bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction ofBurkholderia pseudomalleiDsbA substrates identifies potential virulence factors and vaccine targets
Authors: Vezina Ben , Petit Guillaume A. , Martin Jennifer L. , Halili Maria A.
Published: July 2020

Identification of bacterial virulence factors is critical for understanding disease pathogenesis, drug discovery and vaccine development. In this study we used two approaches to predict virulence factors ofBurkholderia pseudomallei, the Gram-negative bacterium that causes melioidosis.B. pseudomalleiis naturally antibiotic resistant and there are no melioidosis vaccines. To identifyB. pseudomalleiprotein targets for drug discovery and vaccine development, we chose to search for substrates of theB. pseudomalleiperiplasmic disulfide bond forming protein A (DsbA). DsbA introduces disulfide bonds into extra-cytoplasmic proteins and is essential for virulence in many Gram-negative organism, includingB. pseudomallei. The first approach to identifyB. pseudomalleiDsbA virulence factor substrates was a large-scale genomic analysis of 511 uniqueB. pseudomalleidisease-associated strains. This yielded 4,496 core gene products, of which we hypothesise 263 are DsbA substrates. Manual curation of the 263 mature proteins yielded 73 associated with disease pathogenesis or virulence. These were screened for structural homologues to predict potential B-cell epitopes. In the second approach, we searched theB. pseudomalleigenome for homologues of the more than 90 known DsbA substrates in other bacteria. Using this approach, we identified 15 potentialB. pseudomalleiDsbA virulence factor substrates. Two putativeB. pseudomalleivirulence factors were identified by both methods: homologues of PenI family β-lactamase and of succinate dehydrogenase flavoprotein subunit. These two proteins could serve as high priority targets for futureB. pseudomalleivirulence factor characterization.
The major genetic risk factor for severe COVID-19 is inherited from Neandertals
Authors: Zeberg Hugo , Pääbo Svante
Published: July 2020

A recent genetic association study (Ellinghauset al.2020) identified a gene cluster on chromosome 3 as a risk locus for respiratory failure in SARS-CoV-2. Recent data comprising 3,199 hospitalized COVID-19 patients and controls reproduce this and find that it is the major genetic risk factor for severe SARS-CoV-2 infection and hospitalization (COVID-19 Host Genetics Initiative). Here, we show that the risk is conferred by a genomic segment of ~50 kb that is inherited from Neandertals and occurs at a frequency of ~30% in south Asia and ~8% in Europe.
Robust and sensitive detection of SARS-CoV-2 using PCR based methods
Authors: Park Changwoo , Lee Jina , Hassan Zohaib ul , Ku Keun Bon , Kim Seong Jun , Kim Hong Gi , Park Edmond Changkyun , Park Gun-Soo , Park Daeui , Baek Seung-Hwa , Park Dongju , Lee Jihye , Jeon Sangeun , Kim Seungtaek , Lee Chang-Seop , Yoo Hee Min , Kim Seil
Published: July 2020

The World Health Organization (WHO) has declared the Coronavirus disease 2019 (COVID-19) as an international health emergency. Current diagnostic tests are based on the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method, the gold standard test that involves the amplification of viral RNA. However, the RT-qPCR assay has limitations in terms of sensitivity and quantification. In this study, we tested both qPCR and droplet digital PCR (ddPCR) to detect low amounts of viral RNA. The cycle threshold (CT) of viral RNA by RT-PCR significantly varied according to the sequence of primer and probe sets with in vitro transcript (IVT) RNA or viral RNA as templates, whereas the copy number of viral RNA by ddPCR was effectively quantified with IVT RNA, cultured viral RNA, and RNA from clinical samples. Furthermore, the clinical samples were assayed via both methods, and the sensitivity of the ddPCR was determined to be significantly higher than RT-qPCR. These findings suggest that ddPCR could be used as a highly sensitive and compatible diagnostic method for viral RNA detection.
Volatile organic compounds from entomopathogenic and nematophagous fungi, repel banana black weevil (Cosmopolites sordidus)
Authors: Lozano-Soria Ana , Picciotti Ugo , Lopez-Moya Federico , Lopez-Cepero Javier , Porcelli Francesco , Lopez-Llorca Luis Vicente
Published: July 2020

Fungal Volatile Organic Compounds (VOCs) repel banana black weevil (BW),Cosmopolites sordidus(Germar, 1824), the key-pest of banana (Musaspp.). The entomopathogensBeauveria bassiana(Bb1TS11) andMetarhizium robertsii(Mr4TS04) were isolated from banana plantation soils using an insect bait. Bb1TS11 and Mr4TS04 were pathogenic to BW adults. Bb1TS11, Bb203 (from infected palm weevils), Mr4TS04 and the nematophagous fungusPochonia clamydosporia(Pc123), were tested for VOCs production. VOCs were identified by Gas Chromatography/Mass Spectrometry - Solid-Phase Micro Extraction (GC/MS-SPME). GC/MS-SPME identified a total of 97 VOCs in all strains tested. Seven VOCs (C1 – C7) were selected for their abundance or previous record as insect repellents. BW starved adults in the dark showed the highest mobility to banana corm in olfactometry bioassays. C7, produced by all fungal strains, is the best BW repellent (p<0.05), followed by C5. The rest of VOCs have a milder repellency to BW. C1 and C2 (known to repel palm weevil) block the attraction of banana corm and BW pheromone to BW adults in bioassays. Therefore, VOCs from biocontrol fungi can be used in future studies for biomanagement of BW in the field.
Topographic gradients of intrinsic dynamics across neocortex
Authors: Shafiei Golia , Markello Ross D. , de Wael Reinder Vos , Bernhardt Boris C. , Fulcher Ben D. , Misic Bratislav
Published: July 2020

The intrinsic dynamics of neuronal populations are shaped by both macroscale connectome architecture and microscale attributes. Neural activity arising from the interplay of these local and global factors therefore varies from moment to moment, with rich temporal patterns. Here we comprehensively characterize intrinsic dynamics throughout the human brain. Applying massive temporal feature extraction to regional haemodynamic activity, we estimate over 6,000 statistical properties of individual brain regions’ time series across the neocortex. We identify two robust topographic gradients of intrinsic dynamics, one spanning a ventromedial-dorsolateral axis and the other spanning a unimodal-transmodal axis. These gradients are distinct in terms of their temporal composition and reflect spatial patterns of microarray gene expression, intracortical myelin and cortical thickness, as well as structural and functional network embedding. Importantly, these gradients are closely correlated with patterns of functional activation, differentiating cognitiveversusaffective processing and sensoryversushigher-order cognitive processing. Altogether, these findings demonstrate a link between microscale and macroscale architecture, intrinsic dynamics, and cognition.
Modulation of triple artemisinin-based combination therapy pharmacodynamics byPlasmodium falciparumgenotype
Authors: Ansbro Megan R. , Itkin Zina , Chen Lu , Zahoranszky-Kohalmi Gergely , Amaratunga Chanaki , Miotto Olivo , Peryea Tyler , Hobbs Charlotte V. , Suon Seila , Sá Juliana M. , Dondorp Arjen M. , van der Pluijm Rob W. , Wellems Thomas E. , Simeonov Anton , Eastman Richard T.
Published: July 2020

The first-line treatments for uncomplicatedPlasmodium falciparummalaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread ofP. falciparumwith decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamics and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established anin vitrohigh-throughput process for measuring the drug dose-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against fifteen parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification ofplasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.

One Sentence Summary

In vitroprocess to evaluate triple-drug combinations for prioritizing antimalarial combinations forin vivoevaluation.
Neural correlates of modal displacement and discourse-updating under (un)certainty
Authors: Tulling Maxime , Law Ryan , Cournane Ailís , Pylkkänen Liina
Published: July 2020

A hallmark of human thought is the ability to think about not just the actual world, but also about alternative ways the world could be. One way to study this contrast is through language. Language has grammatical devices for expressing possibilities and necessities, such as the wordsmightormust. With these devices, called “modal expressions,” we can study the actual vs. possible contrast in a highly controlled way. While factual utterances such as “There is a monster under my bed” update thehere-and-nowof a discourse model, a modal version of this sentence, “There might be a monster under my bed,” displaces from thehere-and-nowand merely postulates a possibility. We used magnetoencephalography (MEG) to test whether the processes of discourse updating and modal displacement dissociate in the brain. Factual and modal utterances were embedded in short narratives, and across two experiments, factual expressions increased the measured activity over modal expressions. However, the localization of the increase appeared to depend on perspective: signal localizing in right temporo-parietal areas increased when updating others’ beliefs, while frontal medial areas seem sensitive to updating one’s own beliefs. The presence of modal displacement did not elevate MEG signal strength in any of our analyses. In sum, this study identifies potential neural signatures of the process by which facts get added to our mental representation of the world.
Class A Penicillin-Binding Protein-mediated cell wall synthesis promotes structural integrity during peptidoglycan endopeptidase insufficiency
Authors: Murphy Shannon G. , Murtha Andrew N. , Zhao Ziyi , Alvarez Laura , Diebold Peter , Shin Jung-Ho , VanNieuwenhze Michael S. , Cava Felipe , Dörr Tobias
Published: July 2020

The bacterial cell wall is composed primarily of peptidoglycan (PG), a poly-aminosugar that is essential to sustain cell shape, growth and structural integrity. PG is synthesized by two different types of synthase complexes (class A Penicillin-binding Proteins [PBP]s/Lpos and Shape, Elongation, Division, Sporulation [SEDS]/class B PBP pairs) and degraded by ‘autolytic’ enzymes to accommodate growth processes. It is thought that autolsyin activity (and particulary the activity of endopeptidases, EPs) is required for PG synthesis and incorporation by creating gaps that are patched and paved by PG synthases, but the exact relationship between autolysins and the separate synthesis machineries remains incompletely understood. Here, we have probed the consequences of EP depletion for PG synthesis in the diarrheal pathogenVibrio cholerae. We found that EP depletion resulted in severe morphological defects, increased cell mass, a decline in viability, and continuing (yet aberrant) incorporation of cell wall material. Mass increase and cell wall incorporation proceeded in the presence of Rod system inhibitors, but was abolished upon inhibition of aPBPs. However, the Rod system remained functional (i.e., exhibited sustained directed motion) even after prolonged EP depletion, without effectively promoting cell elongation. Lastly, heterologous expression of an EP fromNeisseria gonorrhoeaecould fully complement growth and morphology of an EP-insufficientV. cholerae. Overall, our findings suggest that inV. cholerae, the Rod system requires endopeptidase activity (but not necessarily direct interaction with EPs) to promote cell expansion and substantial PG incorporation, whereas aPBPs are able to engage in sacculus construction even during severe EP insufficiency.

Importance

Synthesis and turnover of the bacterial cell wall must be tightly co-ordinated to avoid structural integrity failure and cell death. Details of this coordination are poorly understood, particularly if and how cell wall turnover enzymes are required for the activity of the different cell wall synthesis machines. Our results suggest that inVibrio cholerae, one class of turnover enzymes, the endopeptidases, are required only for substantial PG incorporation mediated by the Rod system, while the aPBPs maintain structural integrity during endopeptidase insufficiency. Our results suggest that aPBPs are more versatile than the Rod system in their ability to recognize cell wall gaps formed by autolysins other than the major endopeptidases, adding to our understanding of the co-ordination between autolysins and cell wall synthases. A detailed understanding of autolysin biology may promote the development of antibiotics that target these essential turnover processes.
MicroRNA-based cancer mortality risk scoring system and hTERT expression linked with risk-adjusted treatment strategy in early-stage oral squamous cell carcinoma
Authors: Yoon Angela J. , Santella Regina M. , Wang Shuang , Kutler David I. , Carvajal Richard D. , Philipone Elizabeth , Wang Tian , Peters Scott M. , Stewart Claire R. , Momen-Heravi Fatemeh , Troob Scott , Levin Matt , AkhavanAghdam Zohreh , Shackelford Austin J. , Canterbury Carleigh R. , Shimonosono Masataka , Nakagawa Hiroshi
Published: July 2020

We have developed and validated a novel microRNA (miRNA)-based prognostic model to predict survival outcome in oral squamous cell carcinoma (OSCC) patients who are already categorized into ‘early-stage’ by the TNM system. A total of 836 early-stage OSCC patients were assigned the mortality risk scores. We evaluated the efficacy of various treatment regimens in terms of survival benefit compared to surgery only in patients stratified into high and low mortality risk categories. Within the high-risk group, surgery with neck dissection significantly improved the 5-year survival to 75% from 46% (p<0.001) with surgery only. A Cox proportional hazard model on time-to-death suggests a hazard ratio of 0.37 when comparing surgery with neck dissection to surgery only (95% CI: 0.2-0.6; p=0.0005). For the low-risk group, surgery only without neck dissection was the most beneficial treatment modality, as opposed to the high-risk group, in which surgery with neck dissection significantly improved 5-year survival. Regardless of treatment selected, those with risk score ≥1 may benefit from additional therapy to prevent cancer relapse. Based on functional analysis of the prognostic miRNAs, we identified hTERT (human telomerase reverse transcriptase) as a promising drug target to prevent cancer relapse, thereby improving cancer-free survival. We also established a functional platform for patient-derived organoid-based drug testing in an effort to link prognostic marker-based mortality risk assessment with appropriate risk-adjusted therapy to improve overall survival.
Fungal microbiomes are determined by host phylogeny and exhibit widespread associations with the bacterial microbiome
Authors: Harrison Xavier A. , McDevitt Allan D. , Dunn Jenny C. , Griffiths Sarah , Benvenuto Chiara , Birtles Richard , Boubli Jean P. , Bown Kevin , Bridson Calum , Brooks Darren , Browett Samuel S. , Carden Ruth F. , Chantrey Julian , Clever Friederike , Coscia Ilaria , Edwards Katie L. , Ferry Natalie , Goodhead Ian , Highlands Andrew , Hopper Jane , Jackson Joseph , Jehle Robert , da Cruz Kaizer Mariane , King Tony , Lea Jessica M. D. , Lenka Jessica L. , McCubbin Alexandra , McKenzie Jack , de Moraes Bárbara Lins Caldas , O’Meara Denise B. , Pescod Poppy , Preziosi Richard F. , Rowntree Jennifer K. , Shultz Susanne , Silk Matthew J. , Stockdale Jennifer E. , Symondson William O. C. , de la Pena Mariana Villalba , Walker Susan L. , Wood Michael D. , Antwis Rachael E.
Published: July 2020

Interactions between hosts and their resident microbial communities are a fundamental component of fitness for both agents. Though recent research has highlighted the importance of interactions between animals and their bacterial communities, comparative evidence for fungi is lacking, especially in natural populations. Using data from 49 species, we present novel evidence of strong covariation between fungal and bacterial communities across the host phylogeny, indicative of recruitment by hosts for specific suites of microbes. Using co-occurrence networks, we demonstrate that fungi form critical components of putative microbial interaction networks, where the strength and frequency of interactions varies with host taxonomy. Host phylogeny drives differences in overall richness of bacterial and fungal communities, but the effect of diet on richness was only evident in mammals and for the bacterial microbiome. Collectively these data indicate fungal microbiomes may play a key role in host fitness and suggest an urgent need to study multiple agents of the animal microbiome to accurately determine the strength and ecological significance of host-microbe interactions.

SIGNIFICANCE STATEMENT

Microbes perform vital metabolic functions that shape the physiology of their hosts. However, almost all research to date in wild animals has focused exclusively on the bacterial microbiota, to the exclusion of other microbial groups. Although likely to be critical components of the host microbiome, we have limited knowledge of the drivers of fungal composition across host species. Here we show that fungal community composition is determined by host species identity and phylogeny, and that fungi form extensive interaction networks with bacteria in the microbiome of a diverse range of animal species. This highlights the importance of microbial interactions as mediators of microbiome-health relationships in the wild.
Towards the design of multiepitope-based peptide vaccine candidate against SARS-CoV-2
Authors: Odhar Hasanain Abdulhameed , Ahjel Salam Waheed , Humadi Suhad Sami
Published: July 2020

Coronavirus disease 2019 is a current pandemic health threat especially for elderly patients with comorbidities. This respiratory disease is caused by a beta coronavirus known as severe acute respiratory syndrome coronavirus 2. The disease can progress into acute respiratory distress syndrome that can be fatal. Currently, no specific drug or vaccine are available to combat this pandemic outbreak. Social distancing and lockdown have been enforced in many places worldwide. The spike protein of coronavirus 2 is essential for viral entry into host target cells via interaction with angiotensin converting enzyme 2. This viral protein is considered a potential target for design and development of a drug or vaccine. Previously, we have reported several potential epitopes on coronavirus 2 spike protein with high antigenicity, low allergenicity and good stability against specified proteases. In the current study, we have constructed and evaluated a peptide vaccine from these potential epitopes by using in silico approach. This construct is predicted to have a protective immunogenicity, low allergenicity and good stability with minor structural flaws in model build. The population coverage of the used T-cells epitopes is believed to be high according to the employed restricted alleles. The vaccine construct can elicit efficient and long-lasting immune response as appeared through simulation analysis. This multiepitope-based peptide vaccine may represent a potential candidate against coronavirus 2. However, further in vitro and in vivo verification are required.
ConnecTF: A platform to build gene networks by integrating transcription factor-target gene interactions
Authors: Brooks M.D. , Juang C.-L. , Katari M.S. , Alvarez J.M. , Pasquino A.V. , Shih H.-J. , Huang J. , Shanks C. , Cirrone J. , Coruzzi G.M.
Published: July 2020

Deciphering gene regulatory networks (GRNs) is both a promise and challenge of systems biology. The promise is identifying key transcription factors (TFs) that enable an organism to react to changes in its environment. The challenge is constructing GRNs that involve hundreds of TFs and hundreds of thousands of interactions with their genome-wide target genes validated by high-throughput sequencing. To address this challenge, we developed ConnecTF, a species-independent web-based platform for constructing validated GRNs and to refine inferred GRNs via combined analysis of genome-wide studies of TF-target gene binding, TF-target regulation and other TF-centric omic data. We demonstrate the functionality of ConnecTF in three case studies, showing how integration within and across TF-target datasets uncovers biological insights. Case study 1 uses integration of TF-target gene regulation and binding datasets to uncover mode-of-action and identify potential TF partners for 14 TFs in abscisic acid signaling. Case study 2 demonstrates how genome-wide TF-target data and automated functions in ConnecTF are used to conduct precision/recall analysis and pruning of an inferred GRN for nitrogen signaling. In case study 3, we use ConnecTF to chart a network path from NLP7, a master TF in nitrogen signaling, to direct secondary TF2s, to its indirect targets, in an approach called Network Walking. The public version of ConnecTF (https://ConnecTF.org) contains 3,738,278 TF-target interactions for 423 TFs in Arabidopsis, and 839,210 TF-target interactions for 139 TFs in maize. The database and tools in ConnecTF should advance the exploration of GRNs in plant systems biology applications for models and crops.
Sequence dependent co-phase separation of RNA-protein mixtures elucidated using molecular simulations
Authors: Regy Roshan Mammen , Dignon Gregory L. , Zheng Wenwei , Kim Young Chan , Mittal Jeetain
Published: July 2020

Ribonucleoprotein (RNP) granules are membraneless organelles (MLOs) which majorly consist of RNA and RNA-binding proteins and are formed via liquid-liquid phase separation (LLPS). Experimental studies investigating the drivers of LLPS have shown that intrinsically disordered proteins (IDPs) and nucleic acids like RNA play a key role in modulating protein phase separation. There is currently a dearth of modelling techniques which allow one to delve deeper into how RNA plays its role as a modulator/promoter of LLPS in cells using computational methods. Here we present a coarse-grained RNA model developed to fill this gap, which together with our recently developed HPS model for protein LLPS, allows us to capture the factors driving RNA-protein co-phase separation. We explore the capabilities of the modelling framework with the LAF-1 RGG/RNA system which has been well studied in experiments and also with the HPS model previously. Further taking advantage of the fact that the HPS model maintains sequence specificity we explore the role of charge patterning on controlling RNA incorporation into condensates. With increased charge patterning we observe formation of structured or patterned condensates which suggests the possible roles of RNA in not only shifting the phase boundaries but also introducing microscopic organization in MLOs.
Recurrent Neural Network-based Acute Concussion Classifier using Raw Resting State EEG Data
Authors: Thanjavur Karun , Babul Arif , Foran Brandon , Bielecki Maya , Gilchrist Adam , Hristopulos Dionissios T. , Brucar Leyla R. , Virji-Babul Naznin
Published: July 2020

Concussion is a global health concern. Despite its high prevalence, a sound understanding of the mechanisms underlying this type of diffuse brain injury remains elusive. It is, however, well established that concussions cause significant functional deficits; that children and youths are disproportionately affected and have longer recovery time than adults; and recovering individuals are more prone to suffer additional concussions, with each successive injury increasing the risk of long term neurological and mental health complications. Currently, concussion management faces two significant challenges: there are no objective, clinically accepted, brain-based approaches for determining (i) whether an athlete has suffered a concussion, and (ii) when the athlete has recovered. Diagnosis is based on clinical testing and self-reporting of symptoms and their severity. Self-reporting is highly subjective and symptoms only indirectly reflect the underlying brain injury. Here, we introduce a deep learning Long Short Term Memory (LSTM)-based recurrent neural network that is able to distinguish between healthy and acute post-concussed adolescent athletes using only a short (i.e. 90 seconds long) sample of resting state EEG data as input. The athletes were neither required to perform a specific task nor subjected to a stimulus during data collection, and the acquired EEG data was neither filtered, cleaned of artefacts, nor subjected to explicit feature extraction. The LSTM network was trained and tested on data from 27 male, adolescent athletes with sports related concussion, bench marked against 35 healthy, adolescent athletes. During rigorous testing, the classifier consistently identified concussions with an accuracy of >90% and its ensemble-median Area Under the Curve (AUC) corresponds to 0.971. This is the first instance of a high-performing classifier that relies only on easy-to-acquire resting state EEG data. It represents a key step towards the development of an easy-to-use, brain-based, automatic classification of concussion at an individual level.
Automated identification of small drug molecules for Hepatitis C virus through a novel programmatic tool and extensive Molecular Dynamics studies of select drug candidates
Authors: Madaj Rafal , Sanker Akhil , Geoffrey A S Ben , David Host Antony , Verma Shubham , Gracia Judith , Faleti Ayodele Ifeoluwa , Yakubu Abdulbasit Haliru
Published: July 2020

We report a novel python based programmatic tool that automates the dry lab drug discovery workflow for Hepatitis C virus. Firstly, the python program is written to automate the process of data mining PubChem database to collect data required to perform a machine learning based AutoQSAR algorithm through which drug leads for Hepatitis C virus is generated. The workflow of the machine learning based AutoQSAR involves feature learning and descriptor selection, QSAR modelling, validation and prediction. The drug leads generated by the program are required to satisfy the Lipinski’s drug likeness criteria. 50 of the drug leads generated by the program are fed as programmatic inputs to an In Silico modelling package by the program for fast virtual screening and computer modelling of the interaction of the compounds generated as drug leads and the drug target, a viral Helicase of Hepatitis C. The results are stored automatically in the working folder of the user by the program. The program also generates protein-ligand interaction profiling and stores the visualized images in the working folder of the user. Select protein-ligand complexes associated with structurally diverse ligands having lowest binding energy were selected for extensive molecular dynamics simulation studies and subsequently for molecular mechanics generalized-born surface area (MMGBSA) with pairwise decomposition calculations. The molecular mechanics studies predict In Silico that the compounds generated by the program inhibit the viral helicase of Hepatitis C and prevent the replication of the virus. Thus our programmatic tool ushers in the new age of automatic ease in drug identification for Hepatitis C virus through a programmatic tool that completely automates the dry lab drug discovery workflow. The program is hosted, maintained and supported at the GitHub repository link given belowhttps://github.com/bengeof/Automated-drug-identification-programmatic-tool-for-Hepatitis-C-virus
The organizational principles of de-differentiated topographic maps in somatosensory cortex
Authors: Liu Peng , Chrysidou Anastasia , Doehler Juliane , Hebart Martin , Wolbers Thomas , Kuehn Esther
Published: July 2020

Topographic maps are a fundamental feature of cortex architecture in the mammalian brain. One common theory is that the de-differentiation of topographic maps links to impairments in everyday behavior due to less precise functional map readouts. Here, we tested this theory by characterizing de-differentiated topographic maps in primary somatosensory cortex (SI) of younger and older adults by means of ultra-high resolution functional magnetic resonance imaging together with perceptual finger individuation and hand motor performance. Older adults’ SI maps showed similar amplitude and size to younger adults’ maps, but presented with less representational similarity between distant fingers. Larger population receptive field sizes in older adults’ maps did not correlate with behavior, whereas reduced cortical distances between D2 and D3 related to worse finger individuation but better motor performance. Our data uncover the drawbacks of a simple de-differentiation model of topographic map function, and motivate the introduction of feature-based models of cortical reorganization.
Identifying Causative Mechanisms Linking Early-Life Stress to Psycho-Cardio-Metabolic Multi-Morbidity: The EarlyCause Project
Authors: Mariani Nicole , Borsini Alessandra , Cecil Charlotte A.M. , Felix Janine F. , Sebert Sylvain , Cattaneo Annamaria , Walton Esther , Milaneschi Yuri , Cochrane Guy , Amid Clara , Rajan Jeena , Giacobbe Juliette , Sanz Yolanda , Agustí Ana , Sorg Tania , Herault Yann , Miettunen Jouko , Parmar Priyanka , Cattane Nadia , Jaddoe Vincent , Lötjönen Jyrki , Buisan Carme , Ballester Miguel A. González , Piella Gemma , Gelpi Josep L. , Lamers Femke , Penninx Brenda WJH , Tiemeier Henning , von Tottleben Malte , Thiel Rainer , Heil Katharina F. , Järvelin Marjo-Riitta , Pariante Carmine , Mansuy Isabelle M. , Lekadir Karim
Published: July 2020

Introduction

Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards shared risk of these diseases and the development of coordinated preventive and therapeutic interventions.

Methods and analysis

This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union’s Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shape an individual’s physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.

Ethics and dissemination

The study has been approved by the Ethics Board of the European Commission. The results will be published in peer-reviewed academic journals, and disseminated to and communicated with clinicians, patient organisations and media.
Intramolecular quality control: HIV-1 Envelope gp160 signal-peptide cleavage as a functional folding checkpoint
Authors: McCaul Nicholas , Quandte Matthias , Bontjer Ilja , van Zadelhoff Guus , Land Aafke , Sanders Rogier W. , Braakman Ineke
Published: July 2020

Removal of the membrane-tethering signal peptides that target secretory proteins to the endoplasmic reticulum is a prerequisite for proper folding. While generally thought to be removed well before translation termination, we here report two novel post-targeting functions for the HIV-1 gp120 signal peptide, which remains attached until gp120 folding triggers its removal. First, the signal peptide improves fidelity of folding by enhancing conformational plasticity of gp120 by driving disulfide isomerization through a redox-active cysteine, at the same time delaying folding by tethering the N-terminus to the membrane, which needs assembly with the C-terminus. Second, its carefully timed cleavage represents intramolecular quality control and ensures release and stabilization of (only) natively folded gp120. Postponed cleavage and the redox-active cysteine both are highly conserved and important for viral fitness. Considering the ∼15% secretory proteins in our genome and the frequency of N-to-C contacts in protein structures, these regulatory roles of the signal peptide are bound to be more common in secretory-protein biosynthesis.
Acto-myosin cross-bridge stiffness depends on the nucleotide state of the myosin II
Authors: Wang Tianbang , Brenner Bernhard , Nayak Arnab , Amrute-Nayak Mamta
Published: July 2020

How various myosin isoforms fulfill the diverse physiological requirements of distinct muscle types remains unclear. Myosin II isoforms expressed in skeletal muscles determines the mechanical performance of the specific muscles as fast movers, or slow movers but efficient force holders. Here, we employed a single-molecule optical trapping method and compared the chemo-mechanical properties of slow and fast muscle myosin II isoforms. Stiffness of the myosin motor is key to its force-generating ability during muscle contraction. We found that acto-myosin (AM) cross-bridge stiffness depends on its nucleotide state as the myosin progress through the ATPase cycle. The strong actin bound ‘AM.ADP’ state exhibited > 2 fold lower stiffness than ‘AM rigor’ state. The two myosin isoforms displayed similar ‘rigor’ stiffness. We conclude that the time-averaged stiffness of the slow myosin is lower due to prolonged duration of the AM.ADP state, which determines the force-generating potential and contraction speed of the muscle, elucidating the basis for functional diversity among myosins.
Calnexin mediates the maturation of GPI-anchors through ER retention
Authors: Guo Xin-Yu , Liu Yi-Shi , Gao Xiao-Dong , Kinoshita Taroh , Fujita Morihisa
Published: July 2020

The protein folding and lipid moiety status of glycosylphosphatidylinositol-anchored proteins (GPI-APs) are monitored in the endoplasmic reticulum (ER), with calnexin playing dual roles in the maturation of GPI-APs. In the present study, we investigated the functions of calnexin in the quality control and lipid remodeling of GPI-APs in the ER. By directly binding the N-glycan on proteins, calnexin was observed to efficiently retain GPI-APs in the ER until they were correctly folded. In addition, sufficient ER retention time was crucial for GPI-inositol deacylation, which is mediated by post-GPI attachment protein 1 (PGAP1). Once the calnexin/calreticulin cycle was disrupted, misfolded and inositol-acylated GPI-APs could not be retained in the ER and were exposed on the plasma membrane. In calnexin/calreticulin deficient cells, endogenous GPI-anchored alkaline phosphatase was expressed on the cell surface, but its activity was significantly decreased. ER stress induced surface expression of misfolded GPI-APs, but proper GPI-inositol deacylation occurred due to the extended time that they were retained in the ER. Our results indicate that calnexin-mediated ER quality control systems for GPI-APs are necessary for both protein folding and GPI-inositol deacylation.
Enhanced COVID-19 data for improved prediction of survival
Authors: Zeng Wenhuan , Gautam Anupam , Huson Daniel H
Published: July 2020

The current COVID-19 pandemic, caused by the rapid world-wide spread of the SARS-CoV-2 virus, is having severe consequences for human health and the world economy. The virus effects individuals quite differently, with many infected patients showing only mild symptoms, and others showing critical illness. To lessen the impact of the pandemic, one important question is which factors predict the death of a patient? Here, we construct an enhanced COVID-19 dataset by processing two existing databases (from Kaggle and WHO) and using natural language processing methods to enhance the data by adding local weather conditions and research sentiment.

Author summary

In this study, we contribute an enhanced COVID-19 dataset, which contains 183 samples and 43 features. Application of Extreme Gradient Boosting (XGBoost) on the enhanced dataset achieves 95% accuracy in predicting patients survival, with country-wise research sentiment, and then age and local weather, showing the most importance. All data and source code are available at http://ab.inf.uni-tuebingen.de/publications/papers/COVID-19.
Requirement of FLCN tumor suppressor gene for mTORC1-mediated inhibition of TFE3 transcriptional activity
Authors: Li Hua , Oh HyoungBin , Viollet Benoit , Schmidt Laura S. , Linehan W. Marston , Krymskaya Vera P. , Hong Seung-Beom
Published: July 2020

TFE3 is an oncogenic transcription factor whose subcellular localization and activity are regulated by post-translational modifications. TFE3 is hyper-phosphorylated in the cytoplasm of mammalian cells under normal growth conditions, but becomes hypo-phosphorylated and translocates into the nucleus of cells with genetic inactivation of theFLCNtumor suppressor gene, which is responsible for the development of renal cancer, lung cysts and cutaneous hamartomas in patients with Birt-Hogg-Dubé syndrome (BHD). Since FLCN is suggested to play a role in metabolic signaling through its interaction with energy and nutrient sensing kinases AMPK and mTOR, we investigated whether metabolic signaling regulates TFE3 activity through post-translational modifications and subcellular localization. We found that TFE3 was activated by metabolic stresses, such as glucose or amino acid deprivation, and induced gene expression of lysosomal genes,cathepsins, V-ATPaseandmucolipin-1. AMPK activation and/or mTORC1 inhibition by nutrient deprivation, AMPK activator, mTOR or lysosomal inhibitors induced hypo-phosphorylation and subsequent nuclear localization of TFE3. mTORC1 directly phosphorylated TFE3in vitroand the mutation of a putative mTORC1-dependent TFE3 phosphorylation site, Ser 321, was critical for its interaction with 14-3-3 protein, and retention in the cytoplasm. Direct phosphorylation of TFE3 by AMPK was demonstrated by anin vitrokinase assay and the AMPK-mediated phosphorylation sites were determined by mass spectrometry; however, the physiological significance of AMPK-mediated TFE3 phosphorylation requires further investigation. mTORC1-mediated TFE3 phosphorylation under nutrient and growth factor replete conditions was dependent on FLCN expression. In summary, we have shown that TFE3 induces lysosomal gene expression upon activation of AMPK and inhibition_of mTORC1 activity by metabolic stresses or loss of FLCN, which would play important roles not only in catabolic processes but also in the pathogenicity of human disease including cancer.
Accurate plant pathogen effector protein classificationab initiowith deepredeff, an ensemble of convolutional neural networks
Authors: Kristianingsih Ruth , MacLean Dan
Published: July 2020

Plant pathogens cause billions of dollars of crop loss every year and are a major threat to global food security. Effector proteins are the tools such pathogens use to infect the cell, predicting effectors de novo from sequence is difficult because of the heterogeneity of the sequences. We hypothesised that deep learning classifiers based on Convolutional Neural Networks would be able to identify effectors and deliver new insights. We built a training set of manually curated effector sequences from PHI-Base and used these to train a range of model architectures for classifying bacteria, fungal and oomycete sequences. The best performing classifiers had accuracies from 93 % to 84 %. The models were tested against popular effector detection software on our own test data and data provided with those models. We observed better performance from our models. Specifically our models showed greater accuracy and lower tendencies to call false positives on a secreted protein negative test set and a greater generalisability. We used GRAD-CAM activation map analysis to identify the sequences that activated our CNN-LSTM models and found short but distinct N-terminal regions in each taxon that was indicative of effector sequences. No motifs could be observed in these regions but an analysis of amino acid types indicated differing patterns of enrichment and depletion that varied between taxa. We have produced an R package that will allow others to make easy effector predictions using our models.
Mesoscale brain dynamics reorganizes and stabilizes during learning
Authors: Sych Yaroslav , Fomins Aleksejs , Novelli Leonardo , Helmchen Fritjof
Published: July 2020

Adaptive behavior is coordinated by neuronal networks that are distributed across multiple brain regions. How cross-regional interactions reorganize during learning remains elusive. We applied multi-fiber photometry to chronically record simultaneous activity of 12-48 mouse brain regions while mice learned a tactile discrimination task. We found that with learning most regions shifted their peak activity from reward-related action to the reward-predicting stimulus. We corroborated this finding by functional connectivity estimation using transfer entropy, which revealed growth and stabilization of mesoscale networks encompassing basal ganglia, thalamus, cortex, and hippocampus, especially during stimulus presentation. The internal globus pallidus, ventromedial thalamus, and several regions in frontal cortex emerged as hub regions. Our results highlight the cooperative action of distributed brain regions to establish goal-oriented mesoscale network dynamics during learning.
Urban living influences the reproductive success of Darwin’s finches in the Galápagos Islands
Authors: Harvey Johanna A. , Chernicky Kiley , Simons Shelby R. , Verrett Taylor B. , Chaves Jaime A. , Knutie Sarah A.
Published: July 2020

Urbanization is expanding worldwide and can have major consequences for organisms, anthropogenic factors can reduce the fitness of animals but may also have benefits, such as consistent human food availability. Understanding these trade-offs is critically important in environments with unreliable annual natural food availability, such as the Galápagos Islands where urbanization is rapidly increasing. For example, during dry climatic condition years, the reproductive success of bird species, such as Darwin’s finches, is low because low precipitation reduces food availability. Urban areas in the Galápagos provide supplemental human food to finches, which could improve their reproductive success during years with low natural food availability. However, urban finches might face trade-offs, as the incorporation of anthropogenic debris (e.g. string, hair, plastic) into their nests can increase mortality.

In our study, we determined the effect of urbanization on the reproductive effort and success of small ground finches (Geospiza fuliginosa; a species of Darwin’s finch) during a dry year on San Cristóbal Island, Galápagos Islands. We also documented the abundance of anthropogenic debris incorporated in to nests.

We quantified nest building, egg laying, hatching, and fledging of small ground finches in an urban and non-urban area. We also qualified the type of anthropogenic debris in finch nests and the quantified the percent of debris comprising total nest mass. We determined whether incorporating these materials into the nest directly led to entanglement- or ingestion-related mortalities.

Overall, urban finches built more nests, laid more eggs, and produced more fledglings than non-urban finches. However, every nest in the urban area contained anthropogenic-related material, which resulted in entanglement- or ingestion-related mortalities in 18% of nests with nestlings. Non-urban nests did not contain any anthropogenic-related material.

Our study showed that urban living has trade-offs during drier climatic conditions: urban birds have overall higher reproductive success than non-urban birds, but urban birds can also suffer a negative consequence by using anthropogenic-related material for nesting. These results suggest that despite the potential cost of urban living, finches benefit overall from urban living and urbanization may buffer the effects of limited resource availability in the Galápagos Islands.
Speciation and the developmental alarm clock
Authors: Cutter Asher D. , Bundus Joanna D.
Published: July 2020

New species arise as the genomes of populations diverge. The developmental ‘alarm clock’ of speciation sounds off when sufficient divergence in genetic control of development leads hybrid individuals to infertility or inviability, the world awoken to the dawn of new species with intrinsic post-zygotic reproductive isolation. Some developmental stages will be more prone to hybrid dysfunction due to how molecular evolution interacts with the ontogenetic timing of gene expression. Considering the ontogeny of hybrid incompatibilities provides a profitable connection between ‘evo-devo’ and speciation genetics to better link macroevolutionary pattern, microevolutionary process, and molecular mechanisms. Here we explore speciation alongside development, emphasizing their mutual dependence on genetic network features, fitness landscapes, and developmental system drift. We assess models for how ontogenetic timing of reproductive isolation can be predictable. Experiments and theory within this synthetic perspective can help identify new rules of speciation as well as rules in the molecular evolution of development.

Impact Statement

Integrating speciation genetics with ontogeny can identify predictable rules in the molecular evolution of developmental pathways and in the accumulation of reproductive isolation as genomes diverge.
Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex
Authors: Glasgow Stephen D. , Wong Edwin W. , Beamish Ian V. , Lancon Kevin , Gibon Julien , Séguéla Philippe , Ruthazer Edward S. , Kennedy Timothy E.
Published: July 2020

The ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that cholinergic activation of muscarinic receptors on entorhinal cortical neurons mediates plasma membrane recruitment of the netrin-1 receptor deleted-in-colorectal cancer (DCC) to promote muscarinic receptor-mediated persistent firing. Conditional deletion of netrin-1 or DCC, which are required for synaptic plasticity, inhibits cholinergic persistent firing, and leads to deficits in spatial working memory. Together, these findings indicate that normal working memory function requires synergistic action of acetylcholine and netrin-1.