results collectively highlight the role of these two transcription factors in invasive characteristics of bladder cancer in selection and design of targeted options for treatment of MIBC.


title: Isolation and characterisation of quercitrin as a potent anti-sickle cell anaemia agent from Alchornea cordifolia.

abstract: Alchornea cordifolia Mull. Arg. (commonly known as Christmas Bush) has been used traditionally in Africa to treat sickle cell anaemia (a recessive disease, arising from the S haemoglobin [Hb] allele) but the active compounds are yet to be characterised. Herein we describe the use of sequential fractionation coupled with in vitro anti-sickling assays to purify the active component. Sickling was induced in HbSS genotype blood samples using sodium metabisulphite (Na2S2O5) or incubation in 100 % N2. Methanol extracts of A. cordifolia leaves and its sub-fractions showed >70 % suppression of HbSS erythrocyte sickling. Purified compound demonstrated 87.2 {+/-} 2.39 % significant anti-sickling activity and 93.1 {+/-} 2.69 % erythrocyte sickling-inhibition at 0.4 mg/mL. Nuclear magnetic resonance (NMR) spectra and high-resolution mass spectroscopy identified it as quercitrin (quercetin 3-rhamnoside). Purified quercitrin also inhibited the polymerisation of isolated HbS and stabilized sickle erythrocytes membranes. Metabolomic comparisons of blood samples using flow-infusion electrospray-high resolution mass spectrometry indicated that quercitrin could convert HbSS erythrocyte metabolomes to be similar to HbAA. Sickling was associated with changes in anti-oxidants, anaerobic bioenergy and arachidonic acid metabolism, all of which were reversed by quercitrin. The findings described could inform efforts directed to the development of an anti-sickling drug or quality control assessments of A. cordifolia preparations.

category: pharmacology and toxicology


title: Single-cell dissection of obesity-exercise axis in adipose-muscle tissues

abstract: Regular physical exercise has long been recognized to reverse the effects of diet-induced obesity, but the molecular mechanisms mediating these multi-tissue beneficial effects remain uncharacterized. Here, we address this challenge by studying the opposing effects of exercise training and high-fat diet at single-cell, deconvolution and tissue-level resolutions across 3 metabolic tissues. We profile scRNA-seq in 204,883 cells, grouped into 53 distinct cell subtypes/states in 22 major cell types, from subcuta-neous and visceral white adipose tissue (WAT), and skeletal muscle (SkM) in mice with diet and exercise training interventions. With a great number of mesenchymal stem cells (MSCs) profiled, we compared depot-specific adipose stem cell (ASC) states, and defined 7 distinct fibro-adipogenic progenitor (FAP) states in SkM including discovering and validating a novel CD140+/CD34+/SCA1-FAP population. Exercise- and obesity-regulated proportion, transcriptional and cell-cell interaction changes were most strongly pronounced in and centered around ASCs, FAPs, macrophages and T-cells. These changes reflected thermogenesis-vs-lipogenesis and hyperplasia-vs-hypertrophy shifts, clustered in pathways including extracellular matrix remodeling and circadian rhythm, and implicated complex single- and multi-tissue communication including training-associated shift of a cytokine from binding to its decoy receptor on ASCs to true receptor on M2 macrophages in vWAT. Overall, our work provides new insights on the metabolic protective effects of exercise training, uncovers a previously-underappreciated role of MSCs in mediating tissue-specific and multi-tissue effects, and serves as a model for multitissue single-cell analyses in physiologically complex and multifactorial traits exemplified by obesity and exercise training.


title: Viral genome-capsid core senses host environments to prime RNA release

abstract:
Viruses are metastable macromolecular assemblies containing a nucleic acid core packaged by capsid proteins that are primed to disassemble in host-specific environments leading to genome release and replication. The mechanism of how viruses sense environmental changes associated with host entry to prime them for disassembly is unknown. We have applied a combination of mass spectrometry, cryo-EM, and simulation-assisted structure refinement to Turnip crinkle virus (TCV), which serves as a model non-enveloped icosahedral virus (Triangulation number = 3, 180 copies/icosahedron). Our results reveal genomic RNA tightly binds a subset of viral coat proteins to form a stable RNA-capsid core which undergoes conformational switching in response to host-specific environmental changes. These changes include: i) Depletion of Ca2+ which triggers viral particle expansion ii) Increase in osmolytes further disrupt interactions of outer coat proteins from the RNA-capsid core to promote complete viral disassembly. A cryo-EM structure of the expanded particle shows that RNA is asymmetrically extruded from a single 5-fold axis during disassembly. The genomic RNA:capsid protein interactions confer metastability to the TCV capsid and drive release of RNA from the disassembling virion within the plant host cell.

AUTHOR SUMMARYRNA viruses including coronaviruses, dengue, influenza, and HIV are a significant threat to human health. These viral particles are finely tuned to undergo complex conformational changes that allow for response to varied environments. Turnip crinkle virus (TCV) serves as an excellent model for studying RNA virus dynamics. Since TCV is non-enveloped and has no post-translational modifications, we can specifically investigate the contributions of RNA to viral dynamics. Genomic RNA is not a passive entity but plays a crucial and previously uncharacterized role in viral disassembly. Our results reveal that the genomic RNA-capsid core serves as an environmental sensor and undergoes conformational switching in response to host cell conditions.

category: plant biology


title: Patient brain organoids identify a link between the 16p11.2 copy number variant and the RBFOX1 gene.

abstract: Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, like human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 18 patients and controls, profiling 167,958 cells with single cell (sc)RNA-seq. Analysis revealed neuronal-specific differential expression of genes outside of the 16p11.2 region that were related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene which can also harbor CNVs linked to neurodevelopmental phenotypes. We found that many genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with 16p11.2 deletion syndrome, and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.


title: mrHARDIflow : A pipeline tailored for the preprocessing and analysis of Multi-Resolution High Angular diffusion MRI and its application to a variability study of the PRIME-DE database

abstract: The validation of advanced methods in diffusion MRI requires finer acquisition resolutions, which is hard to acquire with decent Signal-to-Noise Ratio (SNR) in humans. The use of Non-Human Primates (NHP) and anaesthesia is key to unlock valid microstructural maps, but tools must be adapted and configured finely for them to work well. Here, we propose a novel processing pipeline implemented in Nextflow, designed for robustness and scalability, in a modular fashion to allow for maintainability and a high level of customization and parametrization, tailored for the analysis of diffusion data acquired on multiple spatial resolutions. Modules of processes and workflows were implemented upon cutting edge and state-of-the-art MRI processing technologies and diffusion modelling algorithms, namely Diffusion Tensor Imaging (DTI), Constrained Spherical Deconvolution (CSD) and DIstribution of Anisotropic MicrOstructural eNvironments in Diffusion-compartment imaging (DIAMOND), a multi-tensor distribution estimator. Using our pipeline, we provide an in-depth study of the variability of diffusion models and measurements computed on 32 subjects from 3 sites of the PRIME-DE, a database containing anatomical (T1, T2), functional (fMRI) and diffusion (DWI) imaging of Non-Human Primate (NHP). Together, they offer images acquired over a range of different spatial resolutions, using single-shell and multi-shell b-value gradient samplings, on multiple scanner vendors, that present artifacts at different level of importance. We also perform a reproducibility study of DTI, CSD and DIAMOND measurements outputed by the pipeline, using the Aix-Marseilles site, to ensure our implementation has minimal impact on their variability. We observe very high reproducibility from a majority of diffusion measurements, only gamma distribution parameters computed on the DIAMOND model display a less reproducible behaviour. This should be taken into consideration when future applications are performed. We also show that even if promising, the PRIME-DE diffusion data exhibits a great level of variability and its usage should be done with care to prevent instilling uncertainty in statistical analyses.


title: Perceived facial happiness during conversation correlates with insular and hypothalamus activity for humans, not robots. An investigation of the somatic marker hypothesis applied to social interactions.

abstract: The somatic marker hypothesis posits that perceiving emotions entails reenacting markers of self emotions, in particular in the autonomous nervous system. Well studied in decision-making tasks, it has not been tested in a social cognitive neuroscience framework, and in particular for the automatic processing of positive emotions during natural interactions. Here, we address this question using a unique corpus of brain activity recorded during unconstrained conversations between participants and a human or a humanoid robot. fMRI recordings are used to test whether activity in the most important brain regions in relation to the autonomic system, the amygdala, hypothalamus and insula, is affected by the level of happiness expressed by the human and robot agents. Results indicate that for the hypothalamus and the insula, in particular the anterior agranular region strongly involved in processing social emotions, activity in the right hemisphere increases with the level of happiness expressed by the human, but not the robot. Results indicate that perceiving positive emotions in social interactions induces the local brain responses predicted by the somatic marker hypothesis, but only when the interacting agent is a real human.


title: Fine-tuning of deep language models as a computational framework of modeling listeners' perspective during language comprehension

abstract: Computational Deep Language Models (DLMs) have been shown to be effective in predicting neural responses during natural language processing. This study introduces a novel computational framework, based on the concept of fine-tuning (Hinton, 2007), for modeling differences in interpretation of narratives based on the listeners perspective (i.e. their prior knowledge, thoughts, and beliefs). We draw on an fMRI experiment conducted by Yeshurun et al. (2017), in which two groups of listeners were listening to the same narrative but with two different perspectives (cheating versus paranoia). We collected a dedicated dataset of ~3000 stories, and used it to create two modified (fine-tuned) versions of a pre-trained DLM, each representing the perspective of a different group of listeners. Information extracted from each of the two fine-tuned models was better fitted with neural responses of the corresponding group of listeners. Furthermore, we show that the degree of difference between the listeners interpretation of the story - as measured both neurally and behaviorally - can be approximated using the distances between the representations of the story extracted from these two fine-tuned models. These models-brain associations were expressed in many language-related brain areas, as well as in several higher-order areas related to the default-mode and the mentalizing networks, therefore implying that computational fine-tuning reliably captures relevant aspects of human language comprehension across different levels of cognitive processing.


title: Characterizing the short-latency evoked response to intracortical microstimulation across a multi-electrode array

abstract:
ObjectivePersons with tetraplegia can use brain-machine interfaces to make visually guided reaches with robotic arms. Without somatosensory feedback, these movements will likely be slow and imprecise, like those of persons who retain movement but have lost proprioception. Intracortical microstimulation (ICMS) has promise for providing artificial somatosensory feedback. If ICMS can mimic naturally occurring neural activity, afferent interfaces may be more informative and easier to learn than interfaces that evoke unnaturalistic activity. To develop such biomimetic stimulation patterns, it is important to characterize the responses of neurons to ICMS.

ApproachUsing a Utah multi-electrode array, we recorded activity evoked by single pulses, and short (~0.2 s) and long (~4 s) trains of ICMS at a wide range of amplitudes and frequencies. As the electrical artifact caused by ICMS typically prevents recording for many milliseconds, we deployed a custom rapid-recovery amplifier with nonlinear gain to limit signal saturation on the stimulated electrode. Across all electrodes after stimulation, we removed the remaining slow return to baseline with acausal high-pass filtering of time-reversed recordings. With these techniques, we could record ~0.7 ms after stimulation offset even on the stimulated electrode.

Main resultsWe recorded likely transsynaptically-evoked activity as early as ~0.7 ms after single pulses of stimulation that was immediately followed by suppressed neural activity lasting 10-150 ms. Instead of this long-lasting inhibition, neurons increased their firing rates for ~100 ms after trains. During long trains, the evoked response on the stimulated electrode decayed rapidly while the response was maintained on non-stimulated channels.

SignificanceThe detailed description of the spatial and temporal response to ICMS can be used to better interpret results from experiments that probe circuit connectivity or function of cortical areas. These results can also contribute to the design of stimulation patterns to improve afferent interfaces for artificial sensory feedback.


title: Visual Attention in The Fovea and The Periphery during Visual Search

abstract: Visual search depends on both the foveal and peripheral visual system, yet the foveal attention mechanisms is still lack of insights. We simultaneously recorded the foveal and peripheral activities in V4, IT and LPFC, while monkeys performed a category-based visual search task. Feature attention enhanced responses of Face-selective, House-selective, and Non-selective foveal cells in visual cortex. While foveal attention effects appeared no matter the peripheral attention effects, paying attention to the foveal stimulus dissipated the peripheral feature attentional effects, and delayed the peripheral spatial attentional effects. When target features appeared both in the foveal and the peripheral, feature attention effects seemed to occur predominately in the foveal, which might not distribute across the visual field according to common view of distributed feature attention effects. As a result, the parallel attentive process seemed to occur during distractor fixations, while the serial process predominated during target fixations in visual search.


title: Increased heterogeneity and task-related reconfiguration of functional connectivity within a lexicosemantic network in autism

abstract:
Autism spectrum disorder (ASD) is highly heterogeneous in etiology and clinical presentation. Findings on intrinsic functional connectivity (FC) or task-induced FC in ASD have been inconsistent including both over- and underconnectivity and diverse regional patterns. As FC patterns change across different cognitive demands, a novel and more comprehensive approach to network architecture in ASD is to examine the change in FC patterns between rest and task states, referred to as reconfiguration. This approach is suitable for investigating inefficient network connectivity that may underlie impaired behavioral functioning in clinical disorders. We used functional magnetic resonance imaging (fMRI) to examine FC reconfiguration during lexical processing, which is often affected in ASD, with additional focus on interindividual variability. Thirty adolescents with ASD and a matched group of 23 typically developing (TD) participants completed a lexicosemantic decision task during fMRI, using multiecho-multiband pulse sequences with advanced BOLD signal sensitivity and artifact removal. Regions of interest (ROIs) were selected based on task-related activation across both groups, and FC and reconfiguration were compared between groups. The ASD group showed increased interindividual variability and overall greater reconfiguration than the TD group. An ASD subgroup with typical performance accuracy (at the level of TD participants) showed reduced similarity and typicality of FC during the task. In this ASD subgroup, greater FC reconfiguration was associated with increased language skills. Findings suggest that intrinsic functional networks in ASD may be inefficiently organized for lexicosemantic decisions and may require greater reconfiguration during task processing, with high performance levels in some individuals being achieved through idiosyncratic mechanisms.

HighlightsFC reconfiguration is a comprehensive approach to examining network architecture
Functional networks are inefficiently organized for lexicosemantic decisions in ASD
ASD may require greater reconfiguration during task processing
Some ASD individuals achieve high performance through idiosyncratic mechanisms


title: Cholinergic control of striatal GABAergic microcircuits

abstract: AO_SCPLOWBSTRACTC_SCPLOWCholinergic interneurons (CINs) are essential elements of striatal circuits and behaviors. While acetylcholine signaling via muscarinic receptors (mAChRs) have been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on GABAergic interneurons (GINs) are equally critical. One demonstration is that CINs stimulation induces large disynaptic inhibition of SPNs mediated by nAChR activation of striatal GINs. While these circuits are ideally positioned to modulate striatal output activity, the neurons involved are not definitively identified due largely to an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs optogenetic activation evokes an intricate dual mechanism involving co-activation of pre- and postsynaptic mAChRs and nAChRs on four GINs populations. Using multi-optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs likely via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms.


title: Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

abstract:
IntroductionCommon alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses.

MethodsIn airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-{beta} or IFN-{lambda}, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6-18 yrs.) and older adults (ages 60-75 yrs.) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 hrs. following infection and supernatant was collected 48 and 96 hrs. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-{beta}1 or IFN-{lambda}2 before SARS-CoV-2 infection.

ResultsDespite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFN{beta}1 or IFN{lambda}2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication.

DiscussionIn addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-{beta}1 or IFN-{lambda}2, markedly reduces SARS-CoV-2 replication.


title: Accurate MHC Motif Deconvolution of Immunopeptidomics Data Reveals a Significant Contribution of DRB3, 4 and 5 to the Total DR Immunopeptidome

abstract: Mass spectrometry (MS) based immunopeptidomics is used in several biomedical applications including neo-epitope discovery in oncology and next-generation vaccine development. Immunopeptidome data are highly complex given the expression of multiple HLA alleles on the cell membrane and presence of co-immunoprecipitated contaminants. The absence of tools that accurately deal with these challenges is currently a major bottleneck for the large-scale application of this technique. Here, we present the MHCMotifDecon that benefits from state-of-the-art HLA class-I and class-II predictions to accurately deconvolute immunopeptidome datasets and assign individual ligands to the most likely HLA allele while discarding co-purified contaminants. We have benchmarked the tool against other state-of-the-art methods and illustrated its application on experimental datasets for HLA-DR demonstrating a previously underappreciated role for HLA-DRB3/4/5 molecules in defining HLA class II immune repertoires. With its ease of use MHCMotifDecon can efficiently guide interpretation of immunopeptidome datasets, serving the discovery of novel T cell targets.


title: Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging

abstract: Secondary lymphoid organs (SLO; including the spleen and lymph nodes) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used time-stamping to indelibly mark cohorts of newly generated naive T cells (a.k.a. recent thymic emigrants - RTE) in mice, and followed their presence, phenotype and retention in SLO. We found that SLO involute asynchronously. Skin-draining lymph nodes (LN) atrophied early (6-9 months) in life and deeper tissue-draining LN and the spleen late (18-20 months), as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTE cohorts of all ages entered SLO and successfully completed post-thymic differentiation. However, in older mice, these cells were poorly retained, and those found in SLO exhibited an emigration phenotype (CCR7loS1P1hi). Transfers of adult RTE into recipients of different ages formally demonstrated that the defect segregates with the age of the SLO microenvironment and not with the age of T cells. Finally, upon intradermal immunization, RTE generated in mice as early as 6-7 months of age barely participated in de novo immune responses and failed to produce well-armed effector cells. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated and pronounced reduction of cutaneous immunity with aging.


title: Bacterial Sensitivity to Chlorhexidine and Povidone-Iodine Antiseptics Over Time: A Systematic Review and Meta-Analysis of Human-Derived Data

abstract:
BackgroundSurgical site infection (SSI) is the most common complication of surgery, increasing healthcare costs and hospital stay. Topical biocides such as chlorhexidine (CHX) and povidone-iodine (PVI) are used for skin antisepsis to minimise SSIs. There is an increasing concern of developing resistance to topical biocides, however the clinical implications of this remains unclear.

OutcomesThe objective of this review was to determine whether the Minimum Bactericidal Concentration (MBC) for topical preparations of CHX or PVI have changed over time, in microbes relevant to SSI.

MethodsWe searched for studies which reported the mean bactericidal concentration (MBC) of laboratory and clinical isolates of common SSI causing microbes to CHX and PVI. We excluded samples derived from non-humans and studies using antimicrobial solvents or mixtures of biocides with other active substances. MBC was pooled in random effects meta-analyses and change in MBC over time was explored using meta-regression.

Results79 studies were including, analysing 6218 microbes between 1976 and 2021. Most studies used CHX (93%) and there was insufficient data for meta-analysis of PVI. Enterobacteriales had the highest MBC for CHX (20 mg/L [95% CI 14, 25]; I2 95%) whilst MRSA had the lowest (3 mg/L [95% CI 1, 2]; I2 93%). There was no change in MBC of CHX to Staphylococci ({beta} 0.12 [-1.13, 1.37]; I2 99%) or Streptococci ({beta} 0.13 [-0.35, 0.62]; I2 97%).

ConclusionsThere is no evidence of change in susceptibility of common SSI-causing microbes to CHX over time. This study provides reassurance that the worldwide guidance that CHX should remain the first-choice agent for skin asepsis prior to surgery.


title: Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

abstract:
Retroviruses are widely distributed in all vertebrates, as are their endogenous form, endogenous retrovirus (ERV), which serves as "fossil" evidence to trace the ancient origins and history of virus-host interactions over millions of years. The retroviral envelope (Env) plays a significant role in host range determination, but major information on genetic diversification in anamniotes is lacking. Here, by incorporating multiple-round in silico similarity search and phylogenomic analysis, 25498 ERVs with gamma-type Env (GTE), covalently associated Env, were discovered by searching against all 974 available fish and 19 amphibian genomes, but no beta-type Env (BTE), noncovalently associated Env, were found. Furthermore, a nine-type classification system of anamniote GTE was proposed by combining phylogenetic and domain/motif analyses. The elastic genomic organization and overall phylogenetic incongruence between anamniotic Env and its neighboring polymerase (Pol) implied that early retroviral diversification in anamniotic vertebrates was facilitated by frequent recombination. At last, host opioid growth factor receptor (OGFr) gene capturing by anamniotic ERVs with GTE was reported for the first time. Overall, our findings overturn traditional Pol genotyping and reveal a complex evolutionary history of anamniotic retroviruses inferred by Env evolution.

Author summaryAlthough the retroviral envelope (Env) protein in amniotes has been well studied, its evolutionary history in anamniotic vertebrates is ambiguous. By analyzing more than 25000 ERVs with gamma-type Env (GTE) in anamniotes, several important evolutionary features were identified. First, GTE were found to be widely distributed among different amphibians and fish. Second, nine types of GTE were discovered, revealing the great genetic diversity. Third, GTE-containing ERVs have rampantly proliferated in certain amphibians such as Ambystoma mexicanum, and the copy number was found to be markedly higher than 10000. Fourth, the incongruence between the Env and Pol phylogenies suggested that frequent recombination shaped the early evolution of anamniote retroviruses. Fifth, an ancient horizontal gene transfer event was discovered from anamniotes to ERVs with GTE. These findings reveal a complex evolution pattern for retroviral Env in anamniotes.


title: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identification of methanogens of clinical interest.

abstract: Methanogens, the archaea uniquely detoxifying fermentative hydrogen into methane in the digestive tract, are increasingly detected in pathology situations, rendering their rapid identification mandatory. We improved the experimental protocol to identify broth-cultured methanogens by matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI- TOF-MS). A database incorporating 34 reference spectra derived from 16 methanogen reference strains representative of eight species, supported further identification of 21 Methanobrevibacter smithii and 14 Methanobrevibacter oralis isolates broth-cultured from human stool and oral fluid, respectively, with scores > 2. In addition, MALDI-TOF-MS differentiated five Methanobrevibacter smithii genotypes incorporated in the study. Data here reported found MALDI-TOF-MS as a first line identification method for methanogens recovered from microbiota and clinical samples.


title: Comparative analysis of Bacillus cereus group isolates' resistance using disk diffusion and broth microdilution and the correlation between resistance phenotypes and genotypes

abstract:
A collection of 85 Bacillus cereus group isolates were screened for phenotypic resistance to nine antibiotics using disk diffusion and broth microdilution. The broth microdilution antimicrobial results were interpreted using the CLSI M45 breakpoints for Bacillus spp. Due to the lack of Bacillus spp. disk diffusion breakpoints, the results obtained with the disk diffusion assay were interpreted using the CLSI M100 breakpoints for Staphylococcus spp. We identified significant (p < 0.05) discrepancies in resistance interpretation between the two methods for ampicillin, gentamicin, rifampicin, tetracycline, and trimethoprim/sulfamethoxazole. Antimicrobial resistance genes were detected using unassembled and assembled whole-genome sequences with Ariba and Abricate, respectively, to assess the sensitivity and specificity for predicting phenotypic resistance based on the presence of antimicrobial resistance genes. We found antimicrobial resistance gene presence to be a poor indicator for phenotypic resistance, calling for further investigation of mechanisms underlying antimicrobial resistance in the B. cereus group. Genes with poor sensitivity and/or specificity, as determined based on broth microdilution results included rph (rifampicin, 0%, 95%), mph genes (erythromycin, 0%, 96%), and all van genes (vancomycin, 100%, 35%). However, Bc (ampicillin, 64%, 100%) and tet genes (tetracycline, 67%, 100%) were highly specific, albeit moderately sensitive indicators of phenotypic resistance based on broth microdilution results. Only beta-lactam resistance genes (Bc, BcII, and blaTEM) were highly sensitive (94%) and specific (100%) markers of resistance to ceftriaxone based on the disk diffusion results, providing further evidence of these beta-lactams role in nonsusceptibility of Bacillus cereus group isolates to ceftriaxone.

IMPORTANCEBacillus cereus group includes human pathogens that can cause severe infections requiring antibiotic treatment. Screening of environmental and food isolates for antimicrobial resistance can provide insight into what antibiotics may be more effective therapeutic options based on the lower prevalence of resistance. Currently, interpretation of antimicrobial susceptibility testing results using the disk diffusion method is complicated by the fact that there are no standard disk diffusion resistance breakpoints defined for Bacillus spp. Hence, the breakpoints for Staphylococcus are often used in research studies. By comparing the results of disk diffusion interpreted using the Staphylococcus spp. breakpoints against broth microdilution interpreted using Bacillus spp. breakpoints, this study demonstrated that disk diffusion results interpretation with Staphylococcus spp. breakpoints are inconsistent. This study also provides new insight into the poor associations between antimicrobial resistance genotypes and phenotypes for the B. cereus group.


title: Spatial metabolomics reveals localized impact of influenza virus infection on the lung tissue metabolome

abstract:
The influenza virus (IAV) is a major cause of respiratory disease, with significant infection increases in pandemic years. Vaccines are a mainstay of IAV prevention, but are complicated by consideration of IAVs vast strain diversity, manufacturing and vaccine uptake limitations. While antivirals may be used for treatment of IAV, they are most effective in early stages of the infection and several virus strains have become drug resistant. Therefore, there is a need for advances in IAV treatment, especially host-directed, personalized therapeutics.Given the spatial dynamics of IAV infection and the relationship between viral spatial distribution and disease severity, a spatial approach is necessary to expand our understanding of IAV pathogenesis. We used spatial metabolomics to address this issue. Spatial metabolomics combines liquid chromatography-tandem mass spectrometry of metabolites extracted from systematic organ sections, 3D models and computational techniques, to develop spatial models of metabolite location and their role in organ function and disease pathogenesis. In this project, we analyzed plasma and systematically sectioned lung tissue samples from uninfected or infected mice. Spatial mapping of sites of metabolic perturbations revealed significantly lower metabolic perturbation in the trachea compared to other lung tissue sites. Using random forest machine learning, we identified metabolites that responded differently in each lung position based on infection, including specific amino acids, lipids and lipid-like molecules, and nucleosides. These results support the implementation of spatial metabolomics to understand metabolic changes upon IAV infection and to identify candidate pathways to be targeted for IAV therapeutics.

ImportanceThe influenza virus is a major health concern. Over 1 billion people become infected annually despite the wide distribution of vaccines, and antiviral agents are insufficient to address current clinical needs. In this study, we used spatial metabolomics to understand changes in the lung and plasma metabolome of mice infected with influenza A virus, compared to uninfected controls. We determined metabolites altered by infection in specific lung tissue sites and distinguished metabolites perturbed by infection between lung tissue and plasma samples. Our findings highlight the importance of a spatial approach to understanding the intersection between lung metabolome, viral infection and disease severity. Ultimately, this approach will expand our understanding of respiratory disease pathogenesis and guide the development of novel host-directed therapeutics.


title: Discovering Novel Antimicrobial Peptides in Generative Adversarial Network

abstract:
Due to the growing number of clinical antibiotic resistance cases in recent years, novel antimicrobial peptides (AMPs) can become ideal for next-generation antibiotics. This study trained a deep convolutional generative adversarial network (GAN) with known AMPs to generate novel AMP candidates. The quality of the GAN-designed peptides was evaluated in silico, and eight of them named GAN-pep 1[~]8 were chosen to be synthesized for further experiments. Disk diffusion testing and minimum inhibitory concentration (MIC) determination were used to determine the antibacterial effects of the synthesized GAN-designed peptides. Seven out of the eight synthesized GAN-designed peptides showed antibacterial activities.

Additionally, GAN-pep 3 and GAN-pep 8 had a broad spectrum of antibacterial effects. Both of them were also effective against antibiotic-resistant bacteria strains such as methicillin-resistant Staphylococcus aureus (S. aureus) and carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa). GAN-pep 3, the most promising GAN-designed peptide candidate, had low MICs against all the tested bacteria.


title: Novel RNA viruses associated with avian haemosporidian parasites

abstract: Avian haemosporidian parasites can cause malaria-like symptoms in their hosts and have been implicated in the demise of some bird species. The newly described Matryoshka RNA viruses (MaRNAV1 and MaRNAV2) infect parasites that in turn infect their vertebrate hosts. MaRNAV2 was the first RNA virus discovered associated with parasites of the genus Leucocytozoon. By analyzing metatranscriptomes from the NCBI SRA database with local sequence alignment tools, we detected two novel RNA viruses; we describe them as MaRNAV3 associated with Leucocytozoon and MaRNAV4 associated with Parahaemoproteus. These had ~40-60% amino acid identity to the RNA-dependent RNA-polymerase (RdRp) of MaRNAV1 and 2, respectively. These findings lead us to hypothesize that MaRNAV_like viruses are widespread and tightly associated with the order Haemosporida since they have been described in human Plasmodium vivax, and now two genera of avian haemosporidians.


title: Genome-wide mapping of histone modification H3K4me3 in bovine oocytes and early embryos

abstract: Reprogramming of histone modifications is critical to safeguard correct gene expression profile during preimplantation development. Of interest, trimethylation of lysine 4 on histone 3 (H3K4me3) exhibits a unique and dynamic landscape with a potential species-specific feature. Here, we address how it is reprogrammed and its functional significance during oocyte maturation and early embryonic development in cows. Notably, the overall signal of H3K4me3 decreased sharply during embryonic genome activation (EGA). By using low input ChIP-seq technology, we find widespread broad H3K4me3 domains in oocytes and early cleaved embryos. The broad domains are gradually removed after fertilization, which is obviously seen during EGA. Meanwhile, H3K4me3 become enriched at promoter regions. Interestingly, the gene expression level displays a positive correlation with the relative H3K4me3 signal of their promoters when embryos reach 16-cell stage. Importantly, disruption of H3K4me3 demethylases KDM5A-5C increases H3K4me3 level, decreases the embryonic developmental rate and results in dysregulation of over a thousand genes. Meanwhile, KDM5 deficiency causes a re-destribution of H3K4me3 across genome. In particular, the positive correlation between promoter H3K4me3 enrichment and gene expression level disappear. Overall, we describe the genomic reprogramming of H3K4me3 in a greater resolution during bovine preimplantation development and propose that KDM5-mediated re-distribution of H3K4me3 plays an important role in modulating oocyte-to-embryonic transition.

category: developmental biology


title: Somatic regulation of female germ cell regeneration and development in planarians

abstract: Female germ cells develop into oocytes, with the capacity for totipotency. In most animals, these remarkable cells are specified during development and cannot be regenerated. By contrast, planarians, known for their regenerative prowess, can regenerate germ cells. To uncover mechanisms required for female germ cell development and regeneration, we generated gonad-specific transcriptomes and identified genes whose expression defines progressive stages of female germ cell development. Strikingly, early female germ cells share molecular signatures with the pluripotent stem cells driving planarian regeneration. We uncovered spatial heterogeneity within somatic ovarian cells and found that a regionally enriched FoxL homolog is required for oocyte differentiation, but not specification, suggestive of functionally distinct somatic compartments. Unexpectedly, a neurotransmitter-biosynthetic enzyme, AADC, is also expressed in somatic gonadal cells, and plays opposing roles in female and male germ cell development. Thus, somatic gonadal cells deploy conserved factors to regulate germ cell development and regeneration in planarians.


title: Reconstruction and variability of tropical pollination networks in the Brazilian Atlantic Forest

abstract:
O_LILoss of biodiversity comprehends not only the extinction of individual species, but also the loss of the ecological interactions among them. Survival of species, continuation of ecosystem functioning in nature, and ecosystem services to humans depend on the maintenance of well-functioning networks of species interactions (e.g. plant-pollinator networks and food webs). Analyses of ecological networks often rely on biased and incomplete survey data, especially in species-rich areas, such as the tropics.
C_LIO_LIWe used a network inference method to reconstruct pollination data compiled from a large tropical rainforest habitat extent. To gain insight into the characteristics of plant-pollinator interactions across the region, we combined the reconstructed pollination network with species distribution modeling to obtain local pollination networks throughout the area. We explored how global network properties relate to natural forest cover and land cover heterogeneity.
C_LIO_LIWe found that some network properties (the sum and evenness of link weights, connectance and nestedness) are positively correlated with forest cover, indicating that networks in sites with more natural habitat have greater diversity of interactions, stability and resilience. Modularity was not related to forest cover, but seemed to reflect habitat heterogeneity, due to the broad spatial scale of the study.
C_LIO_LIWe believe that the methodology suggested here can facilitate the use of incomplete network data in a reliable way, and allow us to better understand and protect networks of species interactions in high biodiversity regions of the world.
C_LI

category: ecology