bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomolecular condensates govern PARP inhibitor trapping and present mechanisms of resistance
Authors: Gopal Angelica A. , Fernandez Bianca , Delano Justin , Weissleder Ralph , Dubach J. Matthew 
Published: April 2022

ABSTRACTPoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of DNA damage. In the context of BRCA mutations, PARPi can be synthetically lethal, presenting ideal genetic targeting. Yet, PARPi function primarily by trapping PARP1 onto sites of DNA damage. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon within biomolecular condensates that correlates with PARPi koff. Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA binding protein recruitment. Furthermore, we found recruitment of the DNA binding protein RPA1 correlates to cell line PARPi sensitivity independent of RPA1 expression, demonstrating that condensate recruitment alone can impact efficacy. These results shed new light on how PARPi function, describe how PARPi properties correlate to trapping potency, and suggest previously unknown mechanisms of PARPi resistance.
Variable paralog expression underlies phenotype variation
Authors: Bailon-Zambrano Raisa , Sucharov Juliana , Mumme-Monheit Abigail , Murry Matthew , Stenzel Amanda , Pulvino Anthony T. , Mitchell Jennyfer M. , Colborn Kathryn L. , Nichols James T. 
Published: April 2022

ABSTRACTHuman faces are variable; we look different from one another. Craniofacial disorders further increase this variability. Here we used the zebrafish mef2ca mutant, which produces variable phenotypes, to understand craniofacial variation. Comparing different mef2ca alleles demonstrated that severity, measured by penetrance and expressivity, correlates with variation. Years of selective breeding for low and high penetrance produced strains that are either resilient, or sensitive, to the mef2ca mutation. Comparing these strains further demonstrates that severity correlates with variation. Gene expression studies indicated that selective breeding upregulated and downregulated mef2ca paralog expression in the low- and high-penetrance strains, respectively. We hypothesized that heritable paralog expression variation underlies mutant phenotype variation. In support, mutagenizing all mef2ca paralogs in the low-penetrance strain demonstrated modular buffering by paralogs. Specifically, some paralogs buffer severity while others buffer variability. We present a novel, mechanistic model for phenotypic variation where cryptic vestigial paralog expression modularly buffers development and contributes to evolution. These studies are a major step forward in understanding of the mechanisms of facial variation, including how some genetically resilient individuals can overcome a deleterious mutation.
The single-cell atlas of the murine reproductive tissues during preterm labor
Authors: Garcia-Flores Valeria , Romero Roberto , Peyvandipour Azam , Galaz Jose , Pusod Errile , Panaitescu Bogdan , Miller Derek , Xu Yi , Tao Li , Liu Zhenjie , Tarca Adi L. , Pique-Regi Roger , Gomez-Lopez Nardhy 
Published: April 2022

SUMMARYPreterm birth, the leading cause of perinatal morbidity and mortality worldwide, frequently results from the syndrome of preterm labor. Intra-amniotic infection is the best-established causal link to preterm labor, and involves premature activation of the parturition cascade in the reproductive tissues. Herein, we utilized single-cell RNA-sequencing (scRNA-seq) to generate a single-cell atlas of the murine uterus, decidua, and cervix in a model of infection-induced preterm labor. We show that preterm labor affects the transcriptomic profiles of specific immune and non-immune cell subsets. Shared and tissue-specific gene expression signatures were identified among affected cells. Importantly, determination of intercellular communications implicates specific cell types preterm labor-associated signaling pathways across tissues. Last,in silicocomparison of murine and human uterine cell-cell interactions reveals conserved signaling pathways implicated in labor. Thus, scRNA-seq provides new insights into the preterm labor-driven cellular landscape and communications in the reproductive tissues.
Environment as a limiting factor of the historical global spread of mungbean
Authors: Ong Pei-Wen , Lin Ya-Ping , Chen Hung-Wei , Lo Cheng-Yu , Burlyaeva Marina , Noble Thomas , Nair Ramakrishnan , Schafleitner Roland , Vishnyakova Margarita , Bishop-von-Wettberg Eric , Samsonova Maria , Nuzhdin Sergey , Ting Chau-Ti , Lee Cheng-Ruei 
Published: April 2022

AbstractWhile the domestication history has been investigated in many crops, the process of cultivation range expansion and factors governing this process received relatively little attention. Here using mungbean (Vigna radiatavar.radiata) as a test case, we investigated the genomes of more than one thousand accessions to illustrate climatic adaptation’s role in dictating the unique routes of cultivation range expansion. Despite the geographical proximity between South and Central Asia, genetic evidence suggests mungbean cultivation first spread from South Asia to Southeast, East, and finally reached Central Asia. Combining evidence from demographic inference, climatic niche modeling, plant morphology, and records from ancient Chinese sources, we showed that the specific route was shaped by the unique combinations of climatic constraints and farmer practices across Asia, which imposed divergent selection favoring higher yield in the south but short-season and more drought-tolerant accessions in the north. Our results suggest that mungbean did not radiate from the domestication center as expected purely under human activity, but instead the spread of mungbean cultivation is highly constrained by climatic adaptation, echoing the idea that human commensals are more difficult to spread through the south-north axis of continents.
Impact of freeze-thaw-induced pit aspiration on stem water transport in a subalpine conifer (Abies veitchii)
Authors: Taneda Haruhiko , Ogasa Mayumi Y. , Yazaki Kenichi , Funayama-Noguchi Sachiko , Miyazawa Yoshiyuki , Mayr Stefan , Maruta Emiko 
Published: April 2022

AbstractDuring winter, subalpine conifers experience frequent freeze-thaw cycles in stem xylem, which may cause embolism and pit aspiration due to increased water volume during the sap to ice transition. This study examined the occurrence and ecological impacts of a combination of freeze-thaw-induced pit aspiration and embolism. In subalpine Abies veitchii trees, the fraction of closed pits and embolized tracheids as well as conductivity losses were measured to examine pit aspiration and its effects, triggered by natural and artificial stem freezing. When trees incurred mild drought stress in February and early March, 70% to 80% of stem conductivity was lost. Cryo-scanning electron microscopy indicated <20% embolized tracheids but ∼90% closed pits. Severe drought stress in late March caused 96 ± 1.2% (mean ± SE) loss of stem conductivity, while the fraction of embolized tracheids increased to 64 ± 6.6%, and aspirated pit fraction decreased to 23 ± 5.6%. Experimental freeze-thaw cycles also induced from 7.1 ± 0.89% to 49 ± 10% pit aspiration, and the fraction of closed pits was positively correlated to the percent loss of stem hydraulic conductivity. Results indicated that freezing-induced pit aspiration is an important factor for stem xylem dysfunction under mild drought. Upon severe drought in winter, stem water transport is predominantly inhibited by xylem embolism.
Drosophila Keap1 oxidative/xenobiotic response factor interacts with B-type lamin to regulate nuclear lamina and heterochromatin
Authors: Carlson Jennifer , Neidviecky Emma , Cook Isabel , Deng Huai 
Published: April 2022

AbstractThe essential function of the Keap1-Nrf2 pathway in mediating transcriptional response to xenobiotic and oxidative stimuli has been well established. However, the mechanisms whereby Keap1 and Nrf2 regulate developmental genes remains unclear. We hypothesized that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins regulate transcription through controlling high-order chromatin structure. Here, we describe evidence supporting that dKeap1 can regulate chromatin through interaction with lamin, the intermediate filament proteins that form nuclear lamina and organize the overall chromatin architecture. dKeap1 and lamin Dm0, the B-type lamin in Drosophila, interact with each other and form complexes in the nucleus. Overexpression of dKeap1 resulted in a redistribution of lamin Dm0 to the intra-nuclear area and consistently, caused a spreading of the heterochromatin marker H3K9me2 from the pericentromeric region to chromosome arms. Overexpression of dKeap1 fusion proteins in the dKeap1 null background significantly disrupted the nuclear lamina morphology, indicating that dKeap1 is required for the maintenance of a normal nuclear lamina. Knock down of dKeap1 partially rescued the lethality caused by lamin Dm0 overexpression, suggesting that dKeap1 and lamin Dm0 function in the same pathway during development. Taken together, these results support a model where dKeap1 regulates chromatin structure and developmental transcription through interaction with lamin proteins, revealing a novel epigenetic function of the Keap1 oxidative/xenobiotic response factor.
A conserved signaling pathway activates bacterial CBASS immune signaling in response to DNA damage
Authors: Lau Rebecca K. , Enustun Eray , Gu Yajie , Nguyen Justin V. , Corbett Kevin D. 
Published: April 2022

AbstractTo protect themselves from the constant threat of bacteriophage (phage) infection, bacteria have evolved diverse immune systems including restriction/modification, CRISPR/Cas, and many others. Here we describe the discovery of a two-protein transcriptional regulator module associated with hundreds of CBASS (Cyclic oligonucleotide Based Anti-phage Signaling System) immune systems, and demonstrate that this module drives expression of its associated CBASS system in response to DNA damage. We show that the helix-turn-helix transcriptional repressor CapH binds the promoter region of its associated CBASS system to repress transcription until it is cleaved by the metallopeptidase CapP. CapP is inactive except in the presence of single-stranded DNA, and CapP activity in cells is stimulated by DNA-damaging drugs. Together, CapH and CapP drive increased expression of their associated CBASS system in response to DNA damage. In both their structures and mechanisms, CapH and CapP resemble regulators that drive increased expression of DNA damage response genes in radiation-resistant Deinococcus, and control the mobilization of prophages and mobile elements in response to DNA damage. We also identify CapH and CapP-related proteins associated with diverse known and putative bacterial immune systems, including DISARM and two uncharacterized operons encoding proteins related to eukaryotic ubiquitin signaling pathways. Overall, our data highlight a mechanism by which bacterial immune systems can sense and respond to a universal stress signal, potentially enabling multiple immune systems to mount a coordinated defensive effort against an invading pathogen.
From defaults to databases: parameter and database choice dramatically impact the performance of metagenomic taxonomic classification tools
Authors: Wright Robyn J. , Comeau André M. , Langille Morgan G.I. 
Published: April 2022

AbstractIn metagenomic analyses of microbiomes, one of the first steps is usually the taxonomic classification of reads by comparison to a database of previously taxonomically classified genomes. While different studies comparing metagenomic taxonomic classification methods have determined that different tools are “best”, there are two tools that have been used the most to-date: Kraken (k-mer based classification against a user-constructed database) and MetaPhlAn (classification by alignment to clade-specific marker genes), the latest versions of which are Kraken2 and MetaPhlAn 3, respectively. We found large discrepancies in both the proportion of reads that were classified as well as the number of species that were identified when we used both Kraken2 and MetaPhlAn 3 to classify reads within metagenomes from human-associated or environmental datasets. We then investigated which of these tools would give classifications closest to the real composition of metagenomic samples using a range of simulated and mock samples and examined the combined impact of tool-parameter-database choice on the taxonomic classifications given. This revealed that there may not be a one-size-fits-all “best” choice. While Kraken2 can achieve better overall performance, with higher precision, recall and F1 scores, as well as alpha- and beta-diversity measures closer to the known composition than MetaPhlAn 3, the computational resources required for this may be prohibitive for many researchers, and the default database and parameters should not be used. We therefore conclude that the best tool-parameter-database choice for a particular application depends on the scientific question of interest, which performance metric is most important for this question and the limit of available computational resources.
Protein Contaminants Matter: Building Universal Protein Contaminant Libraries for DDA and DIA Proteomics
Authors: Frankenfield Ashley M. , Ni Jiawei , Ahmed Mustafa , Hao Ling 
Published: April 2022

ABSTRACTMass spectrometry-based proteomics is constantly challenged by the presence of contaminant background signals. In particular, protein contaminants from reagents and sample handling are often abundant and almost impossible to avoid. For data-dependent acquisition (DDA) proteomics, exclusion list can be used to reduce the influence of protein contaminants. However, protein contamination has not been evaluated and is rarely addressed in data-independent acquisition (DIA). How protein contaminants influence proteomics data is also unclear. In this study, we established protein contaminant FASTA and spectral libraries that are applicable to all proteomic workflows and evaluated the impact of protein contaminants on both DDA and DIA proteomics. We demonstrated that including our contaminant libraries can reduce false discoveries and increase protein identifications, without influencing the quantification accuracy in various proteomic software platforms. With the pressing need to standardize proteomic workflow in the research community, we highly recommend including our contaminant FASTA and spectral libraries in all bottom-up proteomics workflow. Our contaminant libraries and a step-by-step tutorial to incorporate these libraries in different DDA and DIA data analysis platforms can be valuable resources for proteomics researchers, which are freely accessible at https://github.com/HaoGroup-ProtContLib.
The conserved histone chaperone Spt6 facilitates DNA replication and mediates genome instability
Authors: Miller Catherine LW , Winston Fred 
Published: April 2022

SUMMARYHistone chaperones are an important class of proteins that regulate chromatin accessibility for DNA-templated processes. Spt6 is a conserved histone chaperone and key regulator of transcription and chromatin structure. However, its functions outside of these roles have been little explored. In this work, we demonstrate a role for S. cerevisiae Spt6 in DNA replication and more broadly as a regulator of genome stability. Spt6 binds the replication machinery and depletion or mutation of Spt6 impairs DNA replication in vivo. Additionally, spt6 mutants are sensitive to DNA replication stress inducing agents, with increased sensitivity when combined with loss of DNA replication associated factors. Furthermore, spt6 mutants have elevated levels of DNA double strand breaks and recombination. These effects appear to be independent of R-loops, which are not elevated in spt6 mutants. Our results identify Spt6 as a regulator of genome stability, at least in part through a role in DNA replication.
RISKS OF NEONATAL MORTALITY IN NEONATES WITH NEONATAL ENCEPHALOPATHY IN A TERTIARY NEWBORN CARE UNIT IN ZIMBABWE OVER A 12-MONTH PERIOD
Authors: Gannon Hannah , Chimhini Gwen , Cortina-Borja Mario , Chiyaka Tarisai , Mangiza Marcia , Fitzgerald Felicity , Heys Michelle , Neal Sam , Chimhuya Simbarashe 
Published: April 2022

ABSTRACTBackgroundNeonatal encephalopathy (NE) accounts for ∼23% of the 2.4 million annual global neonatal deaths. Most of these deaths occur in sub-Saharan Africa. However, data from low resource settings are scarce. We reviewed risk factors of neonatal mortality in neonates admitted with NE from a tertiary neonatal unit in Zimbabwe.MethodsA retrospective review of risk factors of short-term NE mortality was conducted at Sally Mugabe Central Hospital (SMCH) (November 2018 – October 2019). Data were gathered using a tablet-based data capture and quality improvement newborn care application (Neotree). Analyses were performed on data from all admitted neonates with a diagnosis of NE, incorporating maternal, intrapartum and neonatal risk predictors of the primary outcome, mortality.Results494/2894 neonates had NE on admission and were included. Of these, 94 died giving a NE-case fatality rate (CFR) of 190 per 1000 admitted neonates. Caesarean section (odds ratio (OR) 2.95(95% confidence intervals (CI) 1.39-6.25), convulsions (OR 7.13 (1.41-36.1)), lethargy (OR 3.13 (1.24-7.91)), Thompson score “11-14” (OR 2.98 (1.08-8.22)) or “15-22” (OR 17.61 (1.74-178.0)) were significantly associated with neonatal death. No maternal risk factors were associated with mortality.ConclusionNearly 1 in 5 neonates diagnosed with NE died before discharge, similar to other low-resource setting but more than in typical high resource centres. The Thompson score, a validated, sensitive and specific tool for diagnosing neonates with NE was a good predictor of worse outcomes in this setting. On univariable analysis time-period, specifically a period of staff shortages due to industrial action, had a significant impact on NE mortality. Emergency caesarean section was associated with increased mortality, suggesting perinatal care is likely to be a key moment for future interventions
Updating mortality risk estimation in intensive care units from high-dimensional electronic health records with incomplete data
Authors: Bouvarel Bertrand , Carrat Fabrice , Lapidus Nathanael 
Published: April 2022

AbstractContextIntensive care units (ICU) are subject to a high mortality rate, currently addressed by the implementation of scores (SAPS II, SOFA, APACHE II) assessing the risk of in-hospital mortality from admission data. Their performances are satisfactory to predict death when complications occur early after admission; however, they may become irrelevant in the case of long hospital stays.MethodsUsing the MIMIC-III database, we developed predictive models of short-term mortality in ICU from longitudinal data collected throughout patients’ stays of at least 48 hours. Several statistical learning approaches were compared, including deep neural networks and penalized regression. Missing data were handled using either complete case analysis or multiple imputation. Models’ performances were evaluated via repeated 5-fold cross-validation.ResultsPredictions relying on longitudinal data were more accurate than those relying solely on admission data. Complete case analyses from 19 predictors showed good discrimination (area under the ROC curve [AUC] > 0.77 for several statistical learning approaches) to predict death between 12 and 24 hours onwards, while keeping only 25% of patients in the sample. Multiple imputation allowed to include 70 predictors and keep 95% of patients, with similar performances, hence allowing predictions in patients with incomplete data. Calibration was satisfactory for all models.DiscussionThis proof of concept supports that automated analysis of electronic health records can be of great interest throughout patients’ stays, as a surveillance tool likely to detect lethal complications in ICU soon enough to take corrective measures. Though this framework relies on a large set of predictors, it is robust to data imputation and may be effective early after admission, as data is still scarce.
Cross-sectional association of skeletal muscle mass and strength with dietary habits and physical activity among first-year university students in Japan: Results from KEIJI-U study
Authors: Kusakabe Toru , Arai Hiroshi , Yamamoto Yuji , Nakao Kazuwa , Akamatsu Yasunori , Ishihara Yuki , Tagami Tetsuya , Yasoda Akihiro , Satoh-Asahara Noriko 
Published: April 2022

AbstractBackgroundRecently, the high prevalence of young Japanese people who are underweight has received attention because of its potential impact on healthy life expectancy. Sarcopenia, defined as the presence of low muscle mass and function, is often observed in the underweight. However, few reports have described the prevalence and characteristics of sarcopenia in youth.MethodsIn this cross-sectional study, we measured skeletal muscle mass using a multifrequency bioelectrical impedance analysis device and handgrip strength (HGS) and administered questionnaires on dietary habits and physical activity to 1,264 first-year university students aged 18-20 years (838 males and 426 females). Sarcopenia was diagnosed based on the presence of both low skeletal muscle mass (SMI) and weak HGS according to the Asian Working Group for Sarcopenia.ResultsA total of 145 males (17.3%) and 69 females (16.2%) were diagnosed as underweight. Low SMI was diagnosed in 75 males (8.9%) and 18 females (4.2%), and weak HGS was diagnosed in 28 males (3.3%) and 10 females (2.3%). Then, sarcopenia was diagnosed in 8 males (1.0%) and 5 females (1.2%). There was a significantly higher prevalence of low SMI and/or weak HGS in underweight individuals compared with individuals in the other BMI ranges. The multivariate analyses indicated that SMI and HGS were significantly associated with BMI in both sexes. Furthermore, after adjusting for BMI, both SMI and HGS were significantly associated with physical activity in males, and SMI was significantly associated with energy intake and frequency of breakfast intake in females.ConclusionsFirst-year university students showed a high incidence of being underweight with low SMI and/or weak HGS, but the prevalence of sarcopenia was low in both sexes. BMI, energy intake, frequency of breakfast intake, and physical activity were independently associated with skeletal muscle mass and strength in youth.