bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of a Reverse Genetics System for Influenza D Virus
Authors: Ishida Hiroho , Murakami Shin , Kamiki Haruhiko , Matsugo Hiromichi , Takenaka-Uema Akiko , Horimoto Taisuke 
Published: August 2019

ABSTRACTInfluenza D virus (IDV) was initially isolated in the USA in 2011. IDV is distributed worldwide and is one of the causative agents of bovine respiratory disease complex (BRDC), which exhibits high morbidity and mortality in feedlot cattle. Molecular mechanisms of IDV pathogenicity are still unknown. Reverse genetics systems are vital tools not only for studying the biology of viruses, but also for use in applications such as recombinant vaccine viruses. Here, we report the establishment of a plasmid-based reverse genetics system for IDV. We first verified that the 3′-terminal nucleotide of each 7-segmented genomic RNA contained uracil in contrary to the previous report, and were then able to successfully generate recombinant IDV by co-transfecting 7 plasmids containing these genomic RNAs along with 4 plasmids expressing polymerase proteins and NP into HRT-18G cells. The recombinant virus had a growth deficit compared to the wild-type virus, and we determined the reason for this growth difference by examining the genomic RNA content of the viral particles. We found that recombinant virus incorporated an unbalanced ratio of viral RNA segments into particles as compared to the wild-type virus, and thus we adjusted the amount of each plasmid used in transfection to obtain recombinant virus with the same replicative capacity as wild-type virus. Our work here in establishing a reverse genetics system for IDV will have a broad range of applications, including uses in studies focused on better understanding IDV replication and pathogenicity as well as those contributing to the development of BRDC countermeasures.IMPORTANCEBovine respiratory disease complex (BRDC) exhibits high mortality and morbidity in cattle, causing economic losses worldwide. Influenza D virus (IDV) is considered to be a causative agent of BRDC. Here, we developed a reverse genetics system that allows for the generation of IDV from cloned cDNAs, and the introduction of mutations into the IDV genome. This reverse genetics system will become a powerful tool for use in studies related to understanding the molecular mechanisms of viral replication and pathogenicity, and will also lead to the development of new countermeasures against BRDC.
Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer
Authors: Su Yapeng , Liu Chunmei , Lu Xiang , Li Guideng , Shao Shiqun , Kong Yan , Lee Jihoon W. , Ng Rachel H. , Wong Stephanie , Robert Lidia , Warden Charles , Liu Victoria , Chen Jie , Wang Zhuo , Qin Guangrong , Tang Yin , Cheng Hanjun , Ng Alphonsus H. C. , Peng Songming , Xue Min , Johnson Dazy , Xu Yu , Wang Jinhui , Wu Xiwei , Shmulevich Ilya , Shi Qihui , Levine Raphael , Ribas Antoni , Baltimore David , Guo Jun , Heath James R. , Wei Wei 
Published: August 2019

AbstractDrug-induced dedifferentiation towards a drug-tolerant persister state is a common mechanism cancer cells exploit to escape therapies, posing a significant obstacle to sustained therapeutic efficacy. The dynamic coordination of epigenomic and transcriptomic programs at the early-stage of drug exposure, which initiates and orchestrates these reversible dedifferentiation events, remains largely unexplored. Here we employ high-temporal-resolution multi-omics profiling, information-theoretic approaches, and dynamic system modeling to probe these processes inBRAF-mutant melanoma models and patient specimens. We uncover a hysteretic transition trajectory of melanoma cells in response to oncogene inhibition and subsequent release, driven by the sequential operation of two tightly coupled transcriptional waves, which orchestrate genome-scale chromatin state reconfiguration. Modeling of the transcriptional wave interactions predicts NF-κB/RelA-driven chromatin remodeling as the underlying mechanism of cell-state dedifferentiation, a finding we validate experimentally. Our results identify critical RelA-target genes that are epigenetically modulated to drive this process, establishing a quantitative epigenome gauge to measure cell-state plasticity in melanomas, which supports the potential use of drugs targeting epigenetic machineries to potentiate oncogene inhibition. Extending our investigation to other cancer models, we identify oxidative stress-mediated NF-κB/RelA activation as a common mechanism driving cellular transitions towards drug-tolerant persister states, revealing a novel and pivotal role for the NF-κB signaling axis in linking cellular oxidative stress to cancer progression.
Diversification of DNA-binding specificity via permissive and specificity-switching mutations in the ParB/Noc protein family
Authors: Jalal Adam S. B. , Tran Ngat T. , Stevenson Clare E. , Chan Elliot W. , Lo Rebecca , Tan Xiao , Noy Agnes , Lawson David M. , Le Tung B. K. 
Published: August 2019

ABSTRACTSpecific interactions between proteins and DNA are essential to many biological processes. Yet it remains unclear how the diversification in DNA-binding specificity was brought about, and what were the mutational paths that led to changes in specificity. Using a pair of evolutionarily related DNA-binding proteins, each with a different DNA preference (ParB and Noc: both having roles in bacterial chromosome maintenance), we show that specificity is encoded by a set of four residues at the protein-DNA interface. Combining X-ray crystallography and deep mutational scanning of the interface, we suggest that permissive mutations must be introduced before specificity-switching mutations to reprogram specificity, and that mutational paths to a new specificity do not necessarily involve dual-specificity intermediates. Overall, our results provide insight into the possible evolutionary history of ParB and Noc, and in a broader context, might be useful in understanding the evolution of other classes of DNA-binding proteins.
SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy
Authors: Ding Yonghe , Yang Jingchun , Chen Peng , Lu Tong , Jiao Kunli , Tester David , Jiang Kai , Ackerman Michael J , Li Yigang , Wang Dao Wu , Wang Dao Wen , Lee Hon-Chi , Xu Xiaolei 
Published: August 2019

ABSTRACTBACKGROUNDArrhythogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular remodeling and ventricular arrhythmia. To date, 16 ARVC causative genes have been identified from human genetic studies, accounting for about 60% of ARVC probands. Genetic basis for the remaining 40% ARVC probands remain elusive.METHODSPrompted by a zebrafish mutagenesis screen that suggested theSorbin and SH3 domain-containing 2 (SORBS2)ortholog as a candidate cardiomyopathy gene, we conducted detailed expressionl analysis of Sorbs2 in mice, as well as phenotypic characterization in the Sorbs2 knock-out (KO) mice. The intercalated disc (ICD) expression pattern and ARVC-like phenotypes further prompted us to conduct targeted sequencing of human patients with ARVC to search for rare variants in theSORBS2gene.RESULTSSorbs2is robustly expressed in the mouse heart, encoding an adhesion junction/desmosome protein that is mainly localized to the ICD. A mutation with near complete depletion of the Sorbs2 protein in mouse results in phenotypes characteristic of human ARVC, such as dilated right ventricle (RV), RV dysfunction, spontaneous ventricular tachycardia (VT), and premature death. Sorbs2 is required to maintain the structural integrity of ICD. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Five rare variants were identified from a cohort of 59 ARVC patients, among which two variants affect splicing.CONCLUSIONSSorbs2 KO mouse is an ARVC model andSORBS2is a new ARVC susceptibility gene.
Extraordinary diversity of HLA class I gene expression in single cells contribute to the plasticity and adaptability of human immune system
Authors: Tian Rui , Zhu Hao , Pang Zhiying , Tian Yi , Liang Chao 
Published: August 2019

AbstractHLA, the coding genes of human major histocompatibility (MHC) proteins, play a crucial role in the human adaptive immune system by presenting antigenic peptides to T cell receptors on T cells. HLA-A, HLA-B and HLA-C, these 3 Class I HLA genes are one of the most polymorphic loci in the human genome. For decades, HLA typing has been performed prior to tissue and stem cell transplantation. However, beyond the role in tissue matching, HLA has also been implicated in a wide array of autoimmune diseases and HLA genotypes and expression levels are closely associated with cancer patients prognosis as recent studies have revealed. Recently methods have been developed to perform HLA typing and HLA expression quantification together by using RNA-seq techniques. However, these bulk RNA-seq experiments are measuring an averaged signal of cell populations. Single-cell RNA-seq (scRNA-seq) has regained its popularity due to its power to reliably resolve single RNA transcriptomes at large scales. In our present study, we did HLA typing using three independent scRNA-seq datasets. Interestingly, we found that single cells from the same donor could be classified into different groups where each group has a distinct expressed HLA genotype (e.g., HLA-A, heterozygous or homozygous); in other words, HLA class I genes show abundant allele specific expression in single cells. This phenomenon has been repeatedly observed in a total of 14 donors from 3 independent datasets (one is breast epithelium, another two are multiple myeloma). Our systematic analysis of HLA class I gene expression using multiple scRNA-seq datasets has uncovered a putative mechanism, where by fine tuning HLA class I expressions both at the quantity and allele levels, our immune system is able to handle various internal challenges through single cells equipped with extraordinary diverse HLA expression patterns.
Positively selected variants in functionally important regions of TLR7 inAlouatta guariba clamitanswith yellow fever virus exposure in Northern Argentina
Authors: Torosin Nicole S. , Webster Timothy H. , Argibay Hernan , Ferreyra Hebe , Uhart Marcela , Agostini Ilaria , Knapp Leslie A. 
Published: August 2019

1AbstractIn 2007-2009, a ma jor yellow fever virus (YFV) outbreak in Northern Argentina decimated the local howler monkey (Alouatta) population. We explored the relationship between Toll-like receptor (TLR) 7 and TLR8 gene variation and YFV susceptibility using samples fromAlouattaindividuals alive before the YFV outbreak, individuals that died during the outbreak, and individuals that survived the outbreak and are alive today. We measured genetic divergence betweenAlouattaYFV exposure groups and evaluatedAlouatta-specific substitutions for functional consequences. We did not find different allele frequencies in the post-YFV exposureAlouattagroup compared to the pre-exposure group. However, we identified three nonsynonymous variants in TLR7 inA. guariba clamitans. Two of these substitutions are under positive selection in functionally important regions of the gene. These unique coding differences inA. guariba clamitansmay affect YFV resistance, but more work is necessary to fully explore this hypothesis.
Crif1 Promotes Osteoporosis in Mice after Radiation
Authors: Xiang Lixin , Chen Li , Xiang Yang , Li Fengjie , Zhang Xiaomei , Xiao Yanni , Zou Lingyun , Zhong Jiang F. , Li Shengwen Calvin , Ran Qian , Li Zhongjun 
Published: August 2019

AbstractRadiation induces rapid bone loss and enhances bone resorption and RANKL expression. RANKL provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood. Here, we show that Crif1 expression increases in bone marrow cells after radiation. Conditional Crif1 deletion in bone marrow cells causes decreases in RANKL expression and the RANKL/OPG ratio, and relieves bone loss after radiation in mice. We further demonstrated in vitro that Crif1 promotes RANKL secretion via the cAMP/PKA pathway. Moreover, protein-protein docking screening identified five compounds as Crif1 inhibitors; these compounds dramatically suppressed RANKL secretion and CREB phosphorylation when cells were exposed to forskolin. This study enriches current knowledge of the pathogenesis of osteoporosis and provides insights into potential therapeutic strategies for osteoporosis treatment.
Incorporating Randomness into DNA Steganography to Realize Secondary Secret key, Self-destruction, and Quantum Key Distribution-like Function
Authors: Cui Meiying , Zhang Yixin 
Published: August 2019

AbstractDNA has become a promising candidate as future data storage medium, which makes DNA steganography indispensable in DNA data security. While PCR primers are conventional secret keys in DNA steganography, the information can be read once the primers are intercepted. New steganography approach is needed to make the DNA-encoded information safer, if not unhackable. Herein, by mixing information-carrying DNA with partially degenerated DNA library containing single or multiple restriction sites, we build an additional protective layer, which can be removed by desired restriction enzymes as secondary secret keys. As PCR is inevitable for reading DNA-encrypted information, heating will cause reshuffling and generate endonuclease-resistant mismatched duplexes, especially for DNA with high sequence diversity. Consequently, with the incorporation of randomness, the DNA steganography possesses both quantum key distribution (QKD)-like function for detecting PCR by an interceptor and self-destructive property. With a DNA-ink incorporating the steganography, the authenticity of a writing can be confirmed only by authorized person with the knowledge of all embedded keys.
Arabidopsis ERF109 regulates auxin transport-related genes in root development
Authors: Liu Rui , Cai Xiao-Teng , Zhao Ping-Xia , Xu Ping , Xiang Cheng-Bin 
Published: August 2019

ABSTRACTThe transcription factor ERF109 acts as a crosstalk node between jasmonic acid signaling and auxin biosynthesis by directly regulatingYUC2andASA1during lateral root formation in Arabidopsis. However, whether ERF109 regulates the auxin transport remains unclear. Here we report a mechanism of ERF109-mediated auxin transport in root system. Through root transcriptome comparison betweenerf109, wild type, and35S:ERF109, we found that the genesPIN2andPIN4, encoding the major membrane-based efflux carriers of auxin, were enriched in the overexpression line. In the promoters of these auxin transport genes, GCC-box cis elements were found and potentially bound by ERF109. Moreover,PID, encoding a key regulator in polar auxin transport, was found upregulated in35S:ERF109and down regulated inerf109. Yeast-one-hybrid and chromatin immunoprecipitation assays showed that ERF109 directly bound to the GCC-box ofPIN2,PIN4, andPID. Genetic analyses with double mutants confirmed the function of ERF109 in the regulation of auxin transport in Arabidopsis roots. Taken together, our results show that ERF109 modulates auxin transport by directly regulatingPIN2,PIN4andPID. This ERF109-mediated auxin transport likely works together with ERF109-mediated auxin synthesis to establish auxin maxima for lateral root initiation.
Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations
Authors: Reay William R. , Cairns Murray J. 
Published: August 2019

ABSTRACTThe complex aetiology of schizophrenia is postulated to share factors with other psychiatric disorders. Recently, this has been supported by genome-wide association studies, with several psychiatric phenotypes displaying high genomic correlation with schizophrenia. We sought to investigate pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker test of association. Gene-based analysis of common variation revealed over 50 schizophrenia-associated genes shared with other psychiatric phenotypes; including bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders (P > 0.05). Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype further revealed 330 significantly associated genes (PMeta < 2.7 × 10−6) that were only nominally associated with each disorder individually (P < 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders and uncovered several pleiotropic genes which warrant further investigation.AUTHOR SUMMARYSchizophrenia and other psychiatric disorders have many similarities, and this includes features of their overall genetic risk. Here, we investigate genes which may play a role in schizophrenia as well one or more of seven other psychiatric phenotypes and demonstrate that a number of them are pleiotropic and influence at least one other disorder. We also identify genes amongst the psychiatric disorders studied here which only show association with schizophrenia. Furthermore, we find a number of genes which were only significant when combining genetic association data from schizophrenia and one of the other seven disorders, suggesting there are shared genetic influences that are revealed through the power of joint analysis. This study identifies interesting novel shared (pleiotropic) genes in psychiatry which warrant future study.
Conformational sensors and domain-swapping reveal structural and functional differences between β-arrestin isoforms
Authors: Ghosh Eshan , Dwivedi Hemlata , Baidya Mithu , Srivastava Ashish , Kumari Punita , Stepniewski Tomek , Kim Hee Ryung , Lee Mi-Hye , van Gastel Jaana , Chaturvedi Madhu , Roy Debarati , Pandey Shubhi , Maharana Jagannath , Guixà-Gonzàlez Ramon , Luttrell Louis M. , Chung Ka Young , Dutta Somnath , Selent Jana , Shukla Arun K. 
Published: August 2019

SummaryDesensitization, signaling and trafficking of G protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, β-arrestins (βarrs). The two isoforms of βarrs (βarr1 and 2) share a high degree of sequence and structural similarity, still however, they often mediate distinct functional outcomes in the context of GPCR signaling and regulation. A mechanistic basis for such a functional divergence of βarr isoforms is still lacking. Using a set of complementary approaches including antibody fragment based conformational sensors, we discover structural differences between βarr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain swapped chimeras of βarrs display robust complementation in functional assays thereby, linking the structural differences between the receptor-bound βarr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of βarr isoforms to drive distinct functional outcomes, and underscore the importance of integrating this aspect in the current framework of biased agonism.
Hippocampal-amygdala interactions mediate uncertainty-dependent resistance to extinction following fear conditioning
Authors: Morris John , Windels Francois , Sah Pankaj 
Published: August 2019

AbstractThe partial reinforcement extinction effect (PREE) is a paradoxical learning phenomenon in which omission of reinforcement during acquisition results in more persistent conditioned responding in extinction. Here, we report a significant PREE with an inverted-U, entropy-like distribution against reinforcement probability following tone foot shock fear conditioning in rats, which was associated with increased neural activity in hippocampus and amygdala as indexed by p-ERK and c-fos immunolabelling. In vivo electrophysiological recordings of local field potentials (LFPs) showed that 50% reinforcement was associated with increases in the frequency and power of tone-evoked theta oscillations in both the subiculum region of hippocampus and in basolateral amygdala (BLA) during both acquisition (Day 1) and extinction (Day 2) sessions. Tone-evoked LFPs in 50% reinforced animals also showed increases in coherence and bidirectional Granger Causality between hippocampus and amygdala. The results support a Bayesian interpretation of the PREE, in which the phenomenon is driven by increases in the entropy or uncertainty of stimulus contingencies, and indicate a crucial role for hippocampus in mediating this uncertainty-dependent effect.
Extinction and the temporal distribution of macroevolutionary bursts
Authors: De Lisle Stephen P. , Punzalan David , Rollinson Njal , Rowe Locke 
Published: August 2019

ABSTRACTPhenotypic evolution through deep time is slower than expected from microevolutionary rates. This is the paradox of stasis. Previous models suggest stasis occurs because populations track adaptive peaks that typically move on million-year intervals, raising the equally perplexing question of why peaks shifts are so rare. Here, we consider the possibility that peaks can move more rapidly than populations can adapt, resulting in extinction. We model peak movement with explicit population dynamics, parameterized with published microevolutionary parameters. Allowing extinction greatly increases the parameter space of peak movements that yield the appearance of stasis observed in real data through deep time. Our work highlights population ecology as an important contributor to macroevolutionary dynamics, presenting an alternative perspective on the paradox of stasis where apparent constraint on phenotypic evolution in deep time reflects our restricted view of the subset of earth’s lineages that were fortunate enough to reside on relatively stable peaks.