bluuebunny/crossref_metadata_2025 huggingface dataset:
High-throughput cell-based assays for the preclinical development of DsbA inhibitors as antivirulence therapeutics
Authors: Verderosa Anthony D. , Dhouib Rabeb , Hong Yaoqin , Heras Begoña , Totsika Makrina
Published: March 2020

Antibiotics are failing fast, and the development pipeline is alarmingly dry. New drug research and development is being urged by world health officials, with new antibacterials against multidrug-resistant Gram-negative pathogens as the highest priority. Antivirulence drugs, which are inhibitors of bacterial pathogenicity factors, are a class of promising antibacterials, however, their development is often stifled by lack of standardised preclinical testing akin to what guides antibiotic development. The lack of established target-specific microbiological assays amenable to high-throughput, often means that cell-based testing of virulence inhibitors is absent from the discovery (hit-to-lead) phase, only to be employed at later-stages of lead optimization. Here, we address this by establishing a pipeline of bacterial cell-based assays developed for the identification and early preclinical evaluation of DsbA inhibitors. Inhibitors of DsbA block bacterial oxidative protein folding and were previously identified by biophysical and biochemical assays. Here we use existingEscherichia coliDsbA inhibitors and uropathogenicE. coli(UPEC) as a model pathogen, to demonstrate that a combination of a cell-based AssT sulfotransferase assay and the UPEC motility assay, modified for a higher throughput format, can provide a robust and target-specific platform for the evaluation of DsbA inhibitors. Our pipeline could also be used in fragment and compound screening for the identification of new DsbA inhibitor classes or hits with a broad spectrum of activity. In conclusion, the establishment of accurate, high-throughput microbiological assays for antivirulence drug identification and early preclinical development, is a significant first step towards their translation into effective therapeutics.

Importance

The safety net of last resort antibiotics is quickly vanishing as bacteria become increasingly resistant to most available drugs. If no action is taken, we will likely enter a post-antibiotic era, where common infections and minor injuries are once again lethal. The paucity in new antibiotic discovery of the past decades has compounded the problem of increasing antibiotic resistance, to the point that it now constitutes a global health crisis that demands global action. There is currently an urgent need for new antibacterial drugs with new targets and modes of action. To address this, research and development efforts into antivirulence drugs, such as DsbA inhibitors, have been ramping up globally. However, the development of microbiological assays as tools for effectively identifying and evaluating antivirulence drugs is lagging behind. Here, we present a high-throughput cell-based screening and evaluation pipeline, which could significantly advance development of DsbA inhibitor as antivirulence therapeutics.
Non-CG methylation is superior to CG methylation in genome regulation
Authors: Domb Katherine , Katz Aviva , Yaari Rafael , Kaisler Efrat , Nguyen Vu Hoang , Hong Uyen Vu Thuy , Griess Ofir , Heskiau Karina Gitin , Ohad Nir , Zemach Assaf
Published: March 2020

DNA methylation in plants occurs in CG, CHG, and CHH sites. While depletion of CG methylation in transposons is associated with ample transcriptional activation, it was mainly studied in species with limited non-CG methylation that is linked to CG methylation. Here we profiled transcription in the moss plant,Physcomitrella patens, that has robust non-CG methylation with similar symmetrical CG and CHG methylation levels. Separated contextual methylation mechanisms inPhyscomitrella patensenabled generation of numerous context-specific hypomethylated mutants. Our transcriptome data show that specific elimination of CG methylation is fully complemented by non-CG methylation. Conversely, exclusive removal of non-CG methylation massively dysregulated genes and transposons. Moreover, CHG methylation silenced transposons stronger than CG methylation. Lastly, we found non-CG methylation as crucial for silencing CG-depleted transposons. These results demonstrate the potency of non-CG methylation in genome regulation and suggest that it evolved due to moderate silencing and/or rapid mutability of methylated CGs.
Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease
Authors: van der Graaf Adriaan , Zorro Maria , Claringbould Annique , Vosa Urmo , Aguirre-Gamboa Raul , Li Chan , Mooiweer Joram , Ricano-Ponce Isis , Borek Zuzanna , Koning Frits , Kooy-Winkelaar Yvonne , Sollid Ludvig , Qiao Shuo-Wang ,   BIOS consortium, Kumar Vinod , Li Yang , Franke Lude , Withoff Sebo , Wijmenga Cisca , Sanna Serena , Jonkers Iris
Published: March 2020

Background

Celiac disease (CeD) is a complex T cell–mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD.

Results

We used four different in silico approaches – Mendelian Randomization inverse variance weighting, COLOC, LD overlap and DEPICT – to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signalling and T cell activation pathways. 51 of these genes are targets of known drug compounds and likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene-combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAFD1, and were found to be involved in IFNγ signalling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments that validated the role of TRAFD1 as an immune regulator acting in trans.

Conclusions

Our strategy has confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and the IFNγ signalling and MHC I antigen processing pathways, both major players of immune activation and CeD pathogenesis.
Great Expectations: A Critical Review of and Recommendations for the study of Reward Processing as a Cause and Predictor of Depression
Authors: Nielson Dylan M. , Keren Hanna , O’Callaghan Georgia , Jackson Sarah M. , Douka Ioanna , Zheng Charles Y. , Vidal-Ribas Pablo , Pornpattananangkul Narun , Camp Christopher C. , Gorham Lisa S. , Wei Christine , Kirwan Stuart , Stringaris Argyris
Published: March 2020

Both human and animal studies support the relationship between depression and reward processing abnormalities, giving rise to the expectation that neural signals of these processes may serve as biomarkers or mechanistic treatment targets. Given the great promise of this research line, we scrutinize those findings and the theoretical claims that underlie them. To achieve this, we apply the framework provided by classical work on causality as well as contemporary approaches to prediction. We identify a number of conceptual, practical, and analytical challenges to this line of research, and use a pre-registered meta-analysis to quantify the longitudinal associations between reward processing aberrations and depression. We also investigate the impact of measurement error on reported data. We find that reward processing abnormalities do not reach levels that would be useful for clinical prediction, yet the evidence thus far does not exclude their possible causal role in depression.
Public broadly neutralizing antibodies against hepatitis B virus in individuals with elite serologic activity
Authors: Wang Qiao , Michailidis Eleftherios , Yu Yingpu , Wang Zijun , Hurley Arlene M. , Oren Deena A. , Mayer Christian T. , Gazumyan Anna , Liu Zhenmi , Zhou Yunjiao , Schoofs Till , Yao Kai-hui , Nieke Jan P. , Wu Jianbo , Jiang Qingling , Zou Chenhui , Kabbani Mohanmmad , Quirk Corrine , Oliveira Thiago , Chhosphel Kalsang , Zhang Qianqian , Schneider William M. , Jahan Cyprien , Ying Tianlei , Horowitz Jill , Caskey Marina , Jankovic Mila , Robbiani Davide F. , Wen Yumei , de Jong Ype P. , Rice Charles M. , Nussenzweig Michel C.
Published: March 2020

Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and constitute clinical correlates of recovery from infection. To examine the human neutralizing antibody response to HBV in elite neutralizers we screened 144 individuals. The top individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection, but selected for resistance mutations in mice with established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with a peptide epitope containing residues frequently mutated in human immune escape variants revealed a loop anchored by oppositely charged residues. The structure provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.
Prediction of Protein-Protein Interactions Based on L1-Regularized Logistic Regression and Gradient Tree Boosting
Authors: Yu Bin , Chen Cheng , Zhou Hongyan , Liu Bingqiang , Ma Qin
Published: March 2020

Protein-protein interactions (PPIs) are of great importance to understand genetic mechanisms, disease pathogenesis, and guide drug design. With the increase of PPIs sequence data and development of machine learning, the prediction and identification of PPIs have become a research hotspot in proteomics. In this paper, we propose a new prediction pipeline for PPIs based on gradient tree boosting (GTB). First, the initial feature vector is extracted by fusing pseudo amino acid composition (PseAAC), pseudo-position-specific scoring matrix (PsePSSM), reduced sequence and index-vectors (RSIV) and autocorrelation descriptor (AD). Second, to remove redundancy and noise, we employ L1-regularized logistic regression to select an optimal feature subset. Finally, GTB-PPI model based on GTB is constructed. Five-fold cross-validation showed GTB-PPI achieved the accuracies of 95.15% and 90.47% onSaccharomyces cerevisiaeandHelicobacter pylori, respectively. In addition, GTB-PPI could be applied to predictCaenorhabditis elegans,Escherichia coli,Homo sapiens,andMus musculusindependent test sets, the one-core PPIs network for CD9, and the crossover PPIs network. The results show that GTB-PPI can significantly improve prediction accuracy of PPIs. The code and datasets of GTB-PPI can be downloaded fromhttps://github.com/QUST-AIBBDRC/GTB-PPI/.
Molecular Ecology of Coral Reef Microorganisms in the Western Indian Ocean coast of Kenya
Authors: Wambua Sammy , Gourlé Hadrien , de Villiers Etienne , Karlsson Oskar , Wambiji Nina , Macdonald Angus , Bongcam-Rudloff Erik , de Villiers Santie
Published: March 2020

Coral reefs face increased environmental threats from anthropomorphic climate change and pollution, from agriculture, industries and tourism. They are economically vital for many people worldwide, and harbour a fantastically diverse ecosystem, being the home for many species of fish and algae. Surprisingly little is known about the microbial communities living in and in the surrounding of coral reefs. Here we employ high throughput sequencing for investigating the bacteria living in the water column and upper sediment layer in close proximity to coral reefs on the Kenyan coast of the West Indian Ocean. We show that while the read-level taxonomic distribution of bacteria is similar with ones obtained from 16S metabarcoding, whole metagenome sequencing provides valuable functional insights not available with 16S metabarcoding. We find evidence of pollution, marked by the presence ofVibrioand more importantly the presence of antibiotic resistance notably to vancomycin, that we attribute to the use of avoparcin in agriculture. Additionally, 175 bacterial genomes not previously sequenced were discovered.

Our study is the first whole-metagenome study from the West Indian Ocean, provides a much-needed baseline to study microbes surrounding coral reefs under different conditions as well as the microbiome of coral reefs.
The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones
Authors: Shemesh Netta , Jubran Juman , Abu-Qarn Mehtap , Simonovky Eyal , Basha Omer , Hekselman Idan , Dror Shiran , Vinogradov Ekaterina , Carra Serena , Ben-Zvi Anat , Yeger-Lotem Esti
Published: March 2020

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNA-sequencing profiles to analyze the expression and organization of chaperones across 29 main tissues. We found that relative to protein-coding genes, chaperones were significantly more ubiquitously and highly expressed across all tissues. Nevertheless, differential expression analysis revealed that most chaperones were up- or down-regulated in certain tissues, suggesting that they have tissue-specific roles. In agreement, chaperones that were upregulated in skeletal muscle were highly enriched in mouse myoblasts and in nematode’s muscle tissue, and overlapped significantly with chaperones that are causal for muscle diseases. We also identified a distinct subset of chaperones that formed a uniformly-expressed, cross-family core group conducting basic cellular functions that was significantly more essential for cell survival. Altogether, this suggests a layered architecture of chaperones across tissues that is composed of shared core elements that are complemented by variable elements which give rise to tissue-specific functions and sensitivities, thereby contributing to the tissue-specificity of protein misfolding diseases.

Significance Statement

Protein misfolding diseases, such as neurodegenerative disorders and myopathies, are often manifested in a specific tissue or even a specific cell type. Enigmatically, however, they are typically caused by mutations in widely expressed proteins. Here we focused on chaperones, the main and basic components of the protein-folding machinery of cells. Computational analyses of large scale tissue transcriptomes unveils that the chaperone system is composed of core essential elements that are uniformly expressed across tissues, and of variable elements that are differentially expressed in a tissue-specific manner. This organization allows each tissue to fit the quality control system to its specific requirements and illuminates the mechanisms that underlie a tissue’s susceptibility to protein-misfolding diseases.
MosaicBase: A Knowledgebase of Postzygotic Mosaic Variants in Noncancer Diseases and Asymptomatic Human Individuals
Authors: Yang Xiaoxu , Yang Changhong , Zheng Xianing , Xiong Luoxing , Tao Yutian , Wang Meng , Ye Adam Yongxin , Wu Qixi , Dou Yanmei , Luo Junyu , Wei Liping , Huang August Yue
Published: March 2020

Mosaic variants resulting from postzygotic mutations are prevalent in the human genome and play important roles in human diseases. However, except for cancer-related variant collections, there are no collections of mosaic variants in noncancer diseases and asymptomatic individuals. Here, we present MosaicBase (http://mosaicbase.cbi.pku.edu.cn/ or http://49.4.21.8:8000/), a comprehensive database that includes 6,698 mosaic variants related to 269 noncancer diseases and 27,991 mosaic variants identified in 422 asymptomatic individuals. The genomic and phenotypic information for each variant was manually extracted and curated from 383 publications. MosaicBase supports the query of variants with Online Mendelian Inheritance in Man (OMIM) entries, genomic coordinates, gene symbols, or Entrez IDs. We also provide an integrated genome browser for users to easily access mosaic variants and their related annotations within any genomic region. By analyzing the variants collected in MosaicBase, we found that mosaic variants that directly contribute to disease phenotype showed features distinct from those of variants in individuals with a mild or no phenotype in terms of their genomic distribution, mutation signatures, and fraction of mutant cells. MosaicBase will not only assist clinicians in genetic counseling and diagnosis but also provide a useful resource to understand the genomic baseline of postzygotic mutations in the general human population.
Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
Authors: Castañeda-Zegarra Sergio , Zhang Qindong , Alirezaylavasani Amin , Fernandez-Berrocal Marion , Yao Rouan , Oksenych Valentyn
Published: March 2020

Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation ofMri, PaxxorXlfin mice results in normal or mild phenotype, while combined inactivation ofXlf/Mri, Xlf/Paxx, orXlf/Dna-pkcsleads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion ofTrp53rescues embryonic lethality in mice with combined deficiencies ofXlfandMri. Furthermore,Xlf-/-Mri-/-Trp53+/-andXlf-/-Paxx-/-Trp53+/-mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation ofMri/Paxxresults in live-born mice with modest phenotype, and combined inactivation ofMri/Dna-pkcsresults in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte developmentin vivo. Moreover,Mrigenetically interacts withDna-pkcsandPaxx.
Gradients of functional connectivity in the mouse cortex reflect neocortical evolution
Authors: Huntenburg Julia M. , Yeow Ling Yun , Mandino Francesca , Grandjean Joanes
Published: March 2020

Understanding cortical organization is a fundamental goal of neuroscience that requires comparisons across species and modalities. Large-scale connectivity gradients have recently been introduced as a data-driven representation of the intrinsic organization of the cortex. We studied resting-state functional connectivity gradients in the mouse cortex and found robust spatial patterns across four data sets. The principal gradient of functional connectivity shows a striking overlap with an axis of neocortical evolution from two primordial origins. Additional gradients reflect sensory specialization and aspects of a sensory-to-transmodal hierarchy, and are associated with transcriptomic features. While some of these gradients strongly resemble observations in the human cortex, the overall pattern in the mouse cortex emphasizes the specialization of sensory areas over a global functional hierarchy.

Highlights

The principal gradient of functional connectivity in the mouse cortex recapitulates an axis of neocortical evolution from archicortex and paleocortex.

Additional gradients highlight sensory specialization and reflect aspects of a sensory-to-transmodal hierarchy.

Functional connectivity gradients partly align with gene expression patterns.

Mouse cortical gradients are stable across data sets.
Pheno-RNA, a method to identify genes linked to a specific phenotype: application to cellular transformation
Authors: Darwiche Rabih , Struhl Kevin
Published: March 2020

Cellular transformation is associated with dramatic changes in gene expression, but it is difficult to determine which regulated genes are oncogenically relevant. Here, we describe Pheno-RNA, a general approach to identify candidate genes associated with a specific phenotype. Specifically, we generate a “phenotypic series” by treating a non-transformed breast cell line with a wide variety of molecules that induce cellular transformation to various extents. By performing transcriptional profiling across this phenotypic series, the expression profile of every gene can be correlated with the transformed phenotype. We identify ~200 genes whose expression profiles are very highly correlated with the transformation phenotype, strongly suggesting their importance in transformation. Within biological categories linked to cancer, some genes show high correlations with the transformed phenotype, but others do not. Many genes whose expression profiles are highly correlated with transformation have never been linked to cancer, suggesting the involvement of heretofore unknown genes in cancer.
Brain activity reveals multiple motor-learning mechanisms in a real-world task
Authors: Haar Shlomi , Faisal A. Aldo
Published: March 2020

Many recent studies found signatures of motor learning in neural Beta oscillations (13– 30Hz), and specifically in the post-movement Beta rebound (PMBR). All these studies were in controlled laboratory-tasks in which the task designed to induce the studied learning mechanism. Interestingly, these studies reported opposing dynamics of the PMBR magnitude over learning for the error-based and reward-based tasks (increase versus decrease, respectively). Here we explored the PMBR dynamics during real-world motor-skill-learning in a billiards task using mobile-brain-imaging. Our EEG recordings highlight the opposing dynamics of PMBR magnitudes (increase versus decrease) between different subjects performing the same task. The groups of subjects, defined by their neural dynamics, also showed behavioural differences expected for different learning mechanisms. Our results suggest that when faced with the complexity of the real-world different subjects might use different learning mechanisms for the same complex task. We speculate that all subjects combine multi-modal mechanisms of learning, but different subjects have different predominant learning mechanisms.
Pairwise and Higher-Order Epistatic Interactions Have a Significant Impact on Bronchodilator Drug Response in African American Youth with Asthma
Authors: Magaña J , Contreras MG , Keys KL , Risse-Adams O , Goddard PC , Zeiger AM , Mak ACY , Elhawary JR , Samedy-Bates LA , Lee E , Thakur N , Hu D , Eng C , Salazar S , Huntsman S , Hu T , Burchard EG , White MJ
Published: March 2020

Background

Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables.

Results

We evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 617 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to identify interaction effects. We performed analyses in the full dataset and in sex-stratified subsets. Analysis in the full dataset identified six significant interactions associated with BDR, the strongest of which was an interaction between prenatal smoke exposure, age, and global African ancestry (IG: 1.09%, p=0.005). Sex-stratified analyses yielded additional significant, but divergent, results for females and males, indicating the presence of sex-specific effects.

Conclusions

Our study identified novel interaction effects significantly influencing BDR in African American children with asthma. Notably, we found that the impact of higher-order interactions was greater than that of pairwise or main effects on BDR highlighting the complexity of the network of genetic and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods emphasizing the importance of employing statistical methods optimized to detect both linear and non-linear interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.
Stream-Specific Feedback Inputs to the Primate Primary Visual Cortex
Authors: Federer Frederick , Ta’afua Seminare , Merlin Sam , Hassanpour Mahlega S. , Angelucci Alessandra
Published: March 2020

The sensory neocortex consists of hierarchically-organized areas reciprocally connected via feedforward and feedback circuits. Feedforward connections shape the receptive field properties of neurons in higher areas within parallel streams specialized in processing specific stimulus attributes. Feedback connections, instead, have been implicated in top-down modulations, such as attention, prediction and sensory context. However, their computational role remains unknown, partly because we lack knowledge about rules of feedback connectivity to constrain models of feedback function. For example, it is unknown whether feedback connections maintain stream-specific segregation, or integrate information across parallel streams. Using selective viral-mediated labeling of feedback connections arising from specific cytochrome-oxidase stripes of macaque visual area V2, we find that feedback to the primary visual cortex (V1) is organized into parallel streams resembling the reciprocal feedforward pathways. These results suggest that functionally-specialized V2 feedback channels modulate V1 responses to specific stimulus attributes, an organizational principle that could extend to feedback pathways in other sensory systems.
Genetic elucidation of complex biochemical traits mediating maize innate immunity
Authors: Ding Yezhang , Weckwerth Philipp R. , Poretsky Elly , Murphy Katherine M. , Sims James , Saldivar Evan , Christensen Shawn A. , Char Si Nian , Yang Bing , Tong Anh-dao , Shen Zhouxin , Kremling Karl A. , Buckler Edward S. , Kono Tom , Nelson David R. , Bohlmann Jörg , Bakker Matthew G. , Vaughan Martha M. , Khalil Ahmed S. , Betsiashvili Mariam , Briggs Steven P. , Zerbe Philipp , Schmelz Eric A. , Huffaker Alisa
Published: March 2020

Specialized metabolites constitute key layers of immunity underlying crop resistance; however, challenges in resolving complex pathways limit our understanding of their functions and applications. In maize (Zea mays) the inducible accumulation of acidic terpenoids is increasingly considered as a defense regulating disease resistance. To understand maize antibiotic biosynthesis, we integrated association mapping, pan-genome multi-omic correlations, enzyme structure-function studies, and targeted mutagenesis. We now define ten genes in three zealexin (Zx) gene clusters comprised of four sesquiterpene synthases and six cytochrome P450s that collectively drive the production of diverse antibiotic cocktails. Quadruple mutants blocked in the production of β-macrocarpene exhibit a broad-spectrum loss of disease resistance. Genetic redundancies ensuring pathway resiliency to single null mutations are combined with enzyme substrate-promiscuity creating a biosynthetic hourglass pathway utilizing diverse substrates andin vivocombinatorial chemistry to yield complex antibiotic blends. The elucidated genetic basis of biochemical phenotypes underlying disease resistance demonstrates a predominant maize defense pathway and informs innovative strategies for transferring chemical immunity between crops.
Detection of new Mycobacterium leprae subtype in Bangladesh by genomic characterization to explore transmission patterns
Authors: Tió-Coma Maria , Avanzi Charlotte , Verhard Els M. , Pierneef Louise , van Hooij Anouk , Benjak Andrej , Roy Johan Chandra , Khatun Marufa , Alam Khorshed , Corstjens Paul , Cole Stewart T. , Richardus Jan Hendrik , Geluk Annemieke
Published: March 2020

Mycobacterium leprae, the causative agent of leprosy, is an unculturable bacterium with a considerably reduced genome (3.27 Mb) compared to homologues mycobacteria from the same ancestry. M. leprae transmission is suggested to occur through aerosols but the exact mechanisms of infection remains unclear. In 2001, the genome of M. leprae was first described and subsequently four genotypes (1-4) and 16 subtypes (A-P) were identified providing means to study global transmission patterns for leprosy.

We investigated M. leprae carriage as well as infection in leprosy patients (n=60) and healthy household contacts (HHC; n=250) from Bangladesh using molecular detection of the bacterial element RLEP in nasal swabs (NS) and slit skin smears (SSS). In parallel, we explored bacterial strain diversity by whole-genome sequencing (WGS) and Sanger sequencing.

In the studied cohort in Bangladesh, M. leprae DNA was detected in 33.3% of NS and 22.2% of SSS of patients with bacillary index of 0 whilst in HHC 18.0% of NS and 12.3% of SSS were positive.

The majority of the M. leprae strains detected in this study belonged to genotype 1D (55%), followed by 1A (31%). Importantly, WGS allowed the identification of a new M. leprae genotype, designated 1B-Bangladesh (14%), which clustered separately between the 1A and 1B strains. Moreover, we established that the genotype previously designated 1C, is not an independent subtype but clusters within the 1D genotype.

Intraindividual differences were present between the M. leprae strains obtained including mutations in hypermutated genes, suggesting mixed colonization/infection or in-host evolution.

In summary, we observed that M. leprae is present in asymptomatic contacts of leprosy patients fueling the concept that these individuals contribute to the current intensity of transmission. Our data therefore emphasize the importance of sensitive and specific tools allowing post-exposure prophylaxis targeted at M. leprae-infected or -colonized individuals.
Dicere Non Nocere: Public Disclosure of Identifiable Patient Information by Health Professionals on Social Media
Authors: Katz Matthew S. , Ahmed Wasim , Gutheil Thomas G. , Jagsi Reshma
Published: March 2020

Background

Respecting patient privacy and confidentiality is critical for doctor-patient relationships and public trust in medical professionals. The frequency of potentially identifiable disclosures online during periods of active engagement is unknown. Our aim was to quantify potentially identifiable content shared by physicians and other health care providers on social media using the hashtag #ShareAStoryInOneTweet.

Methods

We used Symplur Signals software to access Twitter’s API and searched for tweets including the hashtag. We identified 1206 tweets by doctors, nurses, and other health professionals out of 43,374 tweets shared May 1-31, 2018. We evaluated tweet content in January 2019, eight months after the study period. To determine the incidence of sharing names or potentially identifiable information about patients, we performed a content analysis of the 754 tweets in which tweets disclosed information about others. We also evaluated whether participants raised concerns about privacy breaches and estimated the frequency of deleted tweets. We used dual, blinded coding for a 10% sample to estimate inter-coder reliability for potential identifiability of tweet content using Cohen’s kappa statistic.

Results

656 participants, including 486 doctors (74.1%) and 98 nurses (14.9%), shared 754 tweets disclosing information about others rather than themselves. Professional participants sharing stories about patient care disclosed the time frame in 95 (12.6%) and included patient names in 15 (2.0%) of tweets. We estimated that friends or families could likely identify the clinical scenario described in 32.1% of the 754 tweets. Among 348 tweets about potentially living patients, we estimated 162 (46.6%) were likely identifiable by patients. Inter-coder reliability in rating the potential identifiability demonstrated 86.8% agreement, with a Cohen’s Kappa of 0.8 suggesting substantial agreement Of the 1206 tweets we identified, 78 (6.5%) had been deleted on the website but were still viewable in the analytics software dataset.

Conclusions

During periods of active sharing online, nurses, physicians, and other health professionals may sometimes share more information than patients or families might expect. More study is needed to determine whether similar events arise frequently online and to understand how to best ensure that patients’ rights are adequately respected.
The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility
Authors: Hartl CL , Ramaswami G , Pembroke WG , Muller S , Pintacuda G , Saha A , Parsana P , Battle A , Lage K , Geschwind DH
Published: March 2020

Gene networks have proven their utility for elucidating transcriptome structure in the brain, yielding numerous biological insights. Most analyses have focused on expression relationships within a circumspect number of regions – how these relationships vary across a broad array of brain regions is largely unknown. By leveraging RNA-sequencing in 864 samples representing 12 brain regions in a cohort of 131 phenotypically normal individuals, we identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. We replicate the majority (81%) of modules in regional microarray datasets. Nearly 40% of expressed genes fall into brain-wide modules corresponding to major cell classes and conserved biological processes. Region-specific modules comprise 25% of expressed genes and correspond to region-specific cell types and processes, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. We further leverage these modules to capture cell-type-specific lncRNA and gene isoforms, both of which contribute substantially to regional synaptic diversity. We identify enrichment of neuropsychiatric disease risk variants in brain wide and multi-regional modules, consistent with their broad impact on cell classes, and highlight specific roles in neuronal proliferation and activity-dependent processes. Finally, we examine the manner in which gene co-expression and gene regulatory networks reflect genetic risk, including the recently framed omnigenic model of disease architecture.
Undinarchaeota illuminate the evolution of DPANN archaea
Authors: Dombrowski Nina , Williams Tom A. , Sun Jiarui , Woodcroft Benjamin J. , Lee Jun-Hoe , Minh Bui Quang , Rinke Christian , Spang Anja
Published: March 2020

Introductory paragraph

The evolution and diversification of Archaea is central to the history of life on Earth. Cultivation-independent approaches have revealed the existence of at least ten archaeal lineages whose members have small cell and genome sizes and limited metabolic capabilities and together comprise the tentative DPANN archaea. However, the phylogenetic diversity of DPANN and the placement of the various lineages of this group in the archaeal tree remain debated. Here, we reconstructed additional metagenome assembled genomes (MAGs) of a thus far uncharacterized archaeal phylum-level lineage UAP2 (CandidatusUndinarchaeota) affiliating with DPANN archaea. Comparative genome analyses revealed that members of the Undinarchaeota have small estimated genome sizes and, while potentially being able to conserve energy through fermentation, likely depend on partner organisms for the acquisition of vitamins, amino acids and other metabolites. Phylogenomic analyses robustly recovered Undinarchaeota as a major independent lineage between two highly supported clans of DPANN: one clan comprising Micrarchaeota, Altiarchaeota and Diapherotrites, and another encompassing all other DPANN. Our analyses also suggest that DPANN archaea may have exchanged core genes with their hosts by horizontal gene transfer (HGT), adding to the difficulty of placing DPANN in the archaeal tree. Together, our findings provide crucial insights into the origins and evolution of DPANN archaea and their hosts.
ebonyaffects pigmentation divergence and cuticular hydrocarbons inDrosophila americanaandD. novamexicana
Authors: Lamb Abigail M. , Wang Zinan , Simmer Patricia , Chung Henry , Wittkopp Patricia J.
Published: March 2020

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Drosophilapigmentation has been a fruitful model system for understanding the genetic and developmental mechanisms underlying phenotypic evolution. For example, prior work has shown that divergence of thetangene contributes to pigmentation differences between two members of the virilis group:Drosophila novamexicana, which has a light yellow body color, andD. americana, which has a dark brown body color. Quantitative trait locus (QTL) mapping and expression analysis has suggested that divergence of theebonygene might also contribute to pigmentation differences between these two species. Here, we directly test this hypothesis by using CRISPR/Cas9 genome editing to generateebonynull mutants inD. americanaandD. novamexicanaand then using reciprocal hemizygosity testing to compare the effects of each species’ebonyallele on pigmentation. We find that divergence ofebonydoes indeed contribute to the pigmentation divergence between species, with effects on both the overall body color as well as a difference in pigmentation along the dorsal abdominal midline. Motivated by recent work inD. melanogaster, we also used theebonynull mutants to test for effects ofebonyon cuticular hydrocarbon (CHC) profiles. We found thatebonyaffects CHC abundance in both species, but does not contribute to qualitative differences in the CHC profiles between these two species. Additional transgenic resources for working withD. americanaandD. novamexicana, such aswhitemutants of both species andyellowmutants inD. novamexicana, were generated in the course of this work and are also described. Taken together, this study advances our understanding of loci contributing to phenotypic divergence and illustrates how the latest genome editing tools can be used for functional testing in non-model species.
Age-related differences in auditory cortex activity during spoken word recognition
Authors: Rogers Chad S. , Jones Michael S. , McConkey Sarah , Spehar Brent , Van Engen Kristin J. , Sommers Mitchell S. , Peelle Jonathan E.
Published: March 2020

Understanding spoken words requires the rapid matching of a complex acoustic stimulus with stored lexical representations. The degree to which the brain networks supporting spoken word recognition are affected by adult aging remains poorly understood. In the current study we used fMRI to measure the brain responses to spoken words in two conditions: an attentive listening condition, in which no response was required, and a repetition task. Listeners were 29 young adults (aged 19–30 years) and 32 older adults (aged 65–81 years) without self-reported hearing difficulty. We found largely similar patterns of activity during word perception for both young and older adults, centered on bilateral superior temporal gyrus. As expected, the repetition condition resulted in significantly more activity in areas related to motor planning and execution (including premotor cortex and supplemental motor area) compared to the attentive listening condition. Importantly, however, older adults showed significantly less activity in probabilistically-defined auditory cortex than young adults when listening to individual words in both the attentive listening and repetition tasks. Age differences in auditory cortex activity were seen selectively for words (no age differences were present for 1-channel vocoded speech, used as a control condition), and could not be easily explained by accuracy on the task, movement in the scanner, or hearing sensitivity (available on a subset of participants). These findings indicate largely similar patterns of brain activity for young and older adults when listening to words in quiet, but suggest less recruitment of auditory cortex by the older adults.
Phosphorylation by Aurora B kinase regulates caspase-2 activity and function
Authors: Lim Yoon , De Bellis Dylan , Sandow Jarrod J. , Capalbo Luisa , D’Avino Pier Paolo , Murphy James M. , Webb Andrew I. , Dorstyn Loretta , Kumar Sharad
Published: March 2020

Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploidy due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cell cycle arrest of mitotically defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here we identify six new phosphorylation sites in caspase-2 and show that a key mitotic kinase, Aurora B kinase (AURKB), phosphorylates caspase-2 at the highly conserved residue S384. We demonstrate that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.
Differentiation reveals the plasticity of age-related change in murine muscle progenitors
Authors: Kimmel Jacob C. , Hendrickson David G. , Kelley David R.
Published: March 2020

Skeletal muscle experiences a decline in lean mass and regenerative potential with age, in part due to intrinsic changes in progenitor cells. However, it remains unclear if age-related changes in progenitors persist across a differentiation trajectory or if new age-related changes manifest in differentiated cells. To investigate this possibility, we performed single cell RNA-seq on muscle mononuclear cells from young and aged mice and profiled muscle stem cells (MuSCs) and fibro/adipose progenitors (FAPs) after differentiation. Differentiation increased the magnitude of age-related change in MuSCs and FAPs, but also masked a subset of age-related changes present in progenitors. Using a dynamical systems approach and RNA velocity, we found that aged MuSCs follow the same differentiation trajectory as young cells, but stall in differentiation near a commitment decision. Our results suggest that age-related changes are plastic across differentiation trajectories and that fate commitment decisions are delayed in aged myogenic cells.
Multicellular feedback control of a genetic toggle-switch in microbial consortia
Authors: Fiore Davide , Salzano Davide , Cristòbal-Cóppulo Enric , Olm Josep M. , di Bernardo Mario
Published: March 2020

We describe a multicellular approach to control a target cell population endowed with a bistable toggle-switch. The idea is to engineer a synthetic microbial consortium consisting of three different cell populations. In such a consortium, two populations, the Togglers, responding to some reference input, can induce the switch of a bistable memory mechanism in a third population, the Targets, so as to activate or deactivate some additional functionalities in the cells. Communication among the three populations is established by orthogonal quorum sensing molecules that are used to close a feedback control loop across the populations. The control design is validated via in-silico experiments in BSim, a realistic agent-based simulator of bacterial populations.
The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment
Authors: Rashid Mohammad H. , Borin Thaiz F. , Ara Roxan , Piranlioglu Raziye , Achyut Bhagelu R. , Korkaya Hasan , Liu Yutao , Arbab Ali S.
Published: March 2020

Myeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Ourin vitrodata suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cellsin vivoby treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.
Population genetic structure in the insular Ryukyu flying fox,Pteropus dasymallus
Authors: Chen Shiang-Fan , Juan Chung-Hao , Rossiter Stephen , Kinjo Teruo , Fukui Dai , Kawai Kuniko , Tsang Susan M. , Veluz Maria Josefa , Sakurai Hiroko , Jang-Liaw Nian-Hong , Osawa Keiko , Ko Wen-Ya , Izawa Masako
Published: March 2020

Small isolated populations are vulnerable to both stochastic events and the negative consequences of genetic drift. For threatened species, the genetic management of such populations has therefore become a crucial aspect of conservation. Flying foxes (Pteropusspp, Chiroptera) are keystone species with essential roles in pollination and seed dispersal in tropical and subtropical ecosystems. Yet many flying fox species are also of conservation concern, having experienced dramatic population declines driven by habitat loss and hunting. The Ryukyu flying fox (Pteropus dasymallus) ranges from Japan and Taiwan to the northern Philippines, and has undergone precipitous population crashes on several islands in recent decades. To assess population genetic structure and diversity inP. dasymallus, and its likely causes, we analyzed mitochondrial and microsatellite DNA. Both markers showed significant genetic differentiation among most island populations with patterns of isolation-by-distance. However, while mitochondrial haplotypes showed some mixing across the region, likely reflecting historical colonization and/or dispersal events, microsatellites markers showed clear subdivisions corresponding to the position of deep ocean trenches. The current distribution ofP. dasymallusand its subspecific diversity therefore appears to have arisen through vicariance coupled with a long history of restricted gene flow across oceanic barriers. We conclude that isolated island subgroups should be managed separately, with efforts directed at reducing further declines.