bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
Authors: Barnada Samantha M. , Isopi Andrew , Tejada-Martinez Daniela , Goubert Clément , Patoori Sruti , Pagliaroli Luca , Tracewell Mason , Trizzino Marco 
Published: January 2022

AbstractDomestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ∼3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ∼750 SVAs are co-opted as functional cis-regulatory elements in human induced pluripotent stem cells. These SVAs are significantly closer to genes and harbor more transcription factor binding sites than non-co-opted SVAs. We show that a long DNA motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs and that these two transcription factors bind consecutively on the TE sequence. We used CRISPRi to epigenetically repress active SVAs in stem cell-like NCCIT cells. Epigenetic perturbation of active SVAs strongly attenuated YY1/OCT4 binding and influenced neighboring gene expression. Ultimately, SVA repression resulted in ∼3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs modulate human gene expression, and uncovered that location and sequence composition contribute to SVA domestication into gene regulatory networks.
Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion
Authors: Ramos Raul , Wu Chi-Hong , Turrigiano Gina G. 
Published: January 2022

AbstractGeneralization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least two weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.
The dorsal hippocampus’ role in context-based timing in rodents
Authors: De Corte Benjamin J. , Farley Sean J. , Heslin Kelsey A. , Parker Krystal L. , Freeman John H. 
Published: January 2022

AbstractTo act proactively, we must predict when future events will occur. Individuals generate temporal predictions using cues that indicate an event will happen after a certain duration elapses. Neural models of timing focus on how the brain represents these cue-duration associations. However, these models often overlook the fact that situational factors frequently modulate temporal expectations. For example, in realistic environments, the intervals associated with different cues will often covary due to a common underlying cause. According to the ‘common cause hypothesis,’ observers anticipate this covariance such that, when one cue’s interval changes, temporal expectations for other cues shift in the same direction. Furthermore, as conditions will often differ across environments, the same cue can mean different things in different contexts. Therefore, updates to temporal expectations should be context-specific. Behavioral work supports these predictions, yet their underlying neural mechanisms are unclear. Here, we asked whether the dorsal hippocampus mediates context-based timing, given its broad role in context-conditioning. Specifically, we trained rats with either hippocampal or sham lesions that two cues predicted reward after either a short or long duration elapsed (e.g., tone-8s / light-16s). Then, we moved rats to a new context and extended the long-cue’s interval (e.g., light-32s). This caused rats to respond later to the short cue, despite never being trained to do so. Importantly, when returned to the initial training context, sham rats shifted back toward both cues’ original intervals. In contrast, lesion rats continued to respond at the long cue’s newer interval. Surprisingly, they still showed contextual modulation for the short cue, responding earlier like shams. These data suggest the hippocampus only mediates context-based timing if a cue is explicitly paired and/or rewarded across distinct contexts. Furthermore, as lesions did not impact timing measures at baseline or acquisiton for the long cue’s new interval, our data suggests that the hippocampus only modulates timing when context is relevant.
TrpA1 is a shear stress mechanosensing channel regulating intestinal homeostasis in Drosophila
Authors: Gong Jiaxin , Nirala Niraj K. , Chen Jiazhang , Wang Fei , Gu Pengyu , Wen Qi , Ip Y. Tony , Xiang Yang 
Published: January 2022

AbstractAdult stem cells are essential for maintaining normal tissue homeostasis and supporting tissue repair. Although genetic and biochemical programs controlling adult stem cell behavior have been extensively investigated, how mechanosensing regulates stem cells and tissue homeostasis is not well understood. Here, we show that shear stress can activate enteroendocrine cells, but not other gut epithelial cell types, to regulate intestine stem cell-mediated gut homeostasis. This shear stress sensing is mediated by transient receptor potential A1 (TrpA1), a Ca2+-permeable ion channel that expressed only in enteroendocrine cells among all gut epithelial cells. Genetic depletion of TrpA1 or modification of its shear stress sensing function causes reduced intestine stem cell proliferation and intestine growth. We further show that among the TrpA1 splice variants, only select isoforms are activated by shear stress. Altogether, our results suggest the naturally occurring mechanical force such as fluid passing generated shear stress regulates intestinal stem cell-mediated tissue growth by activating enteroendocrine cells, and Drosophila TrpA1 as a new shear stress sensor.
Ccdc38is required for sperm flagellum biogenesis and male fertility in mouse
Authors: Zhang Ruidan , Wu Bingbing , Liu Chao , Wang Xiuge , Wang Liying , Xiao Sai , Chen Yinghong , Wei Huafang , Gao Fei , Yuan Li , Li Wei 
Published: January 2022

AbstractSperm flagellum is essential for male fertility, defects in flagellum biogenesis are associated with male infertility. Deficiency of CCDC42 is associated with malformation of the mouse sperm flagella. Here, we find that the testis-specific expressed protein CCDC38 (coiled-coil domain containing 38) interacts with CCDC42 and localizes on manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in distorted manchette, multiple morphological abnormalities of the flagella (MMAF) of spermatozoa, and eventually male sterility. Furthermore, we find that CCDC38 interacts with intra-flagellar transport protein 88 (IFT88) as well as the outer dense fibrous 2 (ODF2), and its depletion reduces the transportation of ODF2 to flagellum. Altogether, our results uncover the essential role of CCDC38 during sperm flagellum biogenesis, and suggesting the defects of these genes might be associated with male infertility in human being.Summary statementWe demonstrated that CCDC38, localizes on manchette and sperm tail, is crucial for male fertility.
Clustering-based COPD Subtypes Have Distinct Longitudinal Outcomes and Multi-omics Biomarkers
Authors: Gregory Andrew , Xu Zhonghui , Pratte Katherine , Lee Sool , Liu Congjian , Chase Robert , Yun Jeong H. , Saferali Aabida , Hersh Craig P. , Bowler Russell P. , Silverman Edwin K. , Castaldi Peter J. , Boueiz Adel 
Published: January 2022

AbstractIntroductionChronic obstructive pulmonary disease (COPD) can progress across several domains, complicating the identification of the determinants of disease progression. In our previous work, we applied k-means clustering to spirometric and chest radiologic measures to identify four COPD-related subtypes: “Relatively resistant smokers (RRS)”, “mild upper lobe predominant emphysema (ULE)”, “airway-predominant disease (AD)”, and “severe emphysema (SE)”. In the current study, we examined longitudinal spirometric and radiologic emphysema changes and prospective risks of COPD exacerbations, incident comorbidities, and mortality of these clusters. We also compared their associations to protein and transcriptomic biomarkers.MethodsWe included 8,266 non-Hispanic white and African-American smokers from the COPDGene study. We used linear regression to investigate associations to five-year prospective changes in spirometric and radiologic measures and to plasma protein and blood gene expression levels. We used Cox-proportional hazard modeling to test for associations to prospective exacerbations, comorbidities, and mortality.ResultsThe RRS, ULE, AD, and SE clusters represented 39%, 15%, 26%, and 20% of the studied cohort at baseline, respectively. The SE cluster had the greatest 5-year FEV1and emphysema progression, and the highest risks of exacerbations, cardiovascular disease (CVD), and mortality. The AD cluster had the highest diabetes risk. After adjustments, only the ULE and AD clusters had elevated CVD mortality risks, while only the ULE cluster had the highest cancer-related mortality risk. These clusters also demonstrated differential protein and gene expression biomarker associations.ConclusionCOPD k-means subtypes demonstrate varying rates of disease progression, prospective comorbidities, mortality, and associations to proteomic and transcriptomic biomarkers.Funding SourcesThis work was supported by NHLBI K08 HL141601, K08 HL146972, R01 HL116931, R01 HL124233, R01 HL126596, R01 HL116473, U01 HL089897, R01 HL147326, R01 HL130512, and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Bayer, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
Hypoxia Dynamically Regulates DBC1 Ubiquitination and Stability by SIAH2 and OTUD5 in Breast Cancer Progression
Authors: Liu Qiangqiang , Luo Qian , Feng Jianyu , Zhao Yanping , Liu Linlin , Ma Biao , Cheng Hongcheng , Zhao Tian , Zhang Jiaojiao , Mu Chenglong , Chen Linbo , Lei Hong , Long Yijia , Su Jingyi , Chen Guo , Li Yanjun , Chen Quan , Zhu Yushan 
Published: January 2022

AbstractDBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is dynamically regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted the competitive binding of SIAH2 with OTUD5 to DBC1, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway.Siah2knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout ofSiah2/DBC1. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.
HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks
Authors: Charaka Vijaya , Chakraborty Sharmista , Tsai Chi-Lin , Wang Xiaoyan , Pandita Raj K , Tainer John A. , Hunt Clayton R , Pandita Tej K. 
Published: January 2022

AbstractEfficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.
Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
Authors: Baidya Mithu , Chaturvedi Madhu , Dwivedi-Agnihotri Hemlata , Ranjan Ashutosh , Devost Dominic , Namkung Yoon , Stepniewski Tomasz Maciej , Pandey Shubhi , Baruah Minakshi , Panigrahi Bhanupriya , Maharana Jagannath , Banerjee Ramanuj , Selent Jana , Laporte Stephane , Hebert Terence E. , Shukla Arun K. 
Published: January 2022

AbstractAgonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs, such as the vasopressin type II receptor (V2R), which exhibit high affinity for βarrs, agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking. We previously found that mutation of a single phosphorylation site in V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes although βarrs are robustly recruited to the plasma membrane. Here, we show that a synthetic intrabody referred to as intrabody30 (Ib30), which selectively recognizes an active-like βarr1 conformation, rescues endosomal translocation of βarr1 for V2RT360A. In addition, Ib30 also rescues agonist-induced ERK1/2 MAP kinase activation for V2RT360A to levels similar to that of the wild-type V2R. Molecular dynamics simulations reveal that Ib30 binding promotes active-like conformation in βarr1 with respect to the inter-domain rotation. Interestingly, we also observe that Ib30 enhances the interaction of βarr1 with β2-adaptin, which provides a mechanistic basis for the ability of Ib30 to promote endosomal trafficking of βarr1. Taken together, our data provide a novel mechanism to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can potentially be integrated in the current paradigm of GPCR-targeted drug discovery.SignificanceThe interaction of G protein-coupled receptors (GPCRs) with β-arrestins (βarrs) is a critical step in their regulatory and signaling paradigms. While intrabodies that bind to GPCRs, G proteins and βarrs have been utilized as biosensors and regulators of functional outcomes, allosteric targeting of receptor-transducer complexes to encode gain of function has not been documented so far. Here, we discover that a conformation-specific synthetic intrabody recognizing GPCR-bound βarr1 can allosterically enhance endosomal trafficking of βarr1 and agonist-induced ERK1/2 MAP kinase activation. This intrabody promotes an active-like βarr1 conformation and enhances the interaction of β2-adaptin with βarr1. Our findings establish a conceptual framework to allosterically modulate protein-protein interactions in GPCR signaling cascade to modulate their trafficking and signaling responses.
Can microfinance-backed entrepreneurship be a holistic empowerment tool for women? Empirical evidence from Kashmir Valley, India
Authors: Khan Shagufta Tariq , Bhat Mohd Abass , Sangmi Mohi-Ud-Din 
Published: January 2022

PurposeThis study investigates the effectiveness of microfinance-backed entrepreneurship as a mechanism for the holistic empowerment of women.Design/methodology/approachThis study employs a mixed-method research-design consisting of quasi-experimental design (quantitative approach) involving women, both entrepreneurs (132) and non-entrepreneurs (238), as well as in-depth semi-structured interviews (qualitative approach).FindingsQuantitative analysis revealed that female entrepreneurs are better off than female non-entrepreneurs in terms of economic, social, political and psychological indicators of empowerment. However, relatively lesser impact was found in terms of political, and to an even smaller extent, social empowerment of women. Analysis of in-depth interviews corroborated these findings confirming that entrepreneurship serves as an effective tool for the holistic empowerment of women. However, non-entrepreneurs also exhibit social empowerment.Research limitations/implicationsGiven the restricted geographical ambit of the study, prudence ought to be exercised in drawing inferences applied to alternate contexts. That the vast majority of questionnaire respondents are illiterate presented a notable impediment in the process of collection of accurate responses.Practical implicationsMicrofinance intervention ought to be specifically directed to cultivating entrepreneurship among women; in particular, to achieve the full benefits of empowerment, women availing microfinance ought to exert full control over their own business ventures.Originality/valueIn analyzing holistic empowerment through microfinance supported businesses set up by women, the study adds to the existing literature on women entrepreneurship and empowerment.
Applications of blockchain in government education sector: a comprehensive review and future research potentials
Authors: Dash Manoj Kumar , Panda Gayatri , Kumar Anil , Luthra Sunil 
Published: January 2022

Purpose
With the time and increase in usage of information technology (IT), blockchain technology is gaining immense attention from researchers, academicians, and practitioners because of its distinctive features such as transference, security and data reliability. The purpose of this study is to endow with a systematic review of literature on blockchain in context to the government education sector in terms of its usage, benefits, obstacles and practical implementation in future areas in education.

Design/methodology/approach
The study adopted a bibliometric visualization tool to classify data in yearly publications, highly cited journals, prominent authors, leading publications in countries and institutions and highly cited papers – the data was extracted from the SCOPUS database by using relevant keywords. Thus, the following research questions were developed: How has blockchain technology been used in the government educational sector? What are the benefits examined in the field of education? What were the problems/obstacles faced using the technology in a government education structure?

Findings
The findings identify and provide a comprehensive review of the technique regarding the present research stream in terms of highest publication, author, journal, subject-wise and relevance of the technology in government education structure. Thus, the future research potential of the technology in the education sector is much more as it is in the initiation stage. A lot of opportunities and benefits need to be extracted at large.

Research limitations/implications
The present findings of the study provide a base work for government education institutions, policy developers and researchers to investigate other areas where the technology can be implemented. Finally, more technology applications will develop strategies for proper data management and cost-effective decisions.

Originality/value
This study explains the relevance of technology in education through bibliometric visualization. The study adopted the review and significance of blockchain technology in the government education sector by identifying its benefits, current scenario, application and future research potential areas.