bluuebunny/crossref_metadata_2025_split huggingface dataset:
Who acquires infection from whom? Estimating herpesvirus transmission rates between wild rodent host groups
Authors: Erazo Diana , Pedersen Amy B. , Gallagher Kayleigh , Fenton Andy 
Published: September 2020

AbstractTo date, few studies of parasite epidemiology have investigated ‘who acquires infection from whom’ in wildlife populations. Nonetheless, identifying routes of disease transmission within a population, and determining the key groups of individuals that drive parasite transmission and maintenance, are fundamental to understanding disease dynamics. Gammaherpesviruses are a widespread group of DNA viruses that infect many vertebrate species, and murine gammaherpesviruses (i.e. MuHV-4) are a standard lab model for studying human herpesviruses, for which much about the pathology and immune response elicited to infection is well understood. However, despite this extensive research effort, primarily in the lab, the transmission route of murine gammaherpesviruses within their natural host populations is not well understood. Here, we aimed to understand wood mouse herpesvirus (WMHV) transmission, by fitting a series of population dynamic models to field data on wood mice naturally infected with WMHV and then estimating transmission parameters within and between demographic groups of the host population. Different models accounted for different combinations of host sex (male/female), age (subadult/adult) and transmission functions (density/frequency-dependent). We found that a density-dependent transmission model incorporating explicit sex groups fitted the data better than all other proposed models. Male-to-male transmission was the highest among all demographic groups, suggesting that male behaviour is a key factor driving WMHV transmission. Our models also suggest that transmission between sexes, although important, wasn’t symmetrical, with infected males playing a significant role in infecting naïve females but not vice versa. Overall this work shows the power of coupling population dynamic models with long-term field data to elucidate otherwise unobservable transmission processes in wild disease systems.
Primary sex determination in chickens depends on DMRT1 dosage, but gonadal sex does not determine secondary sexual characteristics in adult birds
Authors: Ioannidis Jason , Taylor Gunes , Zhao Debiao , Liu Long , Idoko-Akoh Alewo , Gong Daoqing , Lovell-Badge Robin , Guioli Silvana , McGrew Mike , Clinton Michael 
Published: September 2020

AbstractIn birds, males are the homogametic sex (ZZ) and females the heterogametic sex (ZW), and primary sex determination is thought to depend on a sex chromosome gene dosage mechanism. Previous studies have suggested that the most likely sex-determinant is the Z chromosome geneDMRT1(Doublesex and Mab-3 Related Transcription factor 1). To clarify this issue, we used a CRISPR-Cas9 based mono-allelic targeting approach and sterile surrogate hosts to generate birds with targeted mutations in theDMRT1gene. The resulting chromosomally male (ZZ) chicken with a single functional copy ofDMRT1developed ovaries in place of testes, demonstrating the avian sex determining mechanism is based on DMRT1 dosage. These ZZ ovaries expressed typical female markers and showed clear evidence of follicular development. However, these ZZ adult birds with an ovary in place of testes were indistinguishable in appearance to wild type adult males, supporting the concept of cell-autonomous sex identity (CASI) in birds. In experiments where oestrogen synthesis was blocked in control ZW embryos, the resulting gonads developed as testes. In contrast, if oestrogen synthesis was blocked in ZW embryos that lackedDMRT1, the gonads invariably adopted an ovarian fate. Our analysis shows that DMRT1 is the key sex determination switch in birds and that it is essential for testis development, but that production of oestrogen is also a key factor in primary sex determination in chickens, and that this production is linked to DMRT1 expression.
Semi-coordinated allelic-bursting shape dynamic random monoallelic expression in pre-gastrulation embryos
Authors: Naik C H , Hari K , Chandel D , Mandal S , Jolly M K , Gayen S 
Published: September 2020

AbstractIn recent years, allele-specific single-cell RNA-seq (scRNA-seq) analysis has demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pre-gastrulation development remains unknown. Here, we show that dynamic aRME is wide-spread in different lineages of pre-gastrulation embryos. Additionally, the origin of dynamic aRME remains poorly understood. Theoretically, it is believed that independent transcriptional bursting from each allele leads to the dynamic aRME. However, based on analysis of allele-specific burst kinetics of autosomal genes, we found that allelic burst is not perfectly independent, rather it happens in semi-coordinated fashion. Importantly, we show that semi-coordinated allelic bursting of the genes; particularly with low burst frequency, leads to frequent asynchronous allelic bursting, thereby shaping the landscape of dynamic aRME in pre-gastrulation embryos. Altogether, our study provides significant insight into the prevalence and origin of dynamic aRME and cell to cell expression heterogeneity during early mammalian development.
Zika virus NS3 protease and its cellular substrates
Authors: Dabrowska Agnieszka , Milewska Aleksandra , Ner-Kluza Joanna , Suder Piotr , Pyrc Krzysztof 
Published: September 2020

AbstractZika virus is a flavivirus discovered in 1947, but the association between Zika virus infection and brain disorders was not demonstrated until 2015 in Brazil. Infection mostly poses a threat to women during pregnancy, since it may cause microcephaly and other neurological dysfunctions in the developing fetus. However, infection is also associated with Guillain-Barré syndrome. The nonstructural NS3 protein is essential for virus replication because it helps to remodel the cellular microenvironment. Several reports show that this protease can process cellular substrates and thereby modify cellular pathways that are important for the virus. Herein, we explored some of the targets of NS3, but we could not confirm the biological relevance of its protease activity. Thus, although mass spectrometry is highly sensitive and useful in many instances, being also able to show directions, where cell/virus interaction occurs, we believe that biological validation of the observed results is essential.
Mechanism of selectivity reveals novel antifolate drug interactions
Authors: Kordus Shannon Lynn , Lamont Elise A. , Howe Michael D. , Bauman Allison A. , McCue William , Finzel Barry , Baughn Anthony D. 
Published: September 2020

AbstractAntimicrobial agents that target a specific pathogen of interest is the gold standard in drug design.para-Aminosalicylic acid (PAS), remains a cornerstone therapy, in the treatment againstMycobacterium tuberculosis, owing to its high level of selectivity. Despite its high level of selectivity, PAS has been reassigned to treat drug-resistant strains ofM. tuberculosisbecause it causes severe gastrointestinal (GI) distress that results in poor patient compliance. We have previously shown PAS inhibits the folate biosynthetic pathway specifically inhibiting dihydrofolate reductase1,2. In this study, we sought to determine the mechanistic basis of PAS selectivity and determined that PAS can be utilized in folate biosynthesis by other bacterial pathogens. The utilization of PAS ultimately led to the antagonism of key antibiotics, specifically the sulfonamides, used to prophylactically treat individuals with HIV-AIDS3. In addition, we found many bacteria in the GI tract could also utilize PAS to make a hydroxy-folate species which resulted in GI toxicity. Using sulfonamides as a tool to prevent PAS associated toxicity in the GI tract, we discovered that the sulfonamides antagonized the antimycobacterial activity of PAS. These findings indicate a new need for understanding the mechanisms of selective therapies and more important, that HIV-AIDS/M. tuberculosisco-infected individuals should avoid co-treatment of PAS and sulfonamides.
Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy
Authors: Suay-Corredera Carmen , Pricolo Maria Rosaria , Velázquez-Carreras Diana , Pimenta-Lopes Carolina , Sánchez-Ortiz David , Urrutia-Irazabal Iñigo , Vilches Silvia , Dominguez Fernando , Frisso Giulia , Monserrat Lorenzo , García-Pavía Pablo , Herrero-Galán Elías , Alegre-Cebollada Jorge 
Published: September 2020

ABSTRACTHypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C mutant domains. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN, and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, non-pathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.
Targeting G-quadruplex Forming Sequences with Cas9
Authors: Balci Hamza , Globyte Viktorija , Joo Chirlmin 
Published: September 2020

ABSTRACTClustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins, particularly Cas9, have provided unprecedented control on targeting and editing specific DNA sequences. If the target sequences are prone to folding into non-canonical secondary structures, such as G-quadruplex (GQ), the conformational states and activity of CRISPR-Cas9 complex would be influenced, but the impact has not been assessed. Using single molecule FRET, we investigated structural characteristics of the complex formed by CRISPR-Cas9 and target DNA, which contains a potentially GQ forming sequence (PQS) in either the target or the non-target strand (TS or NTS). We observed different conformational states and dynamics depending on the stability of the GQ and the position of PQS. When PQS was in NTS, we observed evidence for GQ formation for both weak and stable GQs. This is consistent with R-loop formation between TS and crRNA releasing NTS from Watson-Crick pairing and facilitating secondary structure formation in it. When PQS was in TS, R-loop formation was adequate to maintain a weak GQ in the unfolded state but not a GQ with moderate or high stability. The observed structural heterogeneity within the target dsDNA and the R-loop strongly depended on whether the PQS was in TS or NTS. We propose these variations in the complex structures to have functional implications for Cas9 activity.
Stage-Specific Long Non-coding RNAs inCryptosporidium parvumas Revealed by Stranded RNA-Seq
Authors: Li Yiran , Baptista Rodrigo P. , Sateriale Adam , Striepen Boris , Kissinger Jessica C. 
Published: September 2020

AbstractCryptosporidiumis a protist parasite that has been identified as the second leading cause of moderate to severe diarrhea in children younger than two and a significant cause of mortality worldwide.Cryptosporidiumhas a complex, obligate, intracellular but extra cytoplasmic lifecycle in a single host. How genes are regulated in this parasite remains largely unknown. Long non-coding RNAs (lncRNAs) play critical regulatory roles, including gene expression across a broad range of organisms.CryptosporidiumlncRNAs have been reported to enter the host cell nucleus and affect the host response. However, no systematic study of lncRNAs inCryptosporidiumhas been conducted to identify additional lncRNAs. In this study, we analyzed aC. parvum in vitrostrand-specific RNA-seq developmental time series covering both asexual and sexual stages to identify lncRNAs associated with parasite development. In total, we identified 396 novel lncRNAs 86% of which are differentially expressed. Nearly 10% of annotated mRNAs have an antisense lncRNA. lncRNAs also appear to occur most often at the 3’ end of their corresponding sense mRNA. Putative lncRNA regulatory regions were identified and many appear to encode bidirectional promoters. A positive correlation trend between lncRNA and the upstream mRNA expression was observed. Evolutionary conservation and expression of lncRNA candidates was observed betweenC. parvum, C. hominisandC. baileyi. TenC. parvumprotein-encoding genes with antisense transcripts haveP. falciparumorthologs that also have antisense transcripts. ThreeC. parvumlncRNAs with exceptional properties (e.g., intron splicing) were experimentally validated using RT-PCR and RT-qPCR. We provide an initial characterization of theC. parvumnon-coding transcriptome to facilitate further investigations into the roles of lncRNAs in parasite development and host-pathogen interactions.
Predictive value of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography for PD‐L1 expression in non‐small cell lung cancer: A systematic review and meta‐analysis
Authors: Seol Hee Yun , Kim Yun Seong , Kim Seong‐Jang 
Published: September 2020

AbstractBackgroundThe purpose of the current study was to investigate the predictive value of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) for programmed death ligand 1 (PD‐L1) in non‐small cell lung cancer (NSCLC) patients through a systematic review and meta‐analysis.MethodsThe PubMed, Cochrane, and EMBASE database, from the earliest available date of indexing through 30 April 2020, were searched for studies evaluating the diagnostic performance of 18F‐FDG PET/CT for prediction of PD‐L1 expression in NSCLC patients.ResultsAcross six studies (1739 patients), the pooled sensitivity for 18F‐FDG PET/CT was 0.72 (95% CI: 0.58–0.82) with heterogeneity (I2 = 90.9, P < 0.001) and a pooled specificity of 0.69 (95% CI: 0.64–0.74) with heterogeneity (I2 = 77.9, P < 0.001). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR +) of 2.3 (95% CI: 1.8–2.9) and negative likelihood ratio (LR‐) of 0.41 (95% CI: 0.26–0.63). The pooled diagnostic odds ratio (DOR) was six (95% CI: 3–11). Hierarchical summary receiver operating characteristic (ROC) curve indicated that the area under the curve was 0.74 (95% CI: 0.70–0.78).ConclusionsThe current meta‐analysis showed a moderate sensitivity and specificity of 18F‐FDG PET/CT for the prediction of PD‐L1 expression in NSCLC patients. The DOR was low and the likelihood ratio scatter‐gram indicated that 18F‐FDG PET/CT might not be useful for the prediction of PD‐L1 expression in NSCLC patients and not for its exclusion.Key pointsSignificant findings of the studyThe current meta‐analysis showed a moderate sensitivity and specificity of 18F‐FDG PET/CT for the prediction of PD‐L1 expression in NSCLC patients. The DOR was low and the likelihood ratio scattergram indicated that 18F‐FDG PET/CT might not be useful for the prediction of PD‐L1 expression in NSCLC patients and not for its exclusion.What this study addsThis study concluded that the role of 18F‐FDG PET/CT in predicting tumor expression of PD‐L1 should be further elucidated.
Electrocardiograhic characteristics in patients with coronavirus infection: A single‐center observational study
Authors: Li Yi , Liu Tong , Tse Gary , Wu Mingxiang , Jiang Jingjing , Liu Ming , Tao Liang 
Published: September 2020

AbstractBackgroundA global outbreak of coronavirus disease (COVID‐19), caused by severe acute respiratory coronavirus 2 (SARS‐CoV‐2), has emerged since December 2019, in Wuhan, China. However, electrocardiograhic (ECG) manifestations of patients with COVID‐19 have not been fully described. We aim to investigate ECG characteristics in COVID‐19 patients and risk factors of intensive care unit (ICU) admission.MethodsThis retrospective observational study included the patients with COVID‐19 at the Wuhan Asia General hospital between February 10, and 26, 2020. Demographic, clinical, and ECG characteristics were collected, and comparisons were made between the ICU and non‐ICU admission groups. Logistic regression was used to identify risk factors of ICU admission.ResultsAmong 135 included patients (median age: 64 years [interquartile range: 48–72]), ST‐T abnormalities (40%) were the most common ECG feature, followed by arrhythmias (38%). Cardiovascular disease (CVD) was presented in 48% of the patients. Six (4.4%) died during hospitalization, and 23 (17.0%) were admitted to the ICU. Compared with non‐ICU group, the ICU group showed higher heart rate (p = .019) and P‐wave duration (p = .039) and was more frequently associated with CVD (p < .001), ST‐T abnormalities (p = .007), arrhythmias (p = .003), QTc interval prolongation (p = .003), and pathological Q waves (p < .001). Twenty‐seven patients were re‐examined ECG during admission, and 17 of them presented new findings compared with their initial ECG presentations. ST‐T abnormalities (p = .040) and history of CVD (p = .0047) were associated with increased risk of ICU hospitalization.ConclusionsCOVID‐19 is frequently related to cardiovascular manifestations including ECG abnormalities and cardiovascular comorbidities. ST‐T abnormalities and CVD at admission were associated with increased odds of ICU admission.
Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis
Authors: Torre‐Fuentes Laura , Matías‐Guiu Jordi A. , Pytel Vanesa , Montero‐Escribano Paloma , Maietta Paolo , Álvarez Sara , Gómez‐Pinedo Ulises , Matías‐Guiu Jorge 
Published: September 2020

AbstractIntroductionNumerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF‐α, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS.MethodsWe used whole‐exome sequencing to study genes coding for TNF‐α receptors and ligands, and proteins promoting TNF‐α expression in 116 individuals from 19 families including at least two MS patients. We compared patients with MS, patients with other autoimmune diseases, and healthy individuals.ResultsGreater polymorphism was observed in several genes in families with familial MS compared to the general population; this may reflect greater susceptibility to autoimmune diseases. Pedigree analysis also revealed that LT‐α variants rs1041981 and rs2229094 and LT‐β variant rs4647197 were associated with MS and that LT‐β variant rs4647183 was associated with other autoimmune diseases. The association between autoimmune disease and TNFAIP2 variant rs1132339 is particularly noteworthy, as is the fact that TNFAIP6 variant rs1046668 appears to follow a recessive inheritance pattern.ConclusionsOur findings support the idea that the risk of familial MS is associated with variants of signaling pathways, including those involving TNF‐α.
Comprehensive analysis of ubiquitin‐specific protease 1 reveals its importance in hepatocellular carcinoma
Authors: Zhao Yalei , Xue Chen , Xie Zhongyang , Ouyang Xiaoxi , Li Lanjuan 
Published: September 2020

AbstractObjectivesIn this study, we comprehensively analysed the role of ubiquitin‐specific protease 1(USP1) in hepatocellular carcinoma (HCC) using data from a set of public databases.Materials and MethodsWe analysed the mRNA expression of USP1 in HCC and subgroups of HCC using Oncomine and UALCAN. Survival analysis of USP1 in HCC was conducted with the Kaplan‐Meier Plotter database. The mutations of USP1 in HCC were analysed using cBioPortal and the Catalogue of Somatic Mutations in Cancer database. Differential genes correlated with USP1 and WD repeat domain 48 (WDR48) were obtained using LinkedOmics. USP1 was knocked down with small interfering RNA (siRNA) or pharmacologically inhibited by ML‐323 in MHCC97H or SK‐Hep‐1 cell lines for function analysis.ResultsHigh USP1 expression predicted unfavourable overall survival in HCC patients. USP1 showed positive correlations with the abundances of macrophages and neutrophils. We identified 98 differential genes that were positively correlated with both USP1 and WDR48. These genes were mainly involved in the cell cycle, aldosterone synthesis and secretion and oestrogen signalling pathways. Interactions between USP1 and WDR 48 were confirmed using co‐immunoprecipitation. USP1 knockdown or ML‐323 treatment reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1.ConclusionsOverall, USP1 is a promising target for HCC treatment with good prognostic value. USP1 and WDR48 function together in regulating cancer cell proliferation via the cell cycle.
Subclinical left ventricular dysfunction in Sjögren’s syndrome assessed by four‐dimensional speckle tracking echocardiography
Authors: Akaycan Jülide , Hidayet Şıho , Bayramoğlu Adil , Yolbaş Servet , Karaca Yücel , Yiğit Yakup , Ulutaş Zeynep 
Published: September 2020

AbstractObjectiveThe aim of this study was to evaluate the left ventricular (LV) systolic strain by four‐dimensional speckle tracking echocardiography (4D‐STE) in order to provide the early detection of myocardial dysfunction in patients with Sjögren's syndrome (SS).MethodsForty consecutive patients with primary SS diagnosed at the rheumatology outpatient clinic and 35 age‐ and sex‐matched healthy volunteers were included in the study. 4DSTE was performed, and global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS) were measured. 4DSTE results were compared with the healthy volunteers.ResultsNo significant differences were observed between the GRS and GCS values of the two groups. A significant difference was observed in the GLS and GAS measurements between the two groups (P = .005 for GLS, P < .001 for GAS). Positive correlation was detected between disease duration and LV‐GLS and LV‐GAS.ConclusionWe demonstrated subclinical systolic dysfunction in SS patients by 4DSTE, which is a sensitive marker of ventricular dysfunction. Deterioration of the LV became more evident as duration of the disease increased. Therefore, we believe that a cardiac evaluation will be of benefit to patients with long‐term SS.