bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying 31 novel breast cancer susceptibility loci using data from genome-wide association studies conducted in Asian and European women
Authors: Shu Xiang , Long Jirong , Cai Qiuyin , Kweon Sun-Seog , Choi Ji-Yeob , Kubo Michiaki , ParK Sue K. , Bolla Manjeet K. , Dennis Joe , Wang Qin , Yang Yaohua , Shi Jiajun , Guo Xingyi , Li Bingshan , Tao Ran , Aronson Kristan J. , Chan Kelvin Y.K. , Chan Tsun L. , Gao Yu-Tang , Hartman Mikael , Ho Weang Kee , Ito Hidemi , Iwasaki Motoki , Iwata Hiroji , John Esther M. , Kasuga Yoshio , Khoo Ui Soon , Kim Mi-Kyung , Kurian Allison W. , Kwong Ava , Li Jingmei , Lophatananon Artitaya , Low Siew-Kee , Mariapun Shivaani , Matsuda Koichi , Matsuo Keitaro , Muir Kenneth , Noh Dong-Young , Park Boyoung , Park Min-Ho , Shen Chen-Yang , Shin Min-Ho , Spinelli John J. , Takahashi Atsushi , Tseng Chiuchen , Tsugane Shoichiro , Wu Anna H. , Xiang Yong-Bing , Yamaji Taiki , Zheng Ying , Milne Roger L. , Dunning Alison M. , Pharoah Paul D.P. , García-Closas Montserrat , Teo Soo-Hwang , Shu Xiao-ou , Kang Daehee , Easton Douglas F. , Simard Jacques , Zheng Wei 
Published: September 2019

ABSTRACTCommon genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 ×10−8. In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 ×10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2, and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.
Comprehensive Spatiotemporal Analysis of Opioid Poisoning Mortality in Ohio from 2010 to 2016
Authors: Park Chihyun , Clemenceau Jean R. , Seballos Anna , Crawford Sara , Lopez Rocio , Coy Tyler , Atluri Gowtham , Hwang Tae Hyun 
Published: September 2019

ABSTRACTObjectiveWe aimed to identify (1) differences in opioid poisoning mortality among population groups, (2) geographic clusters of opioid-related deaths over time, and (3) health conditions co-occurring with opioid-related death in Ohio by computational analysis.Materials and MethodsWe used a large-scale Ohio vital statistic dataset from the Ohio Department of Health (ODH) and U.S. Census data from 2010-2016. We surveyed population differences with demographic profiling and use of relative proportions, conducted spatiotemporal pattern analysis with spatial autocorrelation via Moran statistics at the census tract level, and performed comorbidity analysis using frequent itemset mining and association rule mining.ResultsOur analyses found higher rates of opioid-related death in people aged 25-54, whites, and males. We also found that opioid-related deaths in Ohio became more spatially concentrated during 2010-2016, and tended to be most clustered around Cleveland, Columbus and Cincinnati. Drug abuse, anxiety and cardiovascular disease were found to predict opioid-related death.DiscussionComprehensive data-driven spatiotemporal analysis of opioid-related deaths provides essential identification of demographic, geographic and health factors related to opioid abuse. Future research should access personal health information for more detailed comorbidity analysis, as well as expand spatiotemporal models for real-time use.ConclusionComputational analyses revealed demographic differences in opioid poisoning, changing regional patterns of opioid-related deaths, and health conditions co-occurring with opioid overdose for Ohio from 2010-2016, providing essential knowledge for both government officials and caregivers to establish policies and strategies to best combat the opioid epidemic.
Fluoxetine improves behavioural deficits induced by chronic alcohol addiction by alleviating RNA editing of 5-HT2C receptors in astrocytes
Authors: Li Zexiong , Liang Shanshan , Li Shuai , Chen Beina , Zhang Manman , Xia Maosheng , Guan Dawei , Verkhratsky Alexei , Li Baoman 
Published: September 2019

AbstractThe alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2CR) by regulating adenosine deaminases acting on RNA (ADARs) in neurones. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol addiction increased editing of RNA of 5-HT2CR via up-regulating the expression of ADAR2, consequnetly reducing the release of ATP from astrocytes induced by 5-HT2CR agonist, MK212. At the same time SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. Reduction in ADAR2 activity eliminated the RNA editing of 5-HT2CR in vivo and increased release of astroglial ATP which was suppressed by chronic alcohol consumption. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.
Solving the transcription start site identification problem with ADAPT-CAGE: a Machine Learning algorithm for analysis of CAGE data
Authors: Georgakilas Georgios K , Perdikopanis Nikos , Hatzigeorgiou Artemis 
Published: September 2019

AbstractCap Analysis of Gene Expression (CAGE) experimental protocol has emerged as a powerful experimental technique for assisting in the identification of transcription start sites (TSSs). There is strong evidence that CAGE also identifies capping sites along various other locations of transcribed loci such as splicing byproducts, alternative isoforms and capped molecules overlapping introns and exons. We present ADAPT-CAGE, a Machine Learning framework which is trained to distinguish between CAGE signal derived from TSSs and transcriptional noise. ADAPT-CAGE provides annotation-agnostic, highly accurate and single-nucleotide resolution experimentally derived TSSs on a genome-wide scale. It has been specifically designed aiming for flexibility and ease-of-use by only requiring aligned CAGE data and the underlying genomic sequence. When compared to existing algorithms, ADAPT-CAGE exhibits improved performance on every benchmark that we designed based on both annotation- and experimentally-driven strategies. This performance boost brings ADAPT-CAGE in the spotlight as a computational framework that is able to assist in the refinement of gene regulatory networks, the incorporation of accurate information of gene expression regulators and alternative promoter usage in both physiological and pathological conditions.
LTD at amygdalocortical synapses as a novel mechanism for hedonic learning
Authors: Haley Melissa S. , Bruno Stephen , Fontanini Alfredo , Maffei Arianna 
Published: September 2019

AbstractA novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.
Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines
Authors: Cano-Gamez Eddie , Soskic Blagoje , Roumeliotis Theodoros I. , So Ernest , Smyth Deborah J. , Baldrighi Marta , Willé David , Nakic Nikolina , Esparza-Gordillo Jorge , Larminie Christopher G. C. , Bronson Paola G. , Tough David F. , Rowan Wendy C. , Choudhary Jyoti S. , Trynka Gosia 
Published: September 2019

AbstractNaïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.
Male song sparrows modulate their aggressive signaling in response to plumage signals: experiments with 3-D printed models
Authors: Beck Michelle L. , Akҫay Ҫağlar , Sewall Kendra B. 
Published: September 2019

AbstractCompetitive interactions among conspecifics are often resolved by assessing signals that honestly indicate individual fighting ability or dominance. In territorial species, signals of competitive ability are thought to function primarily during the early stages of territory establishment, but recent evidence suggests that these signals continue to influence interactions with floaters and neighbors well after territory establishment. Here, we examine the influence of the extent of chest spotting displayed by an intruding male on the response of territorial male song sparrows. We exposed males to 3-D printed models with large or small spotting area coupled with conspecific playback and recorded their behavior. We also assessed the response of a subset of males to both the 3-D printed models and a traditional, taxidermic mount to ensure the 3-D models were a realistic stimulus. We found no differences in the number of attacks or proximity to the model due to spotting area. However, territorial males produced more soft songs and tended to sing fewer loud songs, both of which predict attack in our population, in response to the model with less chest spotting. One possibility is that males with less chest spotting elicit a stronger response because they are seen as a greater threat. Based on our previous findings in this system, we think it is more likely that models with less chest spotting are perceived as subordinate and therefore easier to defeat, leading to a stronger response by territory holders. We found males were equally likely to attack 3-D printed models and a taxidermic mount but signaled more aggressively during trials with the taxidermic mount than the 3-D printed models. This suggests that birds recognized the 3-D models as meaningful stimuli but that the use of 3-D printed models should be validated through comparison to a traditional taxidermic mount when possible.
Identification of the Repressive Domain of the Negative Circadian Clock Component CHRONO
Authors: Yang Yu , Li Ning , Qiu Jiameng , Ge Honghua , Qin Ximing 
Published: September 2019

AbstractCircadian rhythm is an endogenous, self-sustainable oscillation that participates in regulating organisms’ physiological activities. Key to this oscillation is a negative feedback by main clock components Periods and Cryptochromes that repress transcriptional activity of BMAL1/CLOCK complexes. In addition, a novel repressor, CHRONO, has been identified recently, but details of CHRONO’s function during repressing the circadian cycle remain unclear. Here we report that a domain of CHRONO mainly composed of α-helixes is critical to repression through the exploitation of protein-protein interactions according to luciferase reporter assays, co-immunoprecipitation, immunofluorescence, genome editing and structural information analysis via circular dichroism spectroscopy. This repression is fulfilled by interactions between CHRONO with a region on the BMAL1 C-terminus where Cryptochrome and CBP bind. Our results indicate that CHRONO and PER differentially function as BMALA/CLOCK-dependent repressors. We further suggest a repression model of how PER, CRY and CHRONO proteins associate with BMAL1, respectively.
The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
Authors: Pedrosa Carolina da S. G. , Souza Leticia R. Q. , de Lima Caroline V. F. , Ledur Pitia F. , Karmirian Karina , Gomes Tiago A. , Barbeito-Andres Jimena , Costa Marcelo do N. , Higa Luiza M. , Bellio Maria , Lara Flavio A. , Tanuri Amilcar , Garcez Patricia P. , Prata-Barbosa Arnaldo , Tovar-Moll Fernanda , Molica Renato J. R. , Rehen Stevens K. 
Published: September 2019

AbstractThe northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak was described in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the amount of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.Author summaryThe uncontrolled spreading of cyanobacteria in drinking water reservoirs has been the cause of serious public health problems worldwide. Toxin-producing cyanobacterial blooms commonly occur during drought periods in the northeast (NE) region of Brazil. During Zika Virus (ZIKV) outbreak in 2015-16, Brazilian NE showed disproportionately higher microcephaly incidence. Here, we test the hypothesis that the cyanotoxin saxitoxin (STX) may act as a co-insult for ZIKV. Water quality surveillance data showed increased cyanobacteria population and higher STX amount in NE region during 2014-2018. In vitro, we observed that neural progenitor cell death was doubled after STX exposure to ZIKV-infected brain organoids. In vivo, chronic ingestion of STX during gestational period potentiated ZIKV-derived brain abnormalities in newborn mice. Our study provides new insights that may explain the discrepancies among Brazilian regions regarding CZS severity. Moreover, the data highlight the importance of cyanobacteria and cyanotoxin freshwater monitoring for future arbovirus outbreaks.
Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis
Authors: Korrapati Soumya , Taukulis Ian , Olszewski Rafal , Pyle Madeline , Gu Shoujun , Singh Riya , Griffiths Carla , Izquierdo Daniel Martin , Boger Erich , Morell Robert J. , Hoa Michael 
Published: September 2019

AbstractThe stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.
A novel polyubiquitin chain linkage formed by viral Ubiquitin prevents cleavage by deubiquitinating enzymes
Authors: Negi Hitendra , Reddy Pothula Puroshotham , Patole Chhaya , Das Ranabir 
Published: September 2019

ABSTRACTTheBaculoviridaefamily of viruses encode a viral Ubiquitin gene. Although the viral Ubiquitin is homologous to eukaryotic Ubiquitin (Ub), preservation of this gene in the viral genome indicates a unique function that is absent in the host eukaryotic Ub. We report the structural, biophysical, and biochemical properties of the viral Ubiquitin fromAutographa Californica Multiple Nucleo-Polyhedrosis Virus(AcMNPV). The structure of viral Ubiquitin (vUb) differs from Ub in the packing of the central helix α1 to the beta-sheet of the β-grasp fold. Consequently, the stability of the fold is lower in vUb compared to Ub. However, the surface properties, ubiquitination activity, and the interaction with Ubiquitin binding domains are similar between vUb and Ub. Interestingly, vUb forms atypical polyubiquitin chain linked by lysine at the 54thposition (K54). The K54-linked polyubiquitin chains are neither effectively cleaved by deubiquitinating enzymes, nor are they targeted by proteasomal degradation. We propose that modification of proteins with the viral Ubiquitin is a mechanism to counter the host antiviral responses.
Uncovering active modulators of native macroautophagy through novel high-content screens
Authors: Safren N , Tank EM , Santoro N , Barmada SJ 
Published: September 2019

AbstractAutophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity, or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. High-content screening of 1,500 tool compounds provided construct validity for the assay and uncovered many new autophagy modulators. In an expanded screen of 24,000 diverse compounds, we identified additional hits with profound effects on autophagy. Further, the autophagy activator NVP-BEZ235 exhibited significant neuroprotective properties in a neurodegenerative disease model. These studies confirm the utility of the Dendra2-LC3 assay, while simultaneously highlighting new autophagy-modulating compounds that display promising therapeutic effects.
Impaired carotid body hypoxic sensing in mice deficient in olfactory receptor 78
Authors: Peng Ying-Jie , Gridina Anna , Nanduri Jayasri , Fox Aaron P. , Prabhakar Nanduri R. 
Published: September 2019

ABSTRACTCarotid bodies are the sensory organs for detecting hypoxemia (decreased arterial blood oxygen levels) and ensuing chemo reflex is a major regulator of breathing and blood pressure. Chang et al (2015) proposed that olfactory receptor 78 (Olfr78) plays a major role in hypoxic sensing by the carotid body. However, such a possibility was questioned by a subsequent study ((Torres-Torrelo et al. 2018). The discrepancy between the two reports prompted the present study to re-examine the role of Olfr78 in hypoxic sensing by the carotid body (CB). Studies were performed on age and gender matched Olfr78 knock out mice generated on BL6 and JAX backgrounds and corresponding wild type mice. Breathing was monitored by plethysmography in un-sedated and efferent phrenic nerve activity in anesthetized mice. Carotid body sensory nerve activity was determined ex vivo and [Ca2+]i responses were monitored in isolated glomus cells, the primary O2 sensing cells of the carotid body. Olfr78 null mice on both BL6 and JAX backgrounds exhibited attenuated hypoxic ventilatory response, whereas breathing responses to CO2 were unaffected. The magnitude of hyperoxia-induced depression of breathing (Dejour’s test), which is an indirect measure of carotid body hypoxic sensing, was markedly reduced in Olfr78 mutant mice on both background strains. Furthermore, carotid body sensory nerve and glomus cell [Ca2+]i responses to hypoxia were attenuated in BL6 and JAX Olfr78 null mice. These results suggest that Olfr78 plays an important role in hypoxic sensing by the carotid body.