bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA
Authors: Yuan Shuai , Peng Lei , Park Jonathan J. , Hu Yingxia , Devarkar Swapnil C. , Dong Matthew B. , Wu Shenping , Chen Sidi , Lomakin Ivan , Xiong Yong 
Published: August 2020

SummaryThe COVID-19 pandemic affects millions of people worldwide with a rising death toll. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its nonstructural protein 1 (Nsp1) to redirect host translation machinery to the viral RNA by binding to the ribosome and suppressing cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the transcriptome in human cells. The changes include repression of major gene clusters in ribosomal RNA processing, translation, mitochondria function, cell cycle and antigen presentation; and induction of factors in transcriptional regulation. We further gained a mechanistic understanding of the Nsp1 function by determining the cryo-EM structure of the Nsp1-40S ribosomal subunit complex, which shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the cryo-EM structure of the 48S preinitiation complex (PIC) formed by Nsp1, 40S, and the cricket paralysis virus (CrPV) internal ribosome entry site (IRES) RNA, which shows that this 48S PIC is nonfunctional due to the incorrect position of the 3’ region of the mRNA. Results presented here elucidate the mechanism of host translation inhibition by SARS-CoV-2, provide insight into viral protein synthesis, and furnish a comprehensive understanding of the impacts from one of the most potent pathogenicity factors of SARS-CoV-2.HighlightsORF screen identified Nsp1 as a major cellular pathogenicity factor of SARS-CoV-2Nsp1 broadly alters the gene expression programs in human cellsNsp1 inhibits translation by blocking mRNA entry channelNsp1 prevents physiological conformation of the 48S PIC
Trans-cinnamaldehyde potently killsEnterococcus faecalisbiofilm cells and prevents biofilm recovery
Authors: Ali Islam A. A. , Cheung Becky P. K. , Matinlinna Jukka. P. , Lévesque Celine M. , Neelakantan Prasanna 
Published: August 2020

AbstractEnterococcus faecalisis a biofilm-forming, nosocomial pathogen that is frequently isolated from failed root canal treatments. Contemporary root canal disinfectants are ineffective in eliminating these biofilms and preventing reinfection. As a result, there is a pressing need to identify novel and safe antibiofilm molecules. The effect of short-term (5 and 15 min) and long-term (24 h) treatments of TC on the viability ofE. faecalisbiofilms was compared with currently used root canal disinfectants. Treatment for 15 min with TC reduced biofilm metabolic activity as effective as 1% sodium hypochlorite and 2% chlorhexidine. Treatment with TC for 24 h was significantly more effective than 2% chlorhexidine in reducing the viable cell counts of biofilms. This serendipitous effect of TC was sustained for 10 days under growth-favoring conditions. For the first time, our study highlights the strong antibacterial activity of TC againstE. faecalisbiofilms, and notably, its ability to prevent biofilm recovery after treatment.
Bmp8a Is a Novel Player in Regulation of Antiviral Immunity
Authors: Zhong Shenjie , Li Haoyi , Wang Yun-Sheng , Wang Ying , Ji Guangdong , Li Hong-Yan , Zhang Shicui , Liu Zhenhui 
Published: August 2020

AbstractBone morphogenetic protein (BMP) is a kind of classical multi-functional growth factor that plays a vital role in the formation and maintenance of bone, cartilage, muscle, blood vessels, and the regulation of energy balance. Whether BMP plays a role in antiviral immunity is unknown. Here we demonstrate that Bmp8a is a newly-identified positive regulator for antiviral immune responses. Thebmp8a−/−zebrafish, when infected with the viruses of GCRV, SVCV or TSVDV, show significantly reduced antiviral immunity, increased viral load and morbidity. We also show for the first time that Bmp8a interacts with Alk6a, which promotes the phosphorylation of Tbk1 and Irf3 through p38 MAPK pathway, and induces the production of type I IFNs in response to virus infection. Upon virus infection,bmp8aexpression is activated through the binding of Stat1a/Stat1b to the GAS motifs inbmp8apromoter region, enlarging the antiviral innate immune signal. Our study uncovers a previously unrecognized role of Bmp8a in regulation of antiviral immune responses and provides a new target for controlling viral infection.
On the numbers of infected and deceased in the second Corona wave
Authors: Janssen Rainer , Mimkes Juergen 
Published: August 2020

SummaryIn Germany and other countries, a second wave of corona infections has been observed since July 2020, after the first wave has subsided. We have investigated both waves by a modified SIR-SI infection model, adapted to the data to the Robert-Koch-Institute (RKI) or the Johns-Hopkins-University (JHU).The first wave is characterized by the SIR model: in a perfect lockdown only a small part of the society is infected and the infections end after a certain time. The SI part considers the incompleteness of any lockdown: at the end of the first wave infections do not completely go down to zero, but continue to rise again, but only slowly due to mouth protection, hygiene and distance keeping. During this first wave the number of deceased people follows the number of infected persons with a fixed time interval and percentage: mostly symptomatic ill people have been tested. This applied to nearly all countries observed, with different intervals and percentages.In the present second wave, the number of daily infections has risen again significantly in some countries, and it may be questioned whether this is due to the increased number of tests. The answer may be given by looking at the daily number of deaths. In Germany, Austria, Italy, Great Britain and others this number has still remained at a constant level for six weeks. In these countries a second wave of died people has not yet arrived. The increased number of tests include obviously mostly asymptomatically infected persons, who do not fall ill or die from coronavirus. However, in some countries, like USA or Israel, the second wave did arrive. The numbers of infected and deceased people both have grown. A real second wave is a permanent threat to all countries.
Disentangling craving- and valence-driven brain responses to smoking cues in individuals with nicotine use disorder
Authors: Haugg Amelie , Manoliu Andrei , Sladky Ronald , Hulka Lea M. , Kirschner Matthias , Brühl Annette B. , Seifritz Erich , Quednow Boris B. , Herdener Marcus , Scharnowski Frank 
Published: August 2020

AbstractTobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behavior is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex, and ventral striatum.However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-driven brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence, and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments.
The impact of COVID-19 on the reproductive health of people living in Australia: findings from an online survey
Authors: Coombe Jacqueline , Kong Fabian , Bittleston Helen , Williams Hennie , Tomnay Jane , Vaisey Alaina , Malta Sue , Goller Jane , Temple-Smith Meredith , Bourchier Louise , Lau Andrew , Hocking Jane S 
Published: August 2020

ABSTRACTIntroductionAustralia introduced ‘lockdown’ measures to control COVID-19 on 22 March 2020. For two months, Australians were asked to remain at home and only leave for essential activities. We investigate the impact this had on sexual and reproductive health (SRH).MethodsAustralians aged 18+ were eligible to participate in an online survey from 23 April-11 May 2020. Questions included contraceptive use, pregnancy intentions and access to SRH services. We report on the experiences of 518 female participants aged <50 years. Pregnancy intentions and contraceptive use were analysed using descriptive statistics. Odds ratios and 95% confidence intervals were calculated to investigate difficulty accessing SRH products and services. Qualitative data were analysed using descriptive thematic analysis.ResultsMost participants (55.4%, 287/518) were aged 18-24 years. Most (76.1%, 379/498) indicated they were trying to avoid pregnancy. The oral contraceptive pill was the most common single method used (20.8%; 107/514). Nearly 20% (101/514) reported they were not using contraception. Older women (OR=0.4; 95%CI: 0.1, 0.9 for 25-34 vs 18-24 years) and those employed (OR=0.4; 95%CI: 0.2, 0.7) had less trouble accessing contraception during lockdown. Women aged 25-34 (OR=0.4; 95%CI: 0.3, 0.7) or 35-49 years (OR=0.3; 95%CI: 0.1, 0.6) were less likely to experience difficulty accessing feminine hygiene products. Qualitative analysis suggested that COVID-19 affected pregnancy plans, with participants delaying childbearing, or deciding to remain childfree.ConclusionCOVID-19 lockdown impacted the SRH of Australian women. Findings highlight the importance of continued access to SRH services and products during global emergencies.KEY MESSAGESNearly a third of participants reported difficulties accessing their usual feminine hygiene products during lockdown in Australia.Participants reported delaying childbearing or deciding to remain childfree due to the COVID-19 pandemic.Ensuring continued access to sexual and reproductive health services and products for all who require them during global emergencies is essential.
The Diagnostic Accuracy of Subjective Dyspnea in Detecting Hypoxemia Among Outpatients with COVID-19
Authors: Berezin Linor , Zhabokritsky Alice , Andany Nisha , Chan Adrienne K. , Gershon Andrea , Lam Philip W. , Leis Jerome A. , MacPhee Scott , Mubareka Samira , Simor Andrew E. , Daneman Nick 
Published: August 2020

AbstractObjectivesThe majority of patients with mild-to-moderate COVID-19 can be managed using virtual care. Dyspnea is challenging to assess remotely, and the accuracy of subjective dyspnea measures in capturing hypoxemia have not been formally evaluated for COVID-19. We explored the accuracy of subjective dyspnea in diagnosing hypoxemia in COVID-19 patients.MethodsThis is a retrospective cohort study of consecutive outpatients with COVID-19 who met criteria for home oxygen saturation monitoring at a university-affiliated acute care hospital in Toronto, Canada from April 3, 2020 to June 8, 2020. Hypoxemia was defined by oxygen saturation <95%. Dyspnea measures were treated as diagnostic tests, and we determined their sensitivity (SN), specificity (SP), negative/positive predictive value (NPV/PPV), and positive/negative likelihood ratios (+LR/-LR) for detecting hypoxemia.ResultsDuring the study period 64/298 (21.5%) of patients met criteria for home oxygen saturation monitoring, and of these 14/64 (21.9%) were diagnosed with hypoxemia. The presence/absence of dyspnea had limited accuracy for diagnosing hypoxemia, with SN 57% (95% CI 30-81%), SP 78% (63%-88%), NPV 86% (72%-94%), PPV 42% (21%-66%), +LR 2.55 (1.3-5.1), -LR 0.55 (0.3-1.0). An mMRC dyspnea score >1 (SP 97%, 95%CI 82%-100%), Roth Maximal Count <12 (SP 100%, 95%CI 75-100%), and Roth Counting time < 8 seconds (SP 93%, 95%CI 66%-100%) had high SP that could be used to rule in hypoxemia, but displayed low SN (≤50%).ConclusionsSubjective dyspnea measures have inadequate accuracy for ruling out hypoxemia in high-risk patients with COVID-19. Safe home management of patients with COVID-19 should incorporate home oxygenation saturation monitoring.
Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140
Authors: Ghiboub Mohammed , Koster Jan , Craggs Peter D. , Li Yim Andrew Y.F. , Shillings Anthony , Hutchinson Sue , Bingham Ryan P. , Gatfield Kelly , Hageman Ishtu L. , Yao Gang , O’Keefe Heather P. , Coffin Aaron , Patel Amish , Sloan Lisa A. , Mitchell Darren J. , Lunven Laurent , Watson Robert J. , Blunt Christopher E. , Harrison Lee A. , Bruton Gordon , Kumar Umesh , Hamer Natalie , Spaull John R. , Zwijnenburg Danny A. , Welting Olaf , Hakvoort Theodorus B.M. , van Limbergen Johan , Henneman Peter , Prinjha Rab K. , de Winther Menno PJ. , Harker Nicola R. , Tough David F. , de Jonge Wouter J. 
Published: August 2020

AbstractSpeckled 140 KDa (SP140) is a nuclear body protein, mainly expressed in immune cells, which contains multiple domains suggestive of an epigenetic reader function; namely a bromodomain, a PHD domain and a SAND domain. Single nucleotide polymorphisms and epigenetic modifications in theSP140locus have been linked to autoimmune and inflammatory diseases including Crohn’s disease (CD). However, little is known about the cellular function of SP140; this is due in part to the fact that, unlike for other many other epigenetic proteins, no small molecule inhibitors have been available to investigate the biological role of SP140. We report the discovery of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in innate immune cells. We show that SP140 is highly expressed in CD68+CD mucosal macrophages and inin vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation, whilst inducing the generation of CD206+regulatory macrophages that mark anti-TNF remission induction in CD patients. ChIP-seq analyses revealed that SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-dependent downstream inflammatory genes. Notably, in CD14+macrophages isolated from CD intestinal-mucosa, GSK761 inhibited the spontaneous expression of cytokines, includingTNF. Together, this study identifies SP140 as a druggable epigenetic reader and therapeutic target for CD.
Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases
Authors: Chaudhry M. Zeeshan , Eschke Kathrin , Hoffmann Markus , Grashoff Martina , Abassi Leila , Kim Yeonsu , Brunotte Linda , Ludwig Stephan , Kröger Andrea , Klawonn Frank , Pöhlmann Stefan , Cicin-Sain Luka 
Published: August 2020

ABSTRACTSince the pandemic spread of SARS-CoV-2, the virus has exhibited remarkable genome stability, but recent emergence of novel variants show virus evolution potential. Here we show that SARS-CoV-2 rapidly adapts to Vero E6 cells that leads to loss of furin cleavage motif in spike protein. The adaptation is achieved by asymptotic expansion of minor virus subpopulations to dominant genotype, but wildtype sequence is maintained at low percentage in the virus swarm, and mediate reverse adaptation once the virus is passaged on human lung cells. The Vero E6-adapted virus show defected cell entry in human lung cells and the mutated spike variants cannot be processed by furin or TMPRSS2. However, the mutated S1/S2 site is cleaved by cathepsins with higher efficiency. Our data show that SARS-CoV-2 can rapidly adapt spike protein to available proteases and advocate for deep sequence surveillance to identify virus adaptation potential and novel variant emergence.Significance StatementRecently emerging SARS-CoV-2 variants B1.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor spike mutation and have been linked to increased virus pathogenesis. The emergence of these novel variants highlight coronavirus adaptation and evolution potential, despite the stable consensus genotype of clinical isolates. We show that subdominant variants maintained in the virus population enable the virus to rapidly adapt upon selection pressure. Although these adaptations lead to genotype change, the change is not absolute and genome with original genotype are maintained in virus swarm. Thus, our results imply that the relative stability of SARS-CoV-2 in numerous independent clinical isolates belies its potential for rapid adaptation to new conditions.
The role of toxin:antitoxin systems and insertion sequences in the loss of virulence inShigella sonnei
Authors: Martyn Jessica E. , Pilla Giulia , Hollingshead Sarah , Lobanovska Mariya , Winther Kristoffer S. , Lea Susan , McVicker Gareth , Tang Christoph M. 
Published: August 2020

SUMMARYTheShigellaplasmid, pINV, contains a 30 kb pathogenicity island (PAI) encoding a Type III secretion system (T3SS) which is essential for virulence. During growth in the laboratory, avirulent colonies ofShigella(which do not express a T3SS) arise spontaneously. Avirulence inShigella flexnerimostly follows loss of the PAI, following recombination between insertion sequences (ISs) on pINV; toxin:antitoxin (TA) systems on pINV promote its retention through post-segregational killing (PSK). We show that avirulence inShigella sonneimainly results from plasmid loss, consistent with previous findings; IS-mediated PAI deletions can occur inS. sonnei, but through different ISs than inS. flexneri. We investigated the molecular basis for frequent loss of theS. sonneiplasmid, pINVSsonn. Introduction into pINVSsonnof CcdAB and GmvAT, toxin:antitoxin TA systems in pINV fromS. flexneribut notS. sonnei, reduced plasmid loss and the emergence of avirulent bacteria. However, plasmid loss remained the leading cause of avirulence. We show that a single amino acid difference in the VapC toxin of the VapBC TA system in pINV also contributes to high frequency plasmid loss inS. sonneicompared toS. flexneri. Our findings demonstrate that the repertoire of ISs, complement of TA systems, and polymorphisms in TA systems influence plasmid dynamics and virulence loss inS. sonnei. Understanding the impact of polymorphisms should be informative about how TA systems contribute to PSK, and could be exploited for generating strains with stable plasmids.
Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Authors: Palanikumar Loganathan , Karpauskaite Laura , Hassan Sarah , Alam Maheen , Al-Sayegh Mohamed , Chehade Ibrahim , Maity Debabrata , Ali Liaqat , Falls Zackary , Samudrala Ram , Kalmouni Mona , Hunashal Yamanappa , Ahmed Jemil , Karapetyan Shake , Pasricha Renu , Esposito Gennaro , Afzal Ahmed J. , Hamilton Andrew D. , Kumar Sunil , Magzoub Mazin 
Published: August 2020

ABSTRACTMissense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent.
Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing
Authors: Tian Luyi , Jabbari Jafar S. , Thijssen Rachel , Gouil Quentin , Amarasinghe Shanika L. , Kariyawasam Hasaru , Su Shian , Dong Xueyi , Law Charity W. , Lucattini Alexis , Chung Jin D. , Naim Timur , Chan Audrey , Ly Chi Hai , Lynch Gordon S. , Ryall James G. , Anttila Casey J.A. , Peng Hongke , Anderson Mary Ann , Roberts Andrew W. , Huang David C.S. , Clark Michael B. , Ritchie Matthew E. 
Published: August 2020

AbstractAlternative splicing shapes the phenotype of cells in development and disease. Long-read RNA-sequencing recovers full-length transcripts but has limited throughput at the single-cell level. Here we developed single-cell full-length transcript sequencing by sampling (FLT-seq), together with the computational pipelineFLAMESto overcome these issues and perform isoform discovery and quantification, splicing analysis and mutation detection in single cells. WithFLT-seqandFLAMES, we performed the first comprehensive characterization of the full-length isoform landscape in single cells of different types and species and identified thousands of unannotated isoforms. We found conserved functional modules that were enriched for alternative transcript usage in different cell populations, including ribosome biogenesis and mRNA splicing. Analysis at the transcript-level allowed data integration with scATAC-seq on individual promoters, improved correlation with protein expression data and linked mutations known to confer drug resistance to transcriptome heterogeneity. Our methods reveal previously unseen isoform complexity and provide a better framework for multi-omics data integration.