bluuebunny/crossref_metadata_2025 huggingface dataset:
Insm1-expressing neurons and secretory cells develop from a common pool of progenitors in the sea anemoneNematostella vectensis
Authors: Tournière Océane , Busengdal Henriette , Gahan James M. , Rentzsch Fabian
Published: April 2021

Neurons are highly specialized cells present in nearly all animals, but their evolutionary origin and relationship to other cell types is not well understood. We use here the sea anemoneNematostella vectensisas a model system for early-branching animals to gain fresh insights into the evolutionary history of neurons. We generated a transgenic reporter line to show that the transcription factorNvInsm1is expressed in post-mitotic cells that give rise to various types of neurons and secretory cells. Expression analyses, double transgenics and gene knockdown experiments show that theNvInsm1-expressing neurons and secretory cells derive from a common pool ofNvSoxB(2)-positive progenitor cells. These findings, together with the requirement forInsm1for the development of neurons and endocrine cells in vertebrates, support a close evolutionary relationship of neurons and secretory cells.
Improved data sets and evaluation methods for the automatic prediction of DNA-binding proteins
Authors: Zaitzeff Alexander , Leiby Nicholas , Motta Francis C. , Haase Steven B. , Singer Jedediah M.
Published: April 2021

Motivation

Accurate automatic annotation of protein function relies on both innovative models and robust datasets. Due to their importance in biological processes, the identification of DNA-binding proteins directly from protein sequence has been the focus of many studies. However, the data sets used to train and evaluate these methods have suffered from substantial flaws. We describe some of the weaknesses of the data sets used in previous DNA-binding protein literature and provide several new data sets addressing these problems. We suggest new evaluative benchmark tasks that more realistically assess real-world performance for protein annotation models. We propose a simple new model for the prediction of DNA-binding proteins and compare its performance on the improved data sets to two previously published models. Additionally, we provide extensive tests showing how the best models predict across taxonomies.

Results

Our new gradient boosting model, which uses features derived from a published protein language model, outperforms the earlier models. Perhaps surprisingly, so does a baseline nearest neighbor model using BLAST percent identity. We evaluate the sensitivity of these models to perturbations of DNA-binding regions and control regions of protein sequences. The successful data-driven models learn to focus on DNA-binding regions. When predicting across taxonomies, the best models are highly accurate across species in the same kingdom and can provide some information when predicting across kingdoms.

Code and Data Availability

All the code and data for this paper can be found athttps://github.com/AZaitzeff/tools_for_dna_binding_proteins.

Contact

alexander.zaitzeff@twosixtech.com
Loss ofUsp22enhances histone H2B monoubiquitination and stimulates intracellular and systemic interferon immunity
Authors: Dietlein Nikolaus , Wang Xi , Correa Esther Rodríguez , Erbil Beyza , Lipka Daniel B. , Begus-Nahrmann Yvonne , Kosinsky Robyn Laura , Johnsen Steven A. , Winkler Thomas H. , Rodewald Hans-Reimer
Published: April 2021

Interferons protect from virus infections by inducing hundreds of interferon-stimulated genes (ISG) which orchestrate anti-viral adaptive and innate immunity. Upon viral infection or type I interferon (IFN) stimulation of cell lines, a histone modification, monoubiquitinated histone 2B (H2Bub1), increases at ISG loci, raising the possibility that a specific chromatin state can broadly stimulate IFN immunity in vivo. Here we show that, in the absence of virus infection or elevated interferon levels, mice lacking the relevant deubiquitinase,Usp22, in immune cells have elevated H2Bub1 levels. Hypermonoubiquitinated H2B is physically associated with dozens of ISG loci, and expression of large numbers of ISG is upregulated. This epigenetic state promotes intracellular and systemic immune phenotypes akin to adaptive and innate interferon immunity, and thereby identifiesUsp22as a negative regulator of interferon immunity.
High-quality genome and methylomes illustrate features underlying evolutionary success of oaks
Authors: Sork Victoria L. , Cokus Shawn J. , Fitz-Gibbon Sorel T. , Zimin Aleksey V. , Puiu Daniela , Garcia Jesse A. , Gugger Paul F. , Henriquez Claudia L. , Zhen Ying , Lohmueller Kirk E. , Pellegrini Matteo , Salzberg Steven L.
Published: April 2021

The genusQuercus, which emerged ~55 million years ago during globally warm temperatures, diversified into ~450 species. We present a high-qualityde novogenome assembly of a California endemic oak,Quercus lobata, revealing features consistent with oak evolutionary success. Effective population size remained large throughout history despite declining since the early Miocene. Analysis of 39,373 mapped protein-coding genes outlined copious duplications consistent with genetic and phenotypic diversity, both by retention of genes created during the ancientγwhole genome hexaploid duplication event and by tandem duplication within families, including the numerous resistance genes and also unexpected candidate genes for an incompatibility system involving multiple non-self-recognition genes. An additional surprising finding is that subcontext-specific patterns of DNA methylation associated with transposable elements reveal broadly-distributed heterochromatin in intergenic regions, similar to grasses (another highly successful taxon). Collectively, these features promote genetic and phenotypic variation that would facilitate adaptability to changing environments.
Directing Cholangiocyte Morphogenesis in Natural Biomaterial Scaffolds
Authors: Smith Quinton , Chen Christopher , Bhatia Sangeeta
Published: April 2021

Patients with Alagille syndrome carry monogenic mutations in the Notch signaling pathway and face complications such as jaundice and cholestasis. Given the presence of intrahepatic ductopenia in these patients, Notch2 receptor signaling has been implicated in driving normal biliary development and downstream branching morphogenesis. As a result,in vitromodel systems of liver epithelium are needed to further mechanistic insight of biliary tissue assembly. Here, we systematically evaluate primary human intrahepatic cholangiocytes as a candidate population for such a platform and describe conditions that direct their branching morphogenesis. We find that extracellular matrix presentation, coupled with mitogen stimulation, promotes biliary branching in a Notch-dependent manner. These results demonstrate the utility of using 3D scaffolds for mechanistic investigation of cholangiocyte branching and provides a gateway to integrate biliary architecture in additionalin vitromodels of liver tissue.
GEM-DeCan: Improved tumor immune microenvironment profiling through novel gene expression and DNA methylation signatures predicts immunotherapy response
Authors: Xie Ting , Solórzano Jacobo , Madrid-Mencía Miguel , Essabbar Abdelmounim , Pernet Julien , Kuo Mei-Shiue , Hucteau Alexis , Coullomb Alexis , Verstraete Nina , Delfour Olivier , Cruzalegui Francisco , Pancaldi Vera
Published: April 2021

Quantifying the proportion of the different cell types present in tumor biopsies remains a priority in cancer research. So far, a number of deconvolution methods have emerged for estimating cell composition using reference signatures, either based on gene expression or on DNA methylation from purified cells. These two deconvolution approaches could be complementary to each other, leading to even more performant signatures, in cases where both data types are available. However, the potential relationship between signatures based on gene expression and those based on DNA methylation remains underexplored.

Here we present five new deconvolution signature matrices, based RNAseq data or on DNA methylation, which can estimate the proportion of immune cells and cancer cells in a tumour sample. We test these signature matrices on available datasets for in-silico and in-vitro mixtures, peripheral blood, cancer samples from TCGA, and a single-cell melanoma dataset. Cell proportions estimates based on deconvolution performed using our signature matrices, implemented within the EpiDISH framework, show comparable or better correlation with FACS measurements of immune cell-type abundance and with various estimates of cancer sample purity and composition than existing methods.

Using publicly available data of 3D chromatin structure in haematopoietic cells, we expanded the list of genes to be included in the RNAseq signature matrices by considering the presence of methylated CpGs in gene promoters or in genomic regions which are in 3D contact with these promoters. Our expanded signature matrices have improved performance compared to our initial RNAseq signature matrix. Finally, we show the value of our signatures in predicting patient response to immune checkpoint inhibitors in three melanoma cancer cohorts, based on bulk tumour sample gene expression.

We also provide GEM-DeCan: a snakemake pipeline, able to run an analysis from raw sequencing data to deconvolution based on various gene expression signature matrices, both for bulk RNASeq and DNA methylation data.
TBX5 drivesAldh1a2expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development
Authors: Rankin Scott A. , Steimle Jeffrey D. , Yang Xinan H. , Rydeen Ariel B. , Agarwal Kunal , Chaturvedi Praneet , Ikegami Kohta , Herriges Michael J. , Moskowitz Ivan P. , Zorn Aaron M.
Published: April 2021

The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. We show thatTbx5regulates an evolutionarily conserved retinoic acid (RA)-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary development. We demonstrate that Tbx5 directly maintains expression of the RA-synthesizing enzymeAldh1a2in the foregut lateral plate mesoderm via an intronic enhancer that is evolutionarily conserved among terrestrial vertebrates.Tbx5promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module and restricting FGF activity to the anterior. Tbx5/Aldh1a2-dependent RA signaling also directly activatesShhtranscription in the adjacent foregut endoderm through the conserved MACS1 enhancer. Epithelial Hedgehog then signals back to the mesoderm, where together with Tbx5 it activates expression ofWnt2/2bthat ultimately induce pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing cardiopulmonary evolution and birth defects.

KEY FINDINGS

Tbx5 regulates second heart field patterning and pulmonary development via retinoic acid (RA) and Hedgehog (Hh) signaling.

Tbx5 directly maintains transcription of the RA-synthesizing enzymeAldh1a2in the posterior second heart field mesoderm via an evolutionarily conserved intronic enhancer.

Downstream of Tbx5, RA directly promotesShhtranscription through the evolutionarily conserved MACS1 endoderm enhancer.

Downstream of Tbx5, RA suppresses FGF signaling to pattern the second heart field while promoting a Hedgehog-Wnt2/2b signaling cascade that induces pulmonary fate.

SUMMARY STATEMENT

Tbx5-dependent Retinoic Acid signaling regulates an evolutionarily conserved gene regulatory network that coordinates cardiac and pulmonary development.
Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections
Authors: Ahrends Tomasz , Aydin Begüm , Matheis Fanny , Classon Cajsa , Furtado Gláucia C. , Lira Sérgio A. , Mucida Daniel
Published: April 2021

The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss and dysmotility during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via β2-adrenergic receptors (β2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and -13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease- or tissue tolerance that preserves ENS number and functionality.
Genomic signatures of a major adaptive event in the pathogenic fungusMelampsora larici-populina
Authors: Persoons Antoine , Maupetit Agathe , Louet Clémentine , Andrieux Axelle , Lipzen Anna , Barry Kerrie W. , Na Hyunsoo , Adam Catherine , Grigoriev Igor V. , Segura Vincent , Duplessis Sébastien , Frey Pascal , Halkett Fabien , De Mita Stéphane
Published: April 2021

Background

The recent availability of genome-wide sequencing techniques has allowed systematic screening for molecular signatures of adaptation, including in non-model organisms. Host-pathogen interactions constitute good models due to the strong selective pressures that they entail. We focused on an adaptive event which affected the poplar rust fungusMelampsora larici-populinawhen it overcame a resistance gene borne by its host, cultivated poplar. Based on 76 virulent and avirulent isolates framing narrowly the estimated date of the adaptive event, we examined the molecular signatures of selection.

Results

Using an array of genome scan methods, we detected a single locus exhibiting a consistent pattern suggestive of a selective sweep in virulent individuals (excess of differentiation between virulent and avirulent samples, linkage disequilibrium, genotype-phenotype statistical association and long-range haplotypes). Our study pinpoints a single gene and further a single amino acid replacement which may have allowed the adaptive event. Although the selective sweep occurred only four years earlier, it does not seem to have affected genome diversity further than the immediate vicinity of the causal locus.

Conclusions

Our results suggest thatM. larici-populinaunder-went a soft selective sweep and possibly a prominent effect of outbreeding and recombination, which we speculate have increased the efficiency of selection.
Genome-wide mediation analysis: bridging the divide between genotype and phenotype via transcriptomic data in maize
Authors: Yang Zhikai , Xu Gen , Zhang Qi , Obata Toshihiro , Yang Jinliang
Published: April 2021

Mapping genotype to phenotype is an essential topic in genetics and genomics research. As the Omics data become increasingly available, genome-wide association study (GWAS) has been widely applied to establish the relationship between genotype and phenotype. However, signals detected by GWAS usually span broad genomic regions with many underneath candidate genes, making it challenging to interpret and validate the molecular functions of the candidate genes. Under the context of genetics research, we hypothesized a causal chain from genotype to phenotype partially mediated by intermediate molecular processes, i.e., gene expression. To test this hypothesis, we applied the high dimensional mediation analysis, a class of causal inference method with an assumed causal chain from the exposure to the mediator to the outcome, and implemented it to the maize diversity panel (N=280 lines). Using 40 publicly available agronomic traits, 66 newly generated metabolic traits, and published RNA-seq data from seven different tissues, we detected N=736 unique mediating genes, explaining an average of 12.7% phenotypic variance due to mediation. Noticeably, 83/736 (11%) genes were identified in mediating more than one trait, suggesting the prevalence of pleiotropic mediating effects. Among those pleiotropic mediators, benzox-azinone synthesis 13 (Bx13), a well-characterized gene encoding a 2-oxoglutarate-dependent dioxygenase, was identified mediating 40 agronomic and metabolic traits in different tissues. Further genetic and genomic analyses of theBx13and adjacent mediating genes suggested a 3D co-regulation modulation likely affect their expression levels and eventually lead to phenotypic consequences. Our results suggested the genome-wide mediation analysis is a powerful tool to integrate Omics data in providing causal inference to connect genotype to phenotype.
Microglia and perivascular macrophages act as antigen presenting cells to promote CD8 T cell infiltration of the brain
Authors: Goddery Emma N. , Fain Cori E , Lipovsky Chloe G , Ayasoufi Katayoun , Yokanovich Lila T. , Malo Courtney S. , Khadka Roman H. , Tritz Zachariah P. , Jin Fang , Hansen Michael J. , Johnson Aaron J.
Published: April 2021

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigen via major histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kband H-2Dbupon infection. Conditional ablation of H-2Kband H-2Dbfrom CNS-myeloid cells allowed us to determine that antigen presentation via H-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler’s murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.
State-dependent network interactions differentially gate sensory input at the motor and command neuron level inCaenorhabditis elegans
Authors: Cecere Zachary T. , Quach Kathleen T. , Yemini Eviatar , How Javier J. , Sharpee Tatyana O. , Chalasani Sreekanth H.
Published: April 2021

Neural responses are influenced by both external stimuli and internal network states. While network states have been linked to behavioral and stimulus states, little is known about how sensory inputs are filtered by whole-brain activity to affect motor and command neurons. Here, we recorded whole-brain activity ofCaenorhabditis elegansexperiencing bacterial food stimuli, and modeled how sensory inputs affect motor and command neurons in a network state-dependent manner. First, we classified active neurons into six functional clusters: two sensory neuron clusters (ON, OFF), and four motor/command neuron clusters (AVA, RME, SMDD, SMDV). Using encoding models, we found that ON and OFF sensory neurons that respond to onset and removal of bacteria, respectively, employ different adaptation strategies. Next, we used decoding models to show that bacterial onset and removal differentially drive AVA and RME cluster activity. To explore state-dependent effects on AVA and RME clusters, we developed a model that identified network states and fitted submodels for each state to predict how each of the six functional clusters drive AVA and RME cluster activity. We also identified network states in which AVA and RME clusters were either largely unperturbed by or receptive to bacterial sensory input. Furthermore, this model allowed us to disentangle the state-dependent contributions of stimulus timescales and bacterial content to neural activity. Collectively, we present an interpretable approach for modeling network dynamics that goes beyond implication of neurons in particular states, and moves toward explicitly dissecting how neural populations work together to produce state dependence.

Significance Statement

A major function of the brain is to transform sensory information into behavior. As the first receiver of sensory input, sensory neuron activity is often most correlated with stimulus features. However, this high-fidelity representation of sensory input becomes diluted as it travels to downstream neurons, where sensory information is integrated with network activity. By the time sensory information reaches motor neurons, it is often difficult to dissociate the influence of sensory input from the influence of network activity. Here, we describe a method that is fully interpretable such that we can show how neural populations on a whole-brain scale interact to produce network states. From there, we can attribute motor neuron activity to network history and sensory input.
Hedgehog pathway members Patched and Costal-2 exhibit differences in overgrowth autonomy inDrosophila melanogaster
Authors: Moore Shannon L. , Adamini Frank C. , Coopes Erik S. , Godoy Dustin , Northington Shyra J. , Stewart Jordan M. , Tillet Richard L. , Bieser Kayla L. , Kagey Jacob D.
Published: April 2021

Genetic screens are used inDrosophila melanogasterto identify genes key in the regulation of organismal development and growth. These screens have defined signaling pathways necessary for tissue and organismal development which are evolutionarily conserved across species, includingDrosophila. Here we have used a Flp/FRT mosaic system to screen for conditional regulators of cell growth and cell division in theDrosophilaeye. The conditional nature of this screen utilizes a block in the apoptotic pathway to prohibit the mosaic mutant cells from dying via apoptosis. From this screen, we identified two different mutants that mapped to the Hedgehog signaling pathway. Previously, we described a novelPtcmutation and here we add to the understanding of disrupting the Hh pathway with a novel allele ofCos2. Both of these Hh components are negative regulators of the pathway, yet they depict mutant differences in the type of overgrowth.Ptcmutations lead to overgrowth consisting of almost entirely wild type issue (non-autonomous overgrowth), while theCos2mutation results in tissue that is overgrown in both the mutant and wild type clones (both autonomous and non-autonomous). These differences in tissue overgrowth are consistent in theDrosophilaeye and wing. The observed difference is correlated with a different pattern of deregulation of Mad, the downstream effector of DPP signaling. This finding provides insight into pathway specific differences that may help to better understand intricacies of developmental processes and human disease.
Double-observer approach with camera traps: Towards an unbiased density estimation of unmarked animal populations
Authors: Nakashima Yoshihiro , Hongo Shun , Mizuno Kaori , Yajima Gota , Dzefck Zeun’s C.B.
Published: April 2021

Camera traps are a powerful tool for wildlife surveys. However, camera traps may not always detect animals passing in front. This constraint may create a substantial bias in estimating critical parameters such as the density of unmarked populations. We proposed the ‘double-observer approach’ with camera traps to counter the constraint, which involves setting up a paired camera trap at a station and correcting imperfect detection with a hierarchal capture-recapture model for stratified populations. We performed simulations to evaluate this approach’s reliability and determine how to obtain desirable data for this approach. We then applied it to 12 mammals in Japan and Cameroon. The results showed that the approach could correct imperfect detection as long as paired camera traps detect animals nearly independently (Correlation coefficient < 0.2). Camera traps should be installed to monitor a predefined small focal area from different directions to satisfy this requirement. The field surveys showed that camera trap might miss animals by 3 %–40%, suggesting that current density estimation models relying on perfect detection may underestimate animal density by the same order of magnitude. We hope that our approach will be incorporated into existing density estimation models to improve their accuracy.
Sensing hand position in Ehlers-Danlos Syndrome
Authors: Clayton Holly A. , ’t Hart Bernard Marius , Henriques Denise Y. P.
Published: April 2021

Purpose

To explore the effect of joint hypermobility on acuity, and plasticity, of hand proprioception.

Materials and Methods

We compared proprioceptive acuity between EDS patients and controls. We then measured any changes in their estimate of hand position after participants adapted their reaches in response to altered visual feedback of their hand. The Beighton Scale was used to quantify the magnitude of joint hypermobility.

Results

There were no differences between the groups in the accuracy of estimates of hand location, nor in the visually-induced changes in hand location. However, EDS patients’ estimates were less precise when based purely on proprioception and could be partially predicted by Beighton score.

Conclusions

EDS patients are less precise at estimating their hand’s location when only afferent information is available, but the presence of efferent signalling may reduce this imprecision. Those who are more hypermobile are more likely to be imprecise.
Immunophenotyping and transcriptional profiling of human plasmablasts in dengue
Authors: Aggarwal Charu , Saini Keshav , Reddy Elluri Seetharami , Singla Mohit , Nayak Kaustuv , Chawla Yadya M. , Maheshwari Deepti , Singh Prabhat , Sharma Pragati , Bhatnagar Priya , Kumar Sanjeev , Gottimukkala Kamalvishnu , Panda Harekrushna , Gunisetty Sivaram , Davis Carl W , Kissick Haydn Thomas , Kabra Sushil Kumar , Lodha Rakesh , Medigeshi Guruprasad R , Ahmed Rafi , MuraliKrishna Kaja , Chandele Anmol
Published: April 2021

Previous studies have shown that plasmablasts expand massively in dengue patients as compared to many other situations such as influenza infection or vaccination. However, a detailed understanding of the phenotypes and transcriptional features of these cells is lacking. Moreover, despite India having nearly a third of global dengue disease burden, there is virtually no information on plasmablasts responses in dengue patients from India. Here, we provide a detailed characterization of plasmablast responses from dengue confirmed febrile children in India. Immunophenotyping and RNA seq analysis showed that in addition to secreting dengue specific antibodies, these massively expanding cells expressed several adhesion molecules, chemokines and chemokine receptors that are involved in endothelial interactions, homing to skin or mucosal tissues including intestine. Surprisingly, we found that these cells also upregulated expression of several cytokine genes that are involved in angiogenesis, leukocyte extravasation and vascular permeability. These transcriptional features were qualitatively similar to plasmablasts from influenza vaccinees. Interestingly, the expansion of the plasmablasts in dengue patients was significantly lower in patients with primary dengue infection compared to those with secondary dengue. Moreover, within the primary dengue patients, their expansion was significantly lower in patients with mild dengue infection (DI) compared to patients with dengue with warning signs (DW) or severe dengue (SD). These results significantly improve our understanding of human plasmablast responses in dengue.

Importance

Dengue is a globally spreading with over 100 million clinical cases annually with symptoms ranging from mild self-limiting febrile illness to more severe and sometimes life-threatening dengue hemorrhagic fever or shock, especially among children. India contributes nearly a third of global dengue disease burden. The pathophysiology of dengue is complex and remains poorly understood despite many advances indicating a key role for antibody dependent enhancement of infection. While serum antibodies have been extensively studied, the characteristics of the cellular factories responsible for antibody production, i.e., plasmablasts, are only beginning to emerge. This study provides a comprehensive understanding of the magnitude, phenotype, functional and transcriptional profiles of human plasmablasts from dengue patients in India.
Reinforcement Learning Based Approach for Ligand Pose Prediction
Authors: Jose Justin , Gupta Kritika , Alam Ujjaini , Jatana Nidhi , Arora Pooja
Published: April 2021

Identification of the potential binding site and the correct ligand pose are two crucial steps among the various steps in protein ligand interaction for a novel or known target. Currently most of the deep learning methods work on protein ligand pocket datasets for various predictions. In this study, we propose a reinforcement learning (RL) based method for predicting the optimized ligand pose where the RL agent also identifies the binding site based on its training. In order to apply various reinforcement learning techniques, we suggest a novel approach to represent the protein ligand complex using graph CNN which would help utilize both atomic and spatial features. To the best of our knowledge, this is the first time an RL based approach has been put forward for predicting optimized ligand pose.
Multi-scale phenological niches of seed fall in diverse Amazonian plant communities
Authors: Pak Damie , Swamy Varun , Alvarez-Loayza Patricia , Cornejo Fernando , Queenborough Simon A. , Metz Margaret R. , Terborgh John , Valencia Renato , Wright S. Joseph , Garwood Nancy C. , Lasky Jesse R.
Published: April 2021

Phenology has long been hypothesized as an avenue for niche partitioning or interspecific facilitation, both promoting species coexistence. Tropical plant communities exhibit striking diversity in reproductive phenology, but many are also noted for large synchronous reproductive events. Here we study whether the phenology of seed fall in such communities is non-random, what are the temporal scales of phenological patterns, and ecological factors that drive reproductive phenology. We applied multivariate wavelet analyses to test for phenological synchrony versus compensatory dynamics (i.e. anti-synchronous patterns where one species’ decline is compensated by the rise of another) among species and across temporal scales. We used data from long-term seed rain monitoring of hyperdiverse plant communities in the western Amazon. We found significant synchronous whole-community phenology at multiple time scales, consistent with shared environmental responses or positive interactions among species. We also observed both compensatory and synchronous phenology within groups of species likely to share traits (confamilials) and seed dispersal mechanisms. Wind-dispersed species exhibited significant synchrony at ~6 mo scales, suggesting these species share phenological niches to match seasonality of wind. Our results suggest that community phenology is shaped by shared environmental responses but that the diversity of tropical plant phenology may partly result from temporal niche partitioning. The scale-specificity and time-localized nature of community phenology patterns highlights the importance of multiple and shifting drivers of phenology.

Open research statement

Data are provided as private-for-peer review. Code and data can be found athttps://github.com/pakdamie/treephenologywhich is currently public.

This submission does not use novel code.
RNA-seq of the medusavirus suggests remodeling of the host nuclear environment at an early infection stage
Authors: Zhang Ruixuan , Endo Hisashi , Takemura Masaharu , Ogata Hiroyuki
Published: April 2021

Nucleo–cytoplasmic large DNA viruses (NCLDVs) undergo a cytoplasmic or nucleo–cytoplasmic cycle, and the latter involves both nuclear and cytoplasmic compartments to proceed viral replication. Medusavirus, a recently isolated NCLDV, has a nucleo–cytoplasmic replication cycle in amoebas during which the host nuclear membrane apparently remains intact, a unique feature among amoeba–infecting giant viruses. The medusavirus genome lacks most transcription genes but encodes a full set of histone genes. To investigate the infection strategy, we performed a time–course RNA–seq experiment. All the viral genes were transcribed and classified into five temporal expression clusters. The immediate early genes (cluster 1, 42 genes) were mostly (83%) of unknown functions, frequently (95%) associated with a palindromic promoter–like motif, and enriched (45%) in putative nuclear–targeting genes. The later genes (clusters 2–5) were assigned to various functional categories. The viral linker histone H1 gene was in cluster 1, whereas the four core histone genes were in cluster 3, suggesting they had distinct roles during the course of the virus infection. The transcriptional profile of the host amoeba,Acanthamoeba castellanii, genes was greatly altered post–infection. Several encystment–related host genes showed increased representation levels at 48 hours post–infection, which is consistent with the previously reported amoeba encystment upon medusavirus infection. Overall, the transcriptional landscape during the course of medusavirus infection suggests that the virus modifies the host nuclear environment immediately after the initiation of infection. –

Importance

Medusavirus is an amoeba-infecting giant virus that was isolated from a hot spring in Japan. It belongs to the proposed family “Medusaviridae” in the phylumNucleocytoviricota. Unlike other amoeba-infecting giant viruses, medusavirus initiates its DNA replication in the host nucleus without disrupting the nuclear membrane. Our RNA-seq analysis of its infection course uncovered ordered viral gene expression profiles. We identified temporal expression clusters of viral genes and associated putative promoter motifs. The subcellular localization prediction showed a clear spatiotemporal correlation between gene expression timing and localization of the encoded proteins. Notably, the immediate early expression cluster was enriched in genes targeting the nucleus, suggesting the priority of remodeling the host intra-nuclear environment during infection. The transcriptional profile of the amoeba genes was greatly altered post-infection. Notably, the expression of encystment-related genes increased 48 hours post-infection, suggesting that encystment may be an antiviral strategy of amoeba.
Plasmid fitness costs are caused by specific genetic conflicts
Authors: Hall James P. J. , Wright Rosanna C. T. , Harrison Ellie , Muddiman Katie J. , Wood A. Jamie , Paterson Steve , Brockhurst Michael A.
Published: April 2021

Plasmids play an important role in bacterial genome evolution by transferring genes between lineages. Fitness costs associated with plasmid acquisition are expected to be a barrier to gene exchange, but the causes of plasmid fitness costs are poorly understood. Single compensatory mutations are often sufficient to completely ameliorate plasmid fitness costs, suggesting that such costs are caused by specific genetic conflicts rather than generic properties of plasmids, such as their size, metabolic burden, or expression level. Here we show — using a combination of experimental evolution, reverse genetics, and transcriptomics — that fitness costs of two divergent large plasmids inPseudomonas fluorescensare caused by inducing maladaptive expression of a chromosomal tailocin toxin operon. Mutations in single genes unrelated to the toxin operon, and located on either the chromosome or the plasmid, ameliorated the disruption associated with plasmid acquisition. We identify one of these compensatory loci, the chromosomal genePFLU4242, as the key mediator of the fitness costs of both plasmids, with the other compensatory loci either reducing expression of this gene or mitigating its deleterious effects by upregulating a putative plasmid-borne ParAB operon. The chromosomal mobile genetic element Tn6291, which uses plasmids for transmission, remained upregulated even in compensated strains, suggesting that mobile genetic elements communicate through pathways independent of general physiological disruption. Plasmid fitness costs caused by specific genetic conflicts are unlikely to act as a long-term barrier to horizontal gene transfer due to their propensity for amelioration by single compensatory mutations, explaining why plasmids are so common in bacterial genomes.
NOTCH1 drives immune-escape mechanisms in B cell malignancies
Authors: Mangolini Maurizio , Maiques-Diaz Alba , Charalampopoulou Stella , Gerhard-Hartmann Elena , Bloehdorn Johannes , Moore Andrew , Lu Junyan , Franklin Valar Nila Roamio , Chilamakuri Chandra Sekkar Reddy , Moutsoupoulos Ilias , Rosenwald Andreas , Stilgenbauer Stephan , Zenz Thorsten , Mohorianu Irina , D’Santos Clive , Deaglio Silvia , Martin-Subero Jose I. , Ringshausen Ingo
Published: April 2021

NOTCH1is a recurrently mutated gene in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Functional studies to investigate its role have been hampered by the inability to genetically manipulate primary human lymphoma cells, attributed to low transduction-efficacy and procedure-associated toxicity. To overcome these limitations, we have developed a novel method to retrovirally transfer genes into malignant human B cells. We generated isogenic human tumor cells from patients with CLL and MCL, differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-γ signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+T cellsin vivo, further contributing to the poor clinical outcome ofNOTCH1-mutated CLL and MCL.
A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination
Authors: Ambjoern Sara Marie , Duxin Julien P. , Hertz Emil PT , Nasa Isha , Duro Joana , Kruse Thomas , Mendez Blanca Lopez , Rymarczyk Beata , Cressey Lauren E. , van Overeem Hansen Thomas , Kettenbach Arminja , Oestergaard Vibe H. , Lisby Michael , Nilsson Jakob
Published: April 2021

Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by promoting RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 loading to sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers.
A compendium of predicted growths and derived symbiotic relationships between 803 gut microbes in 13 different diets
Authors: Singh Rohan , Dutta Anirban , Bose Tungadri , Mande Sharmila S.
Published: April 2021

Gut health is intimately linked to dietary habits and the microbial community (microbiota) that flourishes within. The delicate dependency of the latter on nutritional availability is also strongly influenced by symbiotic relationships (such as, parasitic or mutualistic) between the resident microbes, often affecting their growth rate and ability to produce key metabolites. Since, cultivating the entire repertoire of gut microbes is an infeasible task, metabolic models (genome-based metabolic reconstructions) could be employed to predict their growth patterns and interactions. Here, we have used 803 gut microbial metabolic models from the Virtual Metabolic Human repository, and subsequently optimized and simulated them to grow on 13 dietary compositions. The presented pairwise interaction data (https://osf.io/ay8bq/) and the associated bacterial growth rates are expected to be useful for (a) deducing microbial association patterns, (b) diet-based inference of personalised gut profiles, and (c) as a steppingstone for studying multi-species metabolic interactions.
Polypharmacological Re-programming of Tumor-associated Macrophages Restores Antitumor Immunity
Authors: Nishida-Aoki Nao , Gujral Taranjit S.
Published: April 2021

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME), and they promote tumor progression, metastasis, and resistance to therapies. However, although TAMs represent a promising target for therapeutic intervention, the complexity of TME has made the study of TAMs challenging. Here, we established a physiologically-relevantin vitroTAM polarization system that recapitulates TAM pro-tumoral activities. We used this system for phenotypic kinase inhibitor screening and identified a multi-targeted compound BMS-794833 as the most potent inhibitor of TAM polarization. BMS-794833 decreased pro-tumoral properties of TAMs and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was not dependent on its primary targets (MET and VEGFR2) but on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAP kinases. Our study underlines the efficacy of polypharmacological strategies in re-programming complex signaling cascades activated during TAM polarization.
PanClassif: Improving pan cancer classification of single cell RNA-seq gene expression data using machine learning
Authors: Mahin Kazi Ferdous , Robiuddin Md. , Islam Mujahidul , Ashraf Shayed , Yeasmin Farjana , Shatabda Swakkhar
Published: April 2021

Cancer is one of the major causes of human death per year. In recent years, cancer identification and classification using machine learning have gained momentum due to the availability of high throughput sequencing data. Using RNA-seq, cancer research is blooming day by day and new insights of cancer and related treatments are coming into light. In this paper, we propose PanClassif, a method that requires a very few and effective genes to detect cancer from RNA-seq data and is able to provide performance gain in several wide range machine learning classifiers. We have taken 22 types of cancer samples from The Cancer Genome Atlas (TCGA) having 8287 cancer samples and 680 normal samples. Firstly, PanClassif usesk-Nearest Neighbor (k-NN) smoothing to smooth the samples to handle noise in the data. Then effective genes are selected by Anova based test. For balancing the train data, PanClassif applies an oversampling method, SMOTE. We have performed comprehensive experiments on the datasets using several classification algorithms. Experimental results shows that PanClassif out-perform existing state-of-the-art methods available and shows consistent performance for two single cell RNA-seq datasets taken from Gene Expression Omnibus (GEO). PanClassif improves performances of a wide variety of classifiers for both binary cancer prediction and multi-class cancer classification. PanClassif is available as a python package (https://pypi.org/project/panclassif/). All the source code and materials of PanClassif are available athttps://github.com/Zwei-inc/panclassif.
Subjective confidence reflects representation of Bayesian probability in cortex
Authors: Geurts Laura S. , Cooke James R. H. , van Bergen Ruben S. , Jehee Janneke F. M.
Published: April 2021

What gives rise to the human sense of confidence? Here, we tested the Bayesian hypothesis that confidence is based on a probability distribution represented in neural population activity. We implemented several computational models of confidence, and tested their predictions using psychophysics and fMRI. Using a generative model-based fMRI decoding approach, we extracted probability distributions from neural population activity in human visual cortex. We found that subjective confidence tracks the shape of the decoded distribution. That is, when sensory evidence was more precise, as indicated by the decoded distribution, observers reported higher levels of confidence. We furthermore found that neural activity in the insula, anterior cingulate, and prefrontal cortex was linked to both the shape of the decoded distribution and reported confidence, in ways consistent with the Bayesian model. Altogether, our findings support recent statistical theories of confidence and suggest that probabilistic information guides the computation of one’s sense of confidence.
First record of a mermithid nematode (Nematoda: Mermithidae) parasitizing winged females of gall-forming aphids (Hemiptera: Aphididae: Eriosomatinae)
Authors: Tong Xin , Kanzaki Natsumi , Akimoto Shin-ichi
Published: April 2021

Juvenile mermithid nematodes were found to parasitize winged females (sexuparae) ofErisoma auratumandTetraneura radicicola. The morphological characteristics of mermithid nematodes are briefly described. The 18S rDNA and 28S rDNA extracted from one nematode were sequenced and used to construct a Bayesian phylogenetic tree, on which the host ranges of mermithid nematodes were represented. Our study indicated that mermithid parasitism of sexuparae led to fewer and smaller sexual female embryos. This is the first record of a mermithid in relation to eriosomatine aphids and the fourth record with respect to Aphididae.
Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium
Authors: Pinto Andreia L , Rai Ranjit K , Brown Jonathan C , Griffin Paul , Edgar James R , Shah Anand , Singanayagam Aran , Hogg Claire , Barclay Wendy S , Futter Clare E , Burgoyne Thomas
Published: April 2021

Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein containing envelope.