bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin
Authors: Kaplow Irene M. , Schäffer Daniel E. , Wirthlin Morgan E. , Lawler Alyssa J. , Brown Ashley R. , Kleyman Michael , Pfenning Andreas R. 
Published: December 2020

ABSTRACTBackgroundEvolutionary conservation is an invaluable tool for inferring functional significance in the genome, including regions that are crucial across many species and those that have undergone convergent evolution. Computational methods to test for sequence conservation are dominated by algorithms that examine the ability of one or more nucleotides to align across large evolutionary distances. While these nucleotide alignment-based approaches have proven powerful for protein-coding genes and some non-coding elements, they fail to capture conservation at many enhancers, distal regulatory elements that control spatio-temporal patterns of gene expression. The function of enhancers is governed by a complex, often tissue- and cell type-specific, code that links combinations of transcription factor binding sites and other regulation-related sequence patterns to regulatory activity. Thus, function of orthologous enhancer regions can be conserved across large evolutionary distances, even when nucleotide turnover is high.ResultsWe present a new machine learning-based approach for evaluating enhancer conservation that leverages the combinatorial sequence code of enhancer activity rather than relying on the alignment of individual nucleotides. We first train a convolutional neural network model that is able to predict tissue-specific open chromatin, a proxy for enhancer activity, across mammals. Then, we apply that model to distinguish instances where the genome sequence would predict conserved function versus a loss regulatory activity in that tissue. We present criteria for systematically evaluating model performance for this task and use them to demonstrate that our models accurately predict tissue-specific conservation and divergence in open chromatin between primate and rodent species, vastly out-performing leading nucleotide alignment-based approaches. We then apply our models to predict open chromatin at orthologs of brain and liver open chromatin regions across hundreds of mammals and find that brain enhancers associated with neuron activity and liver enhancers associated with liver regeneration have a stronger tendency than the general population to have predicted lineage-specific open chromatin.ConclusionThe framework presented here provides a mechanism to annotate tissue-specific regulatory function across hundreds of genomes and to study enhancer evolution using predicted regulatory differences rather than nucleotide-level conservation measurements.
Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
Authors: Richter William F. , Shah Rohan N. , Ruthenburg Alexander J. 
Published: December 2020

AbstractMLL-rearranged leukemia depends on H3K79 methylation. Depletion of this transcriptionally-activating mark by DOT1L deletion or high concentrations of the inhibitor pinometostat downregulatesHOXA9andMEIS1, and consequently reduces leukemia survival. Yet some MLL-rearranged leukemias are inexplicably susceptible to low-dose pinometostat, far below concentrations that downregulate this canonical proliferation pathway. In this context, we define alternative proliferation pathways that more directly derive from H3K79me2 loss. By ICeChIP-seq, H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion targets, with paradoxical increases of H3K4me3 and loss of H3K27me3. Although downregulation of polycomb components accounts for some of the proliferation defect, transcriptional downregulation of FLT3 is the major pathway. Loss-of-FLT3-function recapitulates the cytotoxicity and gene expression consequences of low-dose pinometostat, whereas overexpression of constitutively activeSTAT5A, a target of FLT3-ITD-signalling, largely rescues these defects. This pathway also depends on MLL1, indicating combinations of DOT1L, MLL1 and FLT3 inhibitors should be explored for treatingFLT3-mutant leukemia.
Quality of life and depressive symptoms among Peruvian university students during the COVID-19 pandemic
Authors: Figueroa-Quiñones Joel , Ipanaqué-Zapata Miguel , Machay-Pak Daniel , Rodríguez-Ruiz Juan 
Published: December 2020

AbstractObjectivesCharacterize the quality of life and depressive symptoms of university students in Peru during the COVID-19 pandemic and to determine the associated factors.MethodsMulti-centre study in 1634 university students recruited by convenience sampling. Quality of life (QoL) was assessed with the European Quality of Life-5 Dimensions at three levels (EQ-5D-3L) and depressive symptoms with the Patient Health Questionarie-9 (PHQ-9). To evaluate factors associated with QoL and depressive symptoms, linear and adjusted regressions were used, with robust variance reporting coefficients (β).ResultsThe percentage of participants most affected by QoL dimension was: anxiety/depression (47.2%) and pain/discomfort (35.6%). Regarding the Visual Analog Scale (EQ-VAS) of QoL, the score was 76.0 + 25.6. Those who had family economic decline during quarantine (β=-3.4, IC95%=-6.5 to −0.3) or family with chronic diseases (β=-3.7, IC95%=-6.1 to −1.4) presented significantly lower scores in their QoL. Regarding depressive symptomatology, the university students reported a moderate to severe level (28.9%). A higher risk of depressive symptoms was found in residents of Ayacucho (β=0.8, IC95%=0.1 to 1.5), those who were released from quarantine (β=0.7, IC95%=0.2 to 1.2) and those who had a family member with chronic disease (β=1.5, IC95%=1.0 to 2.1).ConclusionsAlmost half and one third of participants reported anxiety/depression, and pain/discomfort in their QoL respectively. Nearly a third presented moderate and severe depressive symptoms. The deterioration of QoL was worse in those who had a decrease in income and a family member with chronic illness. The presence of depressive symptoms was found in students in Ayacucho, those who left home during quarantine and those who had a family member with chronic diseases.
Effect of belt electrode-skeletal muscle electrical stimulation on immobilization-induced muscle fibrosis
Authors: Honda Yuichiro , Tanaka Natsumi , Kajiwara Yasuhiro , Kondo Yasutaka , Kataoka Hideki , Sakamoto Junya , Akimoto Ryuji , Nawata Atsushi , Okita Minoru 
Published: December 2020

AbstractPurposeMacrophage accumulation in response to decreasing myonuclei may be the major mechanism underlying immobilization-induced muscle fibrosis in muscle contracture, an intervention strategy suppressing these lesions is necessary. Therefore, this research investigated the effect of belt electrode-skeletal muscle electrical stimulation (B-SES), a new electrical stimulation device, to the macrophage accumulation via myonuclei decrease in immobilization-induced muscle fibrosis.Materials and Methods18 Wistar male rats were divided into the control group, immobilization group (with plaster cast fixation to immobilize the soleus muscles in a shortened position for 2 weeks), and B-SES group (with muscle contractile exercise through B-SES during the immobilization period). B-SES stimulation was performed at a frequency of 50 Hz and an intensity of 4.7 mA, muscle contractile exercise by B-SES was applied to the lower limb muscles for 20 minutes/session (twice a day) for 2 weeks (6 times/week). The bilateral soleus muscles were used for histological, immunohistochemical, biochemical, and molecular biological analyses.ResultsThe number of myonuclei was significantly higher in the B-SES group than in the immobilization group, and there was no significant difference between the B-SES and control groups. The cross-sectional area of type I and II myofibers in the immobilization and B-SES groups was significantly lower than that in the control group, and the cross-sectional area of type I myofibers in the B-SES group was higher than that in the immobilization group. However, Atrogin-1 and MuRF-1 mRNA expression in the immobilization and B-SES groups was significantly higher than those in the control group. Additionally, the number of macrophages, IL-1β, TGF-β1, and α-SMA mRNA expression, and hydroxyproline expression was significantly lower in the control and B-SES groups than those in the immobilization group.ConclusionThis research surmised that muscle contractile exercise through B-SES prevented immobilization-induced muscle fibrosis, and this alteration suppressed the development of muscle contracture.
CFPU: a cell-free processing unit for high-throughput, automated in vitro circuit characterization
Authors: Swank Zoe , Maerkl Sebastian J. 
Published: December 2020

AbstractForward engineering synthetic circuits is at the core of synthetic biology. Automated solutions will be required to facilitate circuit design and implementation. Circuit design is increasingly being automated with design software, but innovations in experimental automation are lagging behind. Microfluidic technologies made it possible to performin vitrotranscription-translation (tx-tl) reactions with increasing throughput and sophistication, enabling screening and characterization of individual circuit elements and complete circuit designs. Here we developed an automated microfluidic cell-free processing unit (CFPU) that extends high-throughput screening capabilities to a continuous reaction environment, which is essential for the implementation and analysis of more complex and dynamic circuits. The CFPU contains 280 chemostats that can be individually programmed with DNA circuits. Each chemostat is periodically supplied with tx-tl reagents, giving rise to sustained, long-term steady state conditions. Using microfluidic pulse width modulation (PWM) the device is able to generate tx-tl reagent compositions in real-time. The device has higher throughput, lower reagent consumption, and overall higher functionality than current chemostat devices. We applied this technology to map transcription factor based repression under equilibrium conditions and implemented dynamic gene circuits switchable by small molecules. We expect the CFPU to help bridge the gap between circuit design and experimental automation forin vitrodevelopment of synthetic gene circuits.
Quantifying the interplay between rapid bacterial evolution within the mouse intestine and transmission between hosts
Authors: Vasquez Kimberly S. , Willis Lisa , Cira Nate , Ng Katharine M. , Pedro Miguel F. , Aranda-Díaz Andrés , Ranjendram Manohary , Yu Feiqiao Brian , Higginbottom Steven K. , Neff Norma , Sherlock Gavin , Xavier Karina B. , Quake Stephen , Sonnenburg Justin , Good Benjamin H. , Huang Kerwyn Casey 
Published: December 2020

SummaryDue to limitations on high-resolution strain tracking, selection dynamics during gut-microbiota colonization and transmission between hosts remain mostly mysterious. Here, we introduced hundreds of barcodedEscherichia colistrains into germ-free mice and quantified strain-level dynamics and metagenomic changes. Mutants involved in motility and utilization of abundant metabolites were reproducibly selected within days. Even with rapid selection, coprophagy enforced similar barcode distributions across co-housed mice. Whole-genome sequencing of hundreds of isolates quantified evolutionary dynamics and revealed linked alleles. A population-genetics model predicted substantial fitness advantages for certain mutants and that migration accounted for ~10% of the resident microbiota each day. Treatment with ciprofloxacin demonstrated the interplay between selection and transmission. While initial colonization was mostly uniform, in two mice a bottleneck reduced diversity and selected for ciprofloxacin resistance in the absence of drug. These findings highlight the interplay between environmental transmission and rapid, deterministic selection during evolution of the intestinal microbiota.
SOX7 deficiency causes ventricular septal defects through its effects on endocardial-to-mesenchymal transition and the expression ofWnt4andBmp2
Authors: Hernández-García Andrés , Kim Sangbae , Li Yumei , Kim Bum Jun , Zaveri Hitisha P. , Jordan Valerie K. , Ljungberg M. Cecilia , Chen Rui , Lanz Rainer B. , Scott Daryl A. 
Published: December 2020

ABSTRACTSOX7is located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with septal defects.Sox7−/−embryos die of heart failure around E11.5 due to defects in vascular remodeling. These embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. We also observed a ventricular septal defect in a rareSox7flox/−;Tie2-Cre embryo that escaped early lethality. This led us to hypothesize that SOX7 plays a critical developmental role in the endocardium of the atrioventricular (AV) canal. We subsequently used AV explant studies to show that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). Since SOX7 is a transcription factor, we hypothesized that it functions in the endocardium by regulating the expression of EndMT-related genes. To identify these genes in an unbiased manner, we performed RNA-seq on pooled E9.5 hearts tubes harvested fromSox7−/−embryos and their wild-type littermates. We found thatWnt4transcript levels were severely reduced, which we confirmed by RNA in situ hybridization. Previous studies have shown that WNT4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of BMP2 in the myocardium. Consistent with these findings, we found thatBmp2transcript levels were diminished inSox7−/−embryonic hearts. We conclude that SOX7 promotes EndMT in the developing AV canal by modulating the expression ofWnt4andBmp2. These data also provide additional evidence that haploinsufficiency ofSOX7contributes to the congenital heart defects seen in individuals with recurrent 8p23.1 microdeletions.SUMMARY STATEMENTIn the developing atrioventricular canal, SOX7 promotes endocardial-to-mesenchymal transition (EndMT) by positively regulatingWnt4andBmp2expression. SOX7 deficiency leads to the development of hypocellular endothelial cushions and ventricular septal defects.
Origin and evolution of the Zinc Finger Antiviral Protein
Authors: Gonçalves-Carneiro Daniel , Takata Matthew A. , Ong Heley , Shilton Amanda , Bieniasz Paul D. 
Published: December 2020

AbstractThe human zinc finger antiviral protein (ZAP) recognizes RNA by binding to CpG dinucleotides. Mammalian transcriptomes are CpG-poor, and ZAP may have evolved to exploit this feature to specifically target non-self viral RNA. Phylogenetic analyses reveal thatZAPand its paraloguePARP12share an ancestral gene that arose prior to extensive eukaryote divergence, and theZAPlineage diverged from thePARP12lineage in tetrapods. Notably, The CpG content of modern eukaryote genomes varies widely, andZAP-like genes arose subsequent to the emergence of CpG-suppression in vertebrates. Human PARP12 exhibited no antiviral activity against wild type and CpG-enriched HIV-1, but ZAP proteins from several tetrapods had antiviral activity when expressed human cells. In some cases, ZAP antiviral activity required a TRIM25 protein from the same or a related species, suggesting functional co-evolution of these genes. Indeed, a hypervariable sequence in the N-terminal domain of ZAP contributed to species-specific TRIM25 dependence in antiviral activity assays. Crosslinking immunoprecipitation coupled with RNA sequencing revealed that ZAP proteins from human, mouse, bat and alligator exhibit a high degree of CpG-specificity, while some avian ZAP proteins appear more promiscuous. Together, these data suggest that the CpG-rich RNA directed antiviral activity of ZAP-related proteins arose in tetrapods, subsequent to the onset of CpG suppression in certain eukaryote lineages, with subsequent species-specific adaptation of cofactor requirements and RNA target specificity.Author SummaryTo control viral infections, cells have evolved a variety of mechanisms that detect, modify and sometimes eliminate viral components. One of such mechanism is the Zinc Finger Antiviral Protein (ZAP) which binds RNA sequences that are rich in elements composed of a cytosine followed by a guanine. Selection of viral RNA can only be achieved because such elements are sparse in RNAs encoded by human genes. Here, we traced the molecular evolution of ZAP. We found that ZAP and a closely related gene, PARP12, originated from the same ancestral gene that existed in a predecessor of vertebrates and invertebrates. We found that ZAP proteins from mammals, birds and reptiles have antiviral activity but only in the presence of a co-factor, TRIM25, from the same species. ZAP proteins from birds were particularly interesting since they demonstrated a broader antiviral activity, primarily driven by relaxed requirement for cytosine-guanine. Our findings suggest that viruses that infect birds – which are important vectors for human diseases – are under differential selective pressures and this property may influence the outcome of interspecies transmission.
Loss of phosphatidylserine flippase β-subunitTmem30ain podocytes leads to albuminuria and glomerulosclerosis
Authors: Liu Wenjing , Peng Lei , Tian Wanli , Li Yi , Zhang Ping , Sun Kuanxiang , Yang Yeming , Li Xiao , Li Guisen , Zhu Xianjun 
Published: December 2020

AbstractPhosphatidylserine (PS) is asymmetrically concentrated in the cytoplasmic leaflet of eukaryotic cell plasma membranes. This asymmetry is regulated by a group of P4 ATPases (named PS flippases) and its β-subunit TMEM30A. The disruption of PS flippase leads to severe human diseases.Tmem30ais essential in the mouse retina, cerebellum and liver. However, the role ofTmem30ain the kidney, where it is highly expressed, remains unclear. Podocytes in the glomerulus form a branched interdigitating filtration barrier that can prevent the traversing of large cellular elements and macromolecules from the blood into the urinary space. Damage to podocytes can disrupt the filtration barrier and lead to proteinuria and podocytopathy, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and diabetic nephropathy. To investigate the role ofTmem30ain the kidney, we generated a podocyte-specificTmem30aknockout (cKO) mouse model using the NPHS2-Cre line.Tmem30aKO mice displayed albuminuria, podocyte degeneration, mesangial cell proliferation with prominent extracellular matrix accumulation and eventual progression to focal segmental glomerulosclerosis (FSGS). ReducedTMEM30Aexpression was observed in patients with minimal change disease and membranous nephropathy, highlighting the clinical importance of TMEM30A in podocytopathy. Our data demonstrate a critical role ofTmem30ain maintaining podocyte survival and glomerular filtration barrier integrity. Understanding the dynamic regulation of the PS distribution in the glomerulus provides a unique perspective to pinpoint the mechanism of podocyte damage and potential therapeutic targets.
Effects of message framing and evidence type on health information behavior: the case of promoting HPV vaccination
Authors: Xu Xiaoting , Yang Mengqing , Zhao Yuxiang Chris , Zhu Qinghua 
Published: December 2020

PurposeBased on the examination of the roles of message framing and evidence type, this study made an analysis of the promotion methods of intention and information need towards HPV vaccination.Design/methodology/approachThe study conducted a 2 (gain-framed messages vs loss-framed messages) × 2 (statistical evidence vs narrative evidence) quasi-experimental design built upon theories of message framing and evidence type. This experiment recruited college students who were not vaccinated against HPV as participants. The analysis of variance (ANOVA), the analysis of covariance (ANCOVA), and the independent sampleT-test were used to test the hypotheses.FindingsThe results (N = 300) indicate that (1) Loss-framed messages will lead to a more favorable intention towards HPV vaccination than gain-framed messages. (2) Statistical evidence will lead to a more explicit information need than narrative evidence. (3) Message framing and evidence type will interact and (a) for statistical evidence, loss-framed messages will lead to a more favorable intention towards HPV vaccination than gain-framed messages and (b) for narrative evidence, gain-framed messages will lead to a more favorable intention towards HPV vaccination than loss-framed messages. (4) Message framing and evidence type will interact and (a) for loss-framed messages, statistical evidence will stimulate more explicit information need of HPV vaccination than narrative evidence and (b) for gain-framed messages, narrative evidence will stimulate more explicit information need of HPV vaccination than statistical evidence.Originality/valueThis paper can help to further understand the important roles of message framing and evidence type in health behavior promotion. The study contributes to the literature on how health information can be well organized to serve the public health communication and further enhance the health information service.
Identifying health information needs of senior online communities users: a text mining approach
Authors: Qian Yuxing , Gui Wenxuan 
Published: December 2020

PurposeThe purpose of this study is to identify the health information needs of senior online communities (SOCs) users, which could provide a basis for improving senior health information services.Design/methodology/approachA total of 14,933 health-related posts in the two most popular senior online communities (Yinling and Keai) in China are crawled as a corpus. Based on the results of word frequency analysis, text classification is performed based on two aspects: medical systems (Western medicine and traditional Chinese medicine) and topics. The health information needs of SOCs users are revealed from the composition, growth trends and popularity of health information. Finally, some key points of senior health information services are discussed.FindingsThe health information needs of senior users can be divided into four types: coping with aging, dietary nutrition, physical exercise and mental health. These needs are comprehensive and involve a variety of health issues. Users are mainly concerned with physical health issues. In terms of medical systems, the number of Western medicine posts is relatively larger, whereas traditional Chinese medicine appears more in posts on coping with aging and physical exercise. The health information needs of SOCs users are in a stable status. Both the medical systems and topics could have an impact on the popularity of health information, but the number of posts is inconsistent with the level of popularity.Originality/valueThis study combines multiple perspectives to identify the health information needs of seniors in China with a comprehensive overview.