bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of a bioinformatic pipeline to RNA-seq data identifies novel virus-like sequence in human blood
Authors: Melnick Marko , Gonzales Patrick , LaRocca Thomas J. , Dowell Robin D. , Song Yuping , Wuu Joanne , Benatar Michael , Oskarsson Björn , Petrucelli Leonard , Link Christopher D. , Prudencio Mercedes 
Published: January 2021

ABSTRACTNumerous reports have suggested that infectious agents could play a role in neurodegenerative diseases, but specific etiological agents have not been convincingly demonstrated. To search for candidate agents in an unbiased fashion, we have developed a bioinformatic pipeline that identifies microbial sequences in mammalian RNA-seq data, including sequences with no significant nucleotide similarity hits in GenBank. Effectiveness of the pipeline was tested using publicly available RNA-seq data. We then applied this pipeline to a novel RNA-seq dataset generated from a cohort of 120 samples from amyotrophic lateral sclerosis (ALS) patients and controls, and identified sequences corresponding to known bacteria and viruses, as well as novel virus-like sequences. The presence of these novel virus-like sequences, which were identified in subsets of both patients and controls, were confirmed by quantitative RT-PCR. We believe this pipeline will be a useful tool for the identification of potential etiological agents in the many RNA-seq data sets currently being generated.
Long-range allosteric effects - How adenine nucleotides shape the conformational landscape of the Ski2-like RNA helicase, Brr2
Authors: Absmeier Eva , Vester Karen , Ghane Tahereh , Burakovskiy Dmitry , Milon Pohl , Imhof Petra , Rodnina Marina V. , Santos Karine F. , Wahl Markus C. 
Published: January 2021

ABSTRACTBrr2 is an essential Ski2-like RNA helicase that exhibits a unique structure among the spliceosomal helicases. Brr2 harbors a catalytically active N-terminal helicase cassette and a structurally similar, but enzymatically inactive C-terminal helicase cassette. Both cassettes contain a nucleotide binding pocket. Here we use biophysical and computational methods to delineate the functional connectivity between the cassettes and how occupancy of the nucleotide binding sites may influence each other. Our results show that Brr2 exhibits high specificity for adenine nucleotides with both cassettes binding ADP tighter than ATP. Adenine nucleotide affinity for the inactive C-terminal cassette is more than two orders of magnitude higher than that of the active N-terminal cassette, largely determined by slow nucleotide release. Mutations at the inter-cassette surfaces and in the connecting linker diminish the affinity of adenine nucleotides for both cassettes. Abrogation of nucleotide binding at the C-terminal cassette reduces nucleotide binding at the N-terminal cassette, 70 Å away. Molecular dynamics simulations identified structural communication lines that likely mediate the long-range allosteric effects. Together, our results reveal intricate networks of intra-molecular interactions in the complex Brr2 RNA helicase, which fine-tune its nucleotide affinities and which could be exploited for regulating the enzyme during splicing.
Gene network module changes associated with the vertebrate fin to limb transition
Authors: Fernando Pasan C , Mabee Paula M , Zeng Erliang 
Published: January 2021

AbstractEvolutionary phenotypic transitions, such as the fin to limb transition in vertebrate evolution, result from changes in associated genes and their interactions, often in response to changing environment. Identifying the associated changes in gene networks is vital to achieve a better understanding of these transitions. Previous experimental studies have been typically limited to manipulating a small number of genes. To expand the number of analyzed genes and hence, biological knowledge, we computationally isolated and compared the gene modules for paired fins (pectoral fin, pelvic fin) of fishes (zebrafish) to those of the paired limbs (forelimb, hindlimb) of mammals (mouse) using quality-enhanced gene networks from zebrafish and mouse. We ranked module genes according to their weighted-degrees and identified the highest-ranking hub genes, which were important for the module stability. Further, we identified genes conserved during the fin to limb transition and investigated the fates of zebrafish-specific and mouse-specific module genes in relation to their involvements in newly emerged or lost anatomical structures during the aquatic to terrestrial vertebrate transition. This paper presents the results of our investigations and demonstrates a general network-based computational workflow to study evolutionary phenotypic transitions involving diverse model organisms and anatomical entities.
Long Reads Capture Simultaneous Enhancer-Promoter Methylation Status for Cell-type Deconvolution
Authors: Margalit Sapir , Abramson Yotam , Sharim Hila , Manber Zohar , Bhattacharya Surajit , Chen Yi-Wen , Vilain Eric , Barseghyan Hayk , Elkon Ran , Sharan Roded , Ebenstein Yuval 
Published: January 2021

AbstractMotivationWhile promoter methylation is associated with reinforcing fundamental tissue identities, the methylation status of distant enhancers was shown by genome-wide association studies to be a powerful determinant of cell-state and cancer. With recent availability of long-reads that report on the methylation status of enhancer-promoter pairs on the same molecule, we hypothesized that probing these pairs on the single-molecule level may serve the basis for detection of rare cancerous transformations in a given cell population. We explore various analysis approaches for deconvolving cell-type mixtures based on their genome-wide enhancer-promoter methylation profiles.ResultsTo evaluate our hypothesis we examine long-read optical methylome data for the GM12787 cell line and myoblast cell lines from two donors. We identified over 100,000 enhancer-promoter pairs that co-exist on at least 30 individual DNA molecules per pair. We developed a detailed methodology for mixture deconvolution and applied it to estimate the proportional cell compositions in synthetic mixtures based on analyzing their enhancer-promoter pairwise methylation. We found our methodology to lead to very accurate estimates, outperforming our promoter-based deconvolutions. Moreover, we show that it can be generalized from deconvolving different cell types to subtle scenarios where one wishes to deconvolve different cell populations of the same cell-type.AvailabilityThe code used in this work to analyze single-molecule Bionano Genomics optical maps is available via the GitHub repositoryhttps://github.com/ebensteinLab/Single_molecule_methylation_in_EP.Contactuv@post.tau.ac.il(Y.E),roded@tauex.tau.ac.il(R.S)
The effects of maternal social connectivity and integration on offspring survival in a marmot
Authors: Montero Anita Pilar , Williams Dana M. , Martin Julien G.A. , Blumstein Daniel T. 
Published: January 2021

AbstractIn social species, maternal social relationships, in addition to direct care, impact offspring survival but much of what we know about these effects comes from studies of obligately social and cooperatively breeding species. Yellow-bellied marmots (Marmota flaviventer) are a facultatively social species whose social groups vary in composition, size, and cohesiveness. This natural variation in sociality and cooperative breeding behavior makes yellow-bellied marmots an ideal species within which to study the effects of maternal affiliative and agonistic social behavior on offspring. We used social network analysis to investigate the relationship between maternal social connectivity and integration on offspring summer and yearly survival, with the hypothesis that offspring with more affiliative mothers are more likely to survive than the offspring of more agonistic mothers. However, we found the inverse to be true: pups born to mothers who received more affiliative interactions were less likely to survive while the offspring of mothers who were more highly integrated into agonistic networks had enhanced survival. Overall, maternal social network measures were positively and negatively correlated with offspring survival, indicating that pups are influenced by their mother’s social world, often in contradictory ways. Relative predation risk and colony location also mediated the effects of social relationships on pup survival. This study contributes to a small but growing body of work that demonstrates that specific attributes of sociality have specific consequences and that by adopting an attribute-focused view of sociality we are better able to understand how environmental conditions mediate the costs and benefits of sociality.Lay SummaryMaternal social relationships can impact offspring survival but much of what we know about these effects comes from studies of obligately social species. In faculatively social yellow-bellied marmots we found that pups born to mothers who received more affiliative interactions were less likely to survive while the offspring of mothers who were more highly integrated into agonistic networks had enhanced survival. Overall, pups are influenced by their mother’s social world, often in contradictory ways.
Genomic and phenotypic biology of novel strains of Dickeya zeae isolated from pineapple and taro in Hawaii: insights into genome plasticity, pathogenicity, and virulence determinants
Authors: Boluk Gamze , Arizala Dario , Dobhal Shefali , Zhang Jingxin , Hu John , Alvarez Anne M. , Arif Mohammad 
Published: January 2021

ABSTRACTDickeya zeae, a bacterial plant pathogen in the family Pectobacteriaceae, is responsible for a wide range of diseases on potato, maize, rice, banana, pineapple, taro and ornamentals and significantly reduces crop production; D. zeae causes soft rot of taro (Colocasia esculenta) and heart rot of pineapple (Ananas comosus). In this study, we used Pacific Biosciences to sequence two high quality complete genomes of novel strains of D. zeae: PL65 (size - 4.74997 MB; depth - 701; GC - 53.3%) and A5410 (size - 4.7792 MB; depth - 558; GC - 53.6%) isolated from economically important Hawaiian crops, taro and pineapple, respectively. Additional complete genomes of D. zeae representing two additional hosts (rice and banana), and other species for taxonomic comparison, were retrieved from the NCBI GenBank genome database. The genomic analyses indicated truncated type III and IV secretion systems (T3SS and T4SS) in the taro strain, which only harbors 1 and 2 genes of T3SS and T4SS, respectively, and showed high heterogeneity in the type VI secretion system. Unlike the EC1 strain, neither the PL65 nor the A5410 genome harbors the zeamine biosynthesis gene cluster, which plays a key role in bacterial virulence. The ANI and dDDH percentages between the two genomes were 94.47 and 57.00, respectively. In this study, we compared major virulence factors (plant cell wall-degrading extracellular enzymes and protease) produced by D. zeae strains and virulence ability on taro corms and pineapple. Both strains produced protease, pectate lyases and cellulases but no significant quantitative differences were observed (p>0.05) among the strains. All the strains produced symptoms on taro corms and pineapple leaves. Strain PL65 developed symptoms faster than the others. Our study highlights genetic constituents of pathogenicity determinants and genomic heterogeneity that will help understand the virulence mechanisms and aggressiveness of this plant pathogen.
Resurrection of a viral internal ribosome entry site from a 700 year old ancient Northwest Territories cripavirus
Authors: Wang Xinying , Jan Eric 
Published: January 2021

ABSTRACTThe dicistrovirus intergenic region internal ribosome entry site (IGR IRES) uses an unprecedented streamlined mechanism whereby the IRES adopts a triple-pseudoknot (PK) structure to directly bind to the conserved core of the ribosome and drive translation from a non-AUG codon. The origin of this IRES mechanism is not known. Previously, a partial fragment of a divergent dicistrovirus RNA genome, named ancient Northwest territories cripavirus (aNCV), was extracted from 700-year-old caribou feces trapped in a subarctic ice patch. Structural prediction of the aNCV IGR sequence generated a secondary structure similar to contemporary IGR IRES structures. There are, however, subtle differences including 105 nucleotides upstream of the IRES of unknown function. Using filter binding assays, we showed that the aNCV IGR IRES could bind to purified salt-washed human ribosomes and compete with a prototypical IGR IRES for ribosomes. Toeprinting analysis using primer extension pinpointed the putative start site of the aNCV IGR at a GCU alanine codon adjacent to PKI. Using a bicistronic reporter RNA, the aNCV IGR IRES can direct internal ribosome entryin vitroin a manner dependent on the integrity of the PKI domain. Lastly, we generated a chimeric virus clone by swapping the aNCV IRES into the cricket paralysis virus infectious clone. The chimeric infectious clone with an aNCV IGR IRES supported translation and virus infection. The characterization and resurrection of a functional IGR IRES from a divergent 700-year-old virus provides a historical framework in the importance of this viral translational mechanism.IMPORTANCEInternal ribosome entry sites are RNA structures that are used by some positive-sense monopartite RNA viruses to drive viral protein synthesis. The origin of internal ribosome entry sites is not known. Using biochemical approaches, we demonstrate that an RNA structure from an ancient viral genome that was discovered from a 700-year-old caribou feces trapped in subarctic ice is functionally similar to modern internal ribosome entry sites. We resurrect this ancient RNA mechanism by demonstrating that it can support virus infection in a contemporary virus clone, thus providing insights into the origin and evolution of this viral strategy.
Structure of a Plant-Specific Partitivirus Capsid Reveals a Novel Coat Protein Architecture with a Hypervariable Protrusion
Authors: Byrne Matthew , Kashyap Aseem , Esquirol Lygie , Ranson Neil , Sainsbury Frank 
Published: January 2021

SUMMARYPersistent plant viruses may be the most common viruses in wild plants. A growing body of evidence for mutualism between such viruses and their hosts, suggests that they play an important role in ecology and agriculture. Here we present the structure of a plant-specific partitivirus capsid at 2.9 Å resolution by Cryo-EM. Structural features, including theT=1 arrangement of 60 coat protein dimers, are shared with fungal partitiviruses and the picobirnavirus lineage of dsRNA viruses. However, the topology of the capsid is markedly different with protrusions emanating from, and partly comprising, the binding interface of coat protein dimers. We show that a disordered region at the apex of the protrusion is not required for capsid assembly and represents a hypervariable site characteristic of the plant-specific partitiviruses. These results suggest a structural basis for the acquisition of additional functions by partitivirus coat proteins that enables mutualistic relationships with diverse plant hosts.
LBH is a cancer stem cell- and metastasis-promoting oncogene essential for WNT stem cell function in breast cancer
Authors: Garikapati Koteswararao , Ashad-Bishop Kilan , Hong Sunhwa , Qureshi Rehana , Rieger Megan E. , Lindley Linsey E. , Wang Bin , Azzam Diana J. , Khanlari Mahsa , Nadji Mehrad , Jain Chaitanya , Kwon Deukwoo , Ban Yuguang , Gao Zhen , Chen Steven X. , Sims Andrew H. , Kesmodel Susan B. , Slingerland Joyce M. , Briegel Karoline J. 
Published: January 2021

ABSTRACTCancer stem cells (CSCs) initiate tumors, resist treatment, and seed lethal metastases; yet CSC-specific treatments are lacking. Aggressive, treatment-resistant triple-negative breast cancers (TNBC) exhibit WNT pathway activation and are CSC enriched. Here, we show that Limb-Bud- and-Heart (LBH), a WNT/β-catenin target required for normal mammary stem cell self-renewal, marks poor prognosis, stem-like TNBC, and is a key controller of breast cancer stemness. LBH is specifically expressed in tumor-initiating CD44+CD24-/lowbreast CSCs. LBH overexpression confers stem-like, metastatic traits on both TNBC and luminal origin, non-TNBC breast cancer cells by activating stem cell transcriptional programs. Importantly, silencing LBH potently suppresses tumor initiation and metastasisin vivo, and sensitizes TNBC cells to chemotherapy. LBH knockout in the MMTV-Wnt1 breast cancer mouse model, furthermore, revealed LBH is required for WNT-driven breast CSC expansion. Our findings identify LBH as an essential CSC driver downstream of WNT, and a new molecular target for anti-cancer stem cell therapy.
Comparative Genomics and Environmental Distribution of Large dsDNA viruses in the familyAsfarviridae
Authors: Karki Sangita , Moniruzzaman Mohammad , Aylward Frank O. 
Published: January 2021

AbstractTheAsfarviridaeis a family of Nucleo-Cytoplasmic Large DNA Viruses (NCLDV) of which African swine fever virus (ASFV) is the most well-characterized. Recently the discovery of severalAsfarviridaemembers other than ASFV has suggested that this family represents a diverse and cosmopolitan group of viruses, but the genomics and distribution of this family have not been studied in detail. To this end we analyzed five complete genomes and 35 metagenome-assembled genomes (MAGs) of viruses from this family to shed light on their evolutionary relationships and environmental distribution. The Asfarvirus MAGs derive from diverse marine, freshwater, and terrestrial habitats, underscoring the broad environmental distribution of this family. We present phylogenetic analyses using conserved marker genes and whole-genome comparison of pairwise average amino acid identity values, revealing a high level of genomic divergence across disparate Asfarviruses. Further, we found thatAsfarviridaegenomes encode genes with diverse predicted metabolic roles and detectable sequence homology to proteins in bacteria, archaea, and different eukaryotes, highlighting the genomic chimerism that is a salient feature of NCLDV. Our read mapping from Tara oceans metagenomic data also revealed that threeAsfarviridaeMAGs were present in multiple marine samples, indicating that they are widespread in the ocean. In one of these MAGs we identified four marker genes with >95% amino acid identity to genes sequenced from a virus that infects the dinoflagellateHeterocapsa circularisquama(HcDNAV). This suggests a potential host for this MAG, which would thereby represent a near-complete genome of a dinoflagellate-infecting giant virus. Together, these results show thatAsfarviridaeare ubiquitous, comprise similar sequence divergence as other NCLDV families, and include several members that are widespread in the ocean and potentially infect ecologically important protists.
TAK1 blockade as a therapy for retinal neovascularization
Authors: Lin Fan-Li , Wang Jiang-Hui , Chen Jinying , Zhu Linxin , Chuang Yu-Fan , Tu Leilei , Ma Chenkai , Lama Suraj , Ling Damien , Wong Raymond Ching-Bong , Hewitt Alex W. , Tseng Ching-Li , Bui Bang V. , van Wijngaarden Peter , Dusting Gregory J. , Wang Peng-Yuan , Liu Guei-Sheung 
Published: January 2021

ABSTRACTRetinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other pro-inflammatory cytokines. TAK1 is also a key mediator of inflammation, innate immune responses, apoptosis and tissue homeostasis and plays an important role in physiological angiogenesis. Its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. We investigated the regulatory role of TAK1 in pathological angiogenesis in the retina. Transcriptome analysis of human retina featuring retinal neovascularization revealed enrichment of known TAK1-mediated signaling pathways. Selective inhibition of TAK1 activation by 5Z-7-oxozeaenol attenuated aberrant retinal angiogenesis in rats following oxygen-induced retinopathy. Transcriptome profiling revealed that TAK1 activation in human microvascular endothelial cells under TNFα stimulation led to increase the gene expression related to cytokines and leukocyte-endothelial interaction, mainly through nuclear factor kappa B (NFκB) signaling pathways. These results reveal that inhibition of TAK1 signaling may have therapeutic value for the treatment of pathological angiogenesis in the retina.
Phenotypic shifts of tumor associated macrophages and STAT3 mediated suppression of myeloid derived suppressor cells drive sensitization of HER2+tumor immunity
Authors: Sidiropoulos Dimitrios N. , Rafie Christine , Christmas Brian J. , Davis-Marcisak Emily F. , Sharma Gaurav , Bigelow Emma , Gupta Anuj , Yegnasubramanian Srinivasan , Stearns Vered , Connolly Roisin M. , Gaykalova Daria A. , Kagohara Luciane T. , Jaffee Elizabeth M. , Fertig Elana J. , Roussos Torres Evanthia T. 
Published: January 2021

ABSTRACTUnderstanding how novel therapeutic combinations alter solid tumor microenvironments (TME) in immunosuppressive tumors such as breast cancer is essential to improve their responses to immune checkpoint inhibitors (ICIs). Entinostat, an oral histone deacetylase inhibitor (HDACi), has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs, but the precise alterations induced by entinostat and mechanisms of synergy with ICIs remain unknown. Here, we employ single-cell RNA-sequencing on HER2 overexpressing breast tumors from mice treated with entinostat + ICIs to characterize these changes across cell types in the TME. This analysis demonstrates that treatment with entinostat induces a shift from a pro-tumor to an anti-tumor TME signature characterized predominantly by changes in the myeloid cells. Notably, myeloid-derived suppressor cells (MDSCs) are shifted toward the less suppressive granulocytic phenotype in association with reduced signaling through the STAT3 pathway. In addition, tumor-associated macrophages are shifted toward an anti-tumor M1 phenotype by epigenetic reprogramming. Overall, these entinostat-induced TME changes reduce immunosuppression and increase mechanisms of tumor cell killing to improve ICI responses and broaden the population of patients who could potentially benefit from immunotherapy.