bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci
Authors: Bader Aldo S. , Bushell Martin 
Published: April 2020

AbstractThe recent discovery of DNA:RNA hybrids, or R-loops, actively forming at DNA double-strand breaks (DSBs) has unlocked fresh insight into how RNA participates in DNA repair. However, the manner of DSB-induced R-loop formation is vital in determining its mechanism of action and is currently under debate. Here, we analyse published DNA:RNA-hybrid sequencing to elucidate the features that determine DSB-induced R-loop formation. We found that pre-existing transcriptional activity was critical for R-loop generation at break sites, suggesting that these RNAs are transcribed prior to break induction. In addition, this appeared to be a specific DSB response at the break, distinct from traditional, co-transcriptionally formed R-loops. We hypothesise that R-loop formation is orchestrated by the damage response at transcriptionally active DSB loci to specifically maintain these genomic regions. Further investigation is required to fully understand how canonical repair processes regulate R-loops at breaks and how they participate in the repair process.
Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment
Authors: Ju Uk-Il , Jeong Do-Won , Seo Jieun , Park Jun Bum , Park Jong-Wan , Suh Kyung-Suk , Kim Jae Bum , Chun Yang-Sook 
Published: April 2020

AbstractNonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.
Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate
Authors: Hu Lei , Chen Meng , Chen Xueran , Zhao Chenggang , Fang Zhiyou , Wang Hongzhi , Dai Haiming 
Published: April 2020

AbstractMany chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.
RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner
Authors: Mei Lin , Shen Cheng , Miao Ran , Wang Jing-Zi , Cao Mend-Da , Zhang Yi-Sheng , Shi Liang-Hui , Zhao Guo-Hai , Wang Ming-Hai , Wu Li-Sheng , Wei Ji-Fu 
Published: April 2020

AbstractThe RNA methyltransferase NSUN2 has been involved in the cell proliferation and senescence, and is upregulated in various types of cancers. However, the role and potential mechanism of NSUN2 in gastric cancer remains to be determined. Our study showed that NSUN2 was significantly upregulated in gastric cancers, compared to adjacent normal gastric tissues. Moreover, NSUN2 could promote gastric cancer cell proliferation both in vitro and in vivo. Further study demonstrated that CDKN1C (p57Kip2) was the potential downstream gene of regulated by NSUN2 in gastric cancer. NSUN2 could promote gastric cancer cell proliferation through repressing p57Kip2 in an m5C-dependent manner. Our findings suggested that NSUN2 acted as an oncogene through promoting gastric cancer development by repressing p57Kip2 in an m5C-dependent manner, which may provide a novel therapeutic target against gastric cancer.
FUT1 deficiency elicits immune dysregulation and corneal opacity in steady state and under stress
Authors: Kim Kyoung Woo , Ryu Jin Suk , Ko Jung Hwa , Kim Jun Yeob , Kim Hyeon Ji , Lee Hyun Ju , Oh Jang-Hee , Chung Jin Ho , Oh Joo Youn 
Published: April 2020

AbstractFucosylation is a biological process that plays a critical role in multiple cellular functions from cell adhesion to immune regulation. Fucosyltransferases (FUTs) mediate fucosylation, and dysregulation of genes encoding FUTs is associated with various diseases. FUT1 and its fucosylated products are expressed in the ocular surface and ocular adnexa; however, the role of FUT1 in the ocular surface health and disease is yet unclear. Here, we investigated the effects of FUT1 on the ocular surface in steady-state conditions with age and under desiccating stress using a Fut1 knockout (KO) mouse model. We found that corneal epithelial defects and stromal opacity developed in Fut1 KO mice. Also, inflammatory responses in the ocular surface and Th1 cell activation in ocular draining lymph nodes (DLNs) were upregulated. Desiccating stress further aggravated Th1 cell-mediated immune responses in DLNs, lacrimal gland, and ocular surface in Fut1 KO mice, leading to severe corneal epithelial disruption and opacity. Mixed lymphocyte reaction assays revealed that the activity of splenocytes to stimulate CD4 T-cell proliferation was increased in Fut1 KO mice. Together, these data demonstrate that FUT1 deficiency induces immune dysregulation in the ocular surface and corneal opacity in steady state and under desiccating stress.
Confidence reports in decision-making with multiple alternatives violate the Bayesian confidence hypothesis
Authors: Li Hsin-Hung , Ma Wei Ji 
Published: April 2020

AbstractDecision confidence reflects our ability to evaluate the quality of decisions and guides subsequent behavior. Experiments on confidence reports have almost exclusively focused on two-alternative decision-making. In this realm, the leading theory is that confidence reflects the probability that a decision is correct (the posterior probability of the chosen option). There is, however, another possibility, namely that people are less confident if the best two options are closer to each other in posterior probability, regardless of how probable they are in absolute terms. This possibility has not previously been considered because in two-alternative decisions, it reduces to the leading theory. Here, we test this alternative theory in a three-alternative visual categorization task. We found that confidence reports are best explained by the difference between the posterior probabilities of the best and the next-best options, rather than by the posterior probability of the chosen (best) option alone, or by the overall uncertainty (entropy) of the posterior distribution. Our results upend the leading notion of decision confidence and instead suggest that confidence reflects the observer’s subjective probability that they made the best possible decision.
Fatal heart disease among cancer patients
Authors: Stoltzfus Kelsey C. , Zhang Ying , Sturgeon Kathleen , Sinoway Lawrence I. , Trifiletti Daniel M. , Chinchilli Vernon M. , Zaorsky Nicholas G. 
Published: April 2020

AbstractAs the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing and the surviving population is aging, it is necessary to identify cancer patients who are at an increased risk of death from heart disease. The purpose of this study is to identify cancer patients at highest risk of fatal heart disease compared to the general population and other cancer patients at risk of death during the study time period. Here we report that 394,849 of the 7,529,481 cancer patients studied died of heart disease. The heart disease-specific mortality rate is 10.61/10,000-person years, and the standardized mortality ratio (SMR) of fatal heart disease is 2.24 (95% CI: 2.23–2.25). Compared to other cancer patients, patients who are older, male, African American, and unmarried are at a greatest risk of fatal heart disease. For almost all cancer survivors, the risk of fatal heart disease increases with time.
Self-organizing maps of typhoon tracks allow for flood forecasts up to two days in advance
Authors: Chang Li-Chiu , Chang Fi-John , Yang Shun-Nien , Tsai Fong-He , Chang Ting-Hua , Herricks Edwin E. 
Published: April 2020

AbstractTyphoons are among the greatest natural hazards along East Asian coasts. Typhoon-related precipitation can produce flooding that is often only predictable a few hours in advance. Here, we present a machine-learning method comparing projected typhoon tracks with past trajectories, then using the information to predict flood hydrographs for a watershed on Taiwan. The hydrographs provide early warning of possible flooding prior to typhoon landfall, and then real-time updates of expected flooding along the typhoon’s path. The method associates different types of typhoon tracks with landscape topography and runoff data to estimate the water inflow into a reservoir, allowing prediction of flood hydrographs up to two days in advance with continual updates. Modelling involves identifying typhoon track vectors, clustering vectors using a self-organizing map, extracting flow characteristic curves, and predicting flood hydrographs. This machine learning approach can significantly improve existing flood warning systems and provide early warnings to reservoir management.
Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice
Authors: Duerr Julia , Leitz Dominik H. W. , Szczygiel Magdalena , Dvornikov Dmytro , Fraumann Simon G. , Kreutz Clemens , Zadora Piotr K. , Seyhan Agircan Ayça , Konietzke Philip , Engelmann Theresa A. , Hegermann Jan , Mulugeta Surafel , Kawabe Hiroshi , Knudsen Lars , Ochs Matthias , Rotin Daniela , Muley Thomas , Kreuter Michael , Herth Felix J. F. , Wielpütz Mark O. , Beers Michael F. , Klingmüller Ursula , Mall Marcus A. 
Published: April 2020

AbstractIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.
FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku
Authors: Jin Hanyong , Lee Boeun , Luo Yongyang , Choi Yuri , Choi Eui-Hwan , Jin Hong , Kim Kee-Beom , Seo Sang Beom , Kim Yong-Hak , Lee Hyung Ho , Kim Keun Pil , Lee Kangseok , Bae Jeehyeon 
Published: April 2020

AbstractThe balance between major DNA double-strand break (DSB) repair pathways is influenced by binding of the Ku complex, a XRCC5/6 heterodimer, to DSB ends, initiating non-homologous end joining (NHEJ) but preventing additional DSB end resection and homologous recombination (HR). However, the key molecular cue for Ku recruitment to DSB sites is unknown. Here, we report that FOXL2, a forkhead family transcriptional factor, directs DSB repair pathway choice by acetylation-dependent binding to Ku. Upon DSB induction, SIRT1 translocates to the nucleus and deacetylates FOXL2 at lysine 124, leading to liberation of XRCC5 and XRCC6 from FOXL2 and formation of the Ku complex. FOXL2 ablation enhances Ku recruitment to DSB sites, imbalances DSB repair kinetics by accelerating NHEJ and inhibiting HR, and thus leads to catastrophic genomic events. Our study unveils the SIRT1-(de)acetylated FOXL2-Ku axis that governs the balance of DSB repair pathways to maintain genome integrity.
A magma ocean origin to divergent redox evolutions of rocky planetary bodies and early atmospheres
Authors: Deng Jie , Du Zhixue , Karki Bijaya B. , Ghosh Dipta B. , Lee Kanani K. M. 
Published: April 2020

AbstractMagma oceans were once ubiquitous in the early solar system, setting up the initial conditions for different evolutionary paths of planetary bodies. In particular, the redox conditions of magma oceans may have profound influence on the redox state of subsequently formed mantles and the overlying atmospheres. The relevant redox buffering reactions, however, remain poorly constrained. Using first-principles simulations combined with thermodynamic modeling, we show that magma oceans of Earth, Mars, and the Moon are likely characterized with a vertical gradient in oxygen fugacity with deeper magma oceans invoking more oxidizing surface conditions. This redox zonation may be the major cause for the Earth’s upper mantle being more oxidized than Mars’ and the Moon’s. These contrasting redox profiles also suggest that Earth’s early atmosphere was dominated by CO2 and H2O, in contrast to those enriched in H2O and H2 for Mars, and H2 and CO for the Moon.
Accurate estimation of cell composition in bulk expression through robust integration of single-cell information
Authors: Jew Brandon , Alvarez Marcus , Rahmani Elior , Miao Zong , Ko Arthur , Garske Kristina M. , Sul Jae Hoon , Pietiläinen Kirsi H. , Pajukanta Päivi , Halperin Eran 
Published: April 2020

AbstractWe present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data. These transformations significantly improve decomposition performance compared to existing methods when there is significant technical variation in the generation of the reference profile and observed bulk expression. Importantly, compared to existing methods, our approach is extremely efficient, making it suitable for the analysis of large genomic datasets that are becoming ubiquitous. When applied to subcutaneous adipose and dorsolateral prefrontal cortex expression datasets with both bulk RNA-seq and snRNA-seq data, Bisque replicates previously reported associations between cell type proportions and measured phenotypes across abundant and rare cell types. We further propose an additional mode of operation that merely requires a set of known marker genes.
Decoding the stoichiometric composition and organisation of bacterial metabolosomes
Authors: Yang Mengru , Simpson Deborah M. , Wenner Nicolas , Brownridge Philip , Harman Victoria M. , Hinton Jay C. D. , Beynon Robert J. , Liu Lu-Ning 
Published: April 2020

AbstractSome enteric bacteria including Salmonella have evolved the propanediol-utilising microcompartment (Pdu MCP), a specialised proteinaceous organelle that is essential for 1,2-propanediol degradation and enteric pathogenesis. Pdu MCPs are a family of bacterial microcompartments that are self-assembled from hundreds of proteins within the bacterial cytosol. Here, we seek a comprehensive understanding of the stoichiometric composition and organisation of Pdu MCPs. We obtain accurate stoichiometry of shell proteins and internal enzymes of the natural Pdu MCP by QconCAT-driven quantitative mass spectrometry. Genetic deletion of the major shell protein and absolute quantification reveal the stoichiometric and structural remodelling of metabolically functional Pdu MCPs. Decoding the precise protein stoichiometry allows us to develop an organisational model of the Pdu metabolosome. The structural insights into the Pdu MCP are critical for both delineating the general principles underlying bacterial organelle formation, structural robustness and function, and repurposing natural microcompartments using synthetic biology for biotechnological applications.
Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity
Authors: Pfister Simona P. , Schären Olivier P. , Beldi Luca , Printz Andrea , Notter Matheus D. , Mukherjee Mohana , Li Hai , Limenitakis Julien P. , Werren Joel P. , Tandon Disha , Cuenca Miguelangel , Hagemann Stefanie , Uster Stephanie S. , Terrazos Miguel A. , Gomez de Agüero Mercedes , Schürch Christian M. , Coelho Fernanda M. , Curtiss Roy , Slack Emma , Balmer Maria L. , Hapfelmeier Siegfried 
Published: April 2020

AbstractThere is the notion that infection with a virulent intestinal pathogen induces generally stronger mucosal adaptive immunity than the exposure to an avirulent strain. Whether the associated mucosal inflammation is important or redundant for effective induction of immunity is, however, still unclear. Here we use a model of auxotrophicSalmonellainfection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Although live auxotrophicSalmonellano longer causes inflammation, its mucosal virulence factors remain the main drivers of protective mucosal immunity; virulence factor-deficient, like killed, bacteria show reduced efficacy. Assessing the involvement of innate pathogen sensing mechanisms, we show MYD88/TRIF, Caspase-1/Caspase-11 inflammasome, and NOD1/NOD2 nodosome signaling to be individually redundant. In colonized animals we show that microbiota metabolite cross-feeding may recover intestinal luminal colonization but not pathogenicity. Consequent immunoglobulin A immunity and microbial niche competition synergistically protect againstSalmonellawild-type infection.
Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts
Authors: Georgakopoulos-Soares Ilias , Koh Gene , Momen Sophie E. , Jiricny Josef , Hemberg Martin , Nik-Zainal Serena 
Published: April 2020

AbstractThe mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. Here, we introduce a method to evaluate indels, orientating them relative to gene transcription. In so doing, we reveal a number of surprising findings: First, there is a transcriptional strand asymmetry in the distribution of mononucleotide repeat tracts in the reference human genome. Second, there is a strong transcriptional strand asymmetry of indels across 2,575 whole genome sequenced human cancers. We suggest that this is due to the activity of transcription-coupled nucleotide excision repair (TC-NER). Furthermore, TC-NER interacts with mismatch repair (MMR) under physiological conditions to produce strand bias. Finally, we show how insertions and deletions differ in their dependencies on these repair pathways. Our analytical approach reveals insights into the contribution of DNA repair towards indel mutagenesis in human cells.
Endogenous and exogenous control of visuospatial selective attention in freely behaving mice
Authors: You Wen-Kai , Mysore Shreesh P. 
Published: April 2020

AbstractVisuospatial selective attention has been investigated primarily in head-fixed animals and almost exclusively in primates. Here, we develop two human-inspired, discrimination-based behavioral paradigms for studying selective visuospatial attention in freely behaving mice. In the ‘spatial probability’ task, we find enhanced accuracy, sensitivity, and rate of evidence accumulation at the location with higher probability of target occurrence, and opposite effects at the lower probability location. Together with video-based 3D head-tracking, these results demonstrate endogenous expectation-driven shifts of spatial attention. In the ‘flanker’ task, we find that a second stimulus presented with the target, but with conflicting information, causes switch-like decrements in accuracy and sensitivity as a function of its contrast, and slower evidence accumulation, demonstrating exogenous capture of spatial attention. The ability to study primate-like selective attention rigorously in unrestrained mice opens a rich avenue for research into neural circuit mechanisms underlying this critical executive function in a naturalistic setting.
Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes
Authors: Liu Deli , Shoag Jonathan E. , Poliak Daniel , Goueli Ramy S. , Ravikumar Vaishali , Redmond David , Vosoughi Aram , Fontugne Jacqueline , Pan Heng , Lee Daniel , Thomas Domonique , Salari Keyan , Wang Zongwei , Romanel Alessandro , Te Alexis , Lee Richard , Chughtai Bilal , Olumi Aria F. , Mosquera Juan Miguel , Demichelis Francesca , Elemento Olivier , Rubin Mark A. , Sboner Andrea , Barbieri Christopher E. 
Published: April 2020

AbstractBenign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.