bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular and cellular insight into Escherichia coli SslE and its role during biofilm maturation
Authors: Corsini Paula M. , Wang Sunjun , Rehman Saima , Fenn Katherine , Sagar Amin , Sirovica Slobodan , Cleaver Leanne , Edwards-Gayle Charlotte J. C. , Mastroianni Giulia , Dorgan Ben , Sewell Lee M. , Lynham Steven , Iuga Dinu , Franks W. Trent , Jarvis James , Carpenter Guy H. , Curtis Michael. A. , Bernadó Pau , Darbari Vidya C. , Garnett James A. 
Published: February 2021

AbstractEscherichia coli is a Gram-negative bacterium that colonizes the human intestine and virulent strains can cause severe diarrhoeal and extraintestinal diseases. The protein SslE is secreted by a range of pathogenic and some commensal E. coli strains. It can degrade mucins in the intestine, promotes biofilm maturation and it is a major determinant of infection in virulent strains, although how it carries out these functions is not well understood. Here we examine SslE from the E. coli Waksman and H10407 strains and reveal that it has a novel and dynamic structure. In response to acidification within mature biofilms we show how SslE forms a unique functional aggregate that interacts with cellulose and regulates the distribution of exopolysaccharides in macrocolony biofilms. Our data indicates that the spatial organization of SslE polymers and local pH are critical for biofilm maturation and SslE is a key factor that drives persistence of SslE-secreting bacteria during acidic stress.
Moderators of changes in smoking, drinking, and quitting behaviour associated with the first Covid-19 lockdown in England
Authors: Jackson Sarah E. , Beard Emma , Angus Colin , Field Matt , Brown Jamie 
Published: February 2021

AbstractAimTo estimate changes in smoking, drinking, and quitting behaviour from before to during the first Covid-19 lockdown in England, and whether changes differed by age, sex, or social grade.DesignRepresentative cross-sectional surveys of adults, collected monthly between August 2018 and July 2020.SettingEngland.Participants36,980 adults (≥18y).MeasurementsIndependent variables were survey month (pre-lockdown: August-February vs. lockdown months: April-July) and year (pandemic: 2019/20 vs. comparator: 2018/19). Smoking outcomes were smoking prevalence, cessation, quit attempts, quit success, and use of evidence-based or remote cessation support. Drinking outcomes were high-risk drinking prevalence, alcohol reduction attempts, and use of evidence-based or remote support. Moderators were age, sex, and occupational social grade (ABC1=more advantaged/C2DE=less advantaged).FindingsRelative to changes over the same time period in 2018/19, lockdown was associated with significant increases in smoking prevalence (+24.7% in 2019/20 vs. 0.0% in 2018/19, ORadj=1.35[95%CI=1.12-1.63]) and quit attempts (+39.9% vs. −22.2%, ORadj=2.48[1.76-3.50]) among 18-34 year-olds, but not older groups. Increases in cessation (+156.4% vs. −12.5%, ORadj=3.08[1.86-5.09]) and the success rate of quit attempts (+99.2% vs. +0.8%, ORadj=2.29[1.31-3.98]) were also observed, and did not differ significantly by age, sex, or social grade. Lockdown was associated with a significant increase in high-risk drinking prevalence across all sociodemographic groups (+39.5% vs. −7.8%, ORadj=1.80[1.64-1.98]), with particularly high increases among women (ORadj=2.17[1.87-2.53]) and social grades C2DE (ORadj=2.34[2.00-2.74]). Alcohol reduction attempts increased significantly among high-risk drinkers from social grades ABC1 (ORadj=2.31[1.78-3.00]) but not C2DE (ORadj=1.25[0.83-1.88]), with larger increases among those aged 18-34 (ORadj=2.56[1.72-3.81]) and ≥60 (ORadj=1.43[1.05-1.95]) than 35-59 (ORadj=2.51[1.51-4.18]). There were few significant changes in use of support for smoking cessation or alcohol reduction, although samples were small.ConclusionsIn England, the first Covid-19 lockdown was associated with increased smoking prevalence among younger adults, and increased high-risk drinking prevalence among all adults. Smoking cessation activity also increased: more younger smokers made quit attempts during lockdown and more smokers quit successfully. Socioeconomic disparities in drinking behaviour were evident: high-risk drinking increased by more among women and those from less advantaged social grades (C2DE) but the rate of reduction attempts increased only among the more advantaged social grades (ABC1).
Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU-based disease: the Multi-Targeting Drug DREAM Challenge
Authors: Xiong Zhaoping , Jeon Minji , Allaway Robert J , Kang Jaewoo , Park Donghyeon , Lee Jinhyuk , Jeon Hwisang , Ko Miyoung , Jiang Hualiang , Zheng Mingyue , Tan Aik Choon , Guo Xindi ,   The Multi-Targeting Drug DREAM Challenge Community, Dang Kristen K , Tropsha Alex , Hecht Chana , Das Tirtha K. , Carlson Heather A. , Abagyan Ruben , Guinney Justin , Schlessinger Avner , Cagan Ross 
Published: February 2021

AbstractA continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (‘polypharmacology’). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.Author SummaryMany modern drugs are developed with the goal of modulating a single cellular pathway or target. However, many drugs are, in fact, ‘dirty;’ they target multiple cellular pathways or targets. This phenomenon is known as multi-targeting or polypharmacology. While some strive to develop ‘cleaner’ therapeutics that eliminate secondary targets, recent work has shown that multi-targeting therapeutics have key advantages for a variety of diseases. However, while multi-targeting drugs that affect a precisely-defined profile of targets may be more effective, it is difficult to computationally predict which molecules have desirable target profiles. Here, we report the results of a competitive crowdsourcing project (the Multi-Targeting Drug DREAM Challenge), where we challenged participants to predict chemicals that have desired target profiles for cancer and neurodegenerative disease.
CONSTAX2: Improved taxonomic classification of environmental DNA markers
Authors: Liber Julian , Bonito Gregory , Benucci Gian Maria Niccolò 
Published: February 2021

SummaryCONSTAX - the CONSensus TAXonomy classifier - was developed for accurate and reproducible taxonomic annotation of fungal rDNA amplicons and is based upon a consensus approach of RDP, SINTAX and UTAX algorithms. CONSTAX2 can be used to classify prokaryotes and incorporates BLAST-based classifiers to reduce classification errors. Additionally, CONSTAX2 implements a conda-installable, command line tool with improved classification metrics, faster training, multithreading support, capacity to incorporate external taxonomic databases, new isolate matching and high-level taxonomy tools, replete with documentation and example tutorials.Availability and ImplementationCONSTAX2 is available athttps://github.com/liberjul/CONSTAXv2, and is packaged for Linux and MacOS from Bioconda. A tutorial and documentation are available athttps://constax.readthedocs.io/en/latest/.
Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes
Authors: Nakamura Kenta , Neidig Lauren E. , Yang Xiulan , Weber Gerhard J. , El-Nachef Danny , Tsuchida Hiroshi , Dupras Sarah , Kalucki Faith A. , Jayabalu Anu , Futakuchi-Tsuchida Akiko , Nakamura Daisy S. , Marchianò Silvia , Bertero Alessandro , Robinson Melissa R. , Cain Kevin , Whittington Dale , Reinecke Hans , Pabon Lil , Knollmann Björn C. , Kattman Steven , Thies R. Scott , MacLellan W. Robb , Murry Charles E. 
Published: February 2021

AbstractBackgroundEngraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation.ObjectivesWe hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden.MethodshPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA.ResultsEA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0–0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03–1.01; p = 0.05). Without treatment, peak heart rate averaged 305 ± 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185±9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 ± 2.9% to 76.5 ± 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia.ConclusionsThe risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy.Condensed AbstractEngraftment arrhythmia (EA) is a transient but serious complication of cardiac remuscularization therapy. Using a porcine model of cardiac remuscularization and EA, ivabradine and amiodarone were independently effective in suppressing tachycardia and arrhythmia, respectively. Baseline amiodarone combined with adjunctive ivabradine successfully prevented cardiac death, unstable EA and heart failure (hazard ratio 0.00; 95% confidence interval, 0–0.297; p = 0.002) and significantly suppressed peak daily heart rate and arrhythmia burden (p=0.006 and 0.003, respectively). Antiarrhythmic treatment was successfully discontinued after one-month without recrudescence of arrhythmia. We conclude that EA can be suppressed by combined amiodarone and ivabradine drug therapy.
A glycan gate controls opening of the SARS-CoV-2 spike protein
Authors: Sztain Terra , Ahn Surl-Hee , Bogetti Anthony T. , Casalino Lorenzo , Goldsmith Jory A. , Seitz Evan , McCool Ryan S. , Kearns Fiona L. , Acosta-Reyes Francisco , Maji Suvrajit , Mashayekhi Ghoncheh , McCammon J. Andrew , Ourmazd Abbas , Frank Joachim , McLellan Jason S. , Chong Lillian T. , Amaro Rommie E. 
Published: February 2021

AbstractSARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded “down” to an exposed “up” state in order to bind the human ACE2 receptor and infect cells. While snapshots of the “up” and “down” states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Together with ManifoldEM analysis of cryo-EM data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408, and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.
Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV
Authors: Alrubayyi Aljawharah , Gea-Mallorquí Ester , Touizer Emma , Hameiri-Bowen Dan , Kopycinski Jakub , Charlton Bethany , Fisher-Pearson Natasha , Muir Luke , Rosa Annachiara , Roustan Chloe , Earl Christopher , Cherepanov Peter , Pellegrino Pierre , Waters Laura , Burns Fiona , Kinloch Sabine , Dong Tao , Dorrell Lucy , Rowland-Jones Sarah , McCoy Laura E. , Peppa Dimitra 
Published: February 2021

AbstractThere is an urgent need to understand the nature of immune responses generated against SARS-CoV-2, to better inform risk-mitigation strategies for people living with HIV (PLWH). Although not all PLWH are considered immunosuppressed, residual cellular immune deficiency and ongoing inflammation could influence COVID-19 disease severity, the evolution and durability of protective memory responses. Here, we performed an integrated analysis, characterizing the nature, breadth and magnitude of SARS-CoV-2-specific immune responses in PLWH, controlled on ART, and HIV negative subjects. Both groups were in the convalescent phase of predominately mild COVID-19 disease. The majority of PLWH mounted SARS-CoV-2 Spike- and Nucleoprotein-specific antibodies with neutralizing activity and SARS-CoV-2-specific T cell responses, as measured by ELISpot, at levels comparable to HIV negative subjects. T cell responses against Spike, Membrane and Nucleocapsid were the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. Notably, the overall magnitude of SARS-CoV-2-specific T cell responses related to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses were observed. Both humoral and cellular responses to SARS-CoV-2 were detected at 5-7 months post-infection, providing evidence of medium-term durability of responses irrespective of HIV serostatus. Incomplete immune reconstitution on ART and a low CD4:CD8 ratio could, however, hamper the development of immunity to SARS-CoV-2 and serve as a useful tool for risk stratification of PLWH. These findings have implications for the individual management and potential effectiveness of vaccination against SARS-CoV-2 in PLWH.One Sentence SummaryAdaptive immune responses to SARS-CoV-2 in the setting of HIV infection
Hepatitis C Virus E1 Protein Enhances Macrophage iNOS Expression In Vitro
Authors: Munkhjargal Batkhishig , Enkhtuvshin Bilguun , Ulziisaikhan Uranbileg , Tuvdenjamts Baljinnyam , Unurbuyan Khulan , Sandagdorj Dolgorsuren , Baasandalai Tuul , Enkhjargal Baasansuren , Sandag Tsogtsaikhan , Tsolmon Bilegtsaikhan , Lkhagvasuren Enkhsaikhan 
Published: February 2021

AbstractObjectiveHepatitis C virus (HCV) is a single-stranded RNA virus that causes chronic hepatitis, cirrhosis, and liver cancer. Approximately 170 million individuals are infected with HCV worldwide. The pathogenesis of HCV-associated liver injury is thought to be due to the host antiviral immune response, including the T cell response, and excessive production of proinflammatory cytokines, reactive oxygen species, and nitric oxide (NO).Interferon-γ (IFN-γ) is a key cytokine in the adaptive immune response that is primarily secreted from CD4+ T helper cells to induce cytotoxic T lymphocyte (CTL) cell response against HCV infection. Another important role of IFN-γ is the activation of macrophages in the liver resulting in inhibition of viral replication and increased NO production.Enhanced inducible nitric oxide synthase (iNOS) expression and NO production observed in the liver of HCV-infected patients is positively correlated with viral load and hepatic inflammation. HCV-infected macrophages are major producers of NO in the liver. It is not completely understood how HCV proteins affect iNOS expression and what the role of IFN-γ is in HCV protein expression in HCV-infected macrophages. In this study, we examined the effect of INF-γ and HCV proteins on iNOS expression in the Raw264.7 cell line.ResultsConsistent with other studies, HCV core and NS5A proteins induced iNOS expression in macrophages. Moreover, HCV E1 protein-enhanced iNOS expression is highest in the presence and absence of IFN-γ activation.ConclusionThese results indicate that hepatitis C virus core, NS5A, E1 protein regulates iNOS protein expression in IFN-γ-activated and resting macrophage cell lines. These findings points to a future research direction for understanding the pathogenesis of HCV-related liver inflammation.
“A compressed representation of spatial distance in the rodent hippocampus’’
Authors: Sheehan Daniel J. , Charczynski Stephen , Fordyce Blake A. , Hasselmo Michael E. , Howard Marc W. 
Published: February 2021

AbstractPrincipal cells in the rodent hippocampus often fire in response to traversal through a specific spatial location (place cells), as well as elapsed time during an imposed temporal delay or after stimulus offset (time cells). Sequences of time cells unfold rapidly at first, with many time cells with narrow time fields. As the triggering event recedes into the past, time cells are fewer and have broader fields. This means that the representation of time in the hippocampus is compressed with greater resolution for time points near the present. Using tetrode recordings we measured individual CA1 units while rats traveled along a track that could be changed in length. Consistent with previous results, most place cells coded for distance from the starting point of the trajectory. Critically, place cells became less numerous and showed gradually widening fields with distance from the starting location. These results suggest that as the animal leaves a landmark, the hippocampal place code forms a compressed representation of distance from the starting location. The representation of time and space in the hippocampus have similar properties suggesting that they arise from similar computational mechanisms.Significance StatementThe hippocampus represents relationships between events in time and space. It has been hypothesized that temporal and spatial relationships are the result of a common computational mechanism. Previous work has shown that the representation of time in the hippocampus is compressed, with less neural resolution for more temporally remote events, consistent with the observation that temporal memory is worse for events further in the past. This paper shows an analogous result for spatial relationships. Place cells coded for distance from the start of a journey. As distance increased, place fields became broader and less numerous, showing a decrease in spatial resolution. This result suggests a unified coding scheme for the dimensions of time and space in the rodent hippocampus.
Human primed endothelial colony forming cells exert neuroprotective effects in the growth restricted newborn piglet
Authors: Chand Kirat K. , Patel Jatin , Bjorkman Tracey , Sim Seen-Ling , Miller Stephanie M. , Teo Elliot , Jones Lara , Sun Jane , Colditz Paul B. , Khosrotehrani Kiarash , Wixey Julie A. 
Published: February 2021

AbstractThe fetal brain is particularly vulnerable to the detrimental effects of fetal growth restriction (FGR) with subsequent abnormal neurodevelopment being common. There are no current treatments to protect the FGR newborn from lifelong neurological disorders. This study examines whether pure fetal mesenchymal stem cells and endothelial colony forming cells (ECFC) from the human term placenta are neuroprotective through modulating neuroinflammation and supporting the brain vasculature. We determined that one dose of these primed ECFCs (pECFC) on the first day of life to the newborn FGR piglet improved damaged vasculature, restored the neurovascular unit, reduced brain inflammation and improved adverse neuronal and white matter changes present in the FGR newborn piglet brain. These findings could not be reproduced using mesenchymal stromal cells alone. These results demonstrate pECFC treatment exerts beneficial effects on multiple cellular components in the FGR brain and act as a neuroprotectant.One Sentence SummaryStem cell treatment improves brain outcomes in the growth restricted newborn
Computational Fluid Dynamics Modeling of Cough Transport in an Aircraft Cabin
Authors: Zee Malia , Davis Angela C. , Clark Andrew D. , Wu Tateh , Jones Stephen P. , Waite Lindsay L. , Cummins Joshua J. , Olson Nels A. 
Published: February 2021

AbstractTo characterize the transport of respiratory pathogens during commercial air travel, Computational Fluid Dynamics simulations were performed to track particles expelled by coughing by a passenger assigned to different seats on a Boeing 737 aircraft. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby passengers. Different airflow rates were used, as well as different initial conditions to account for random fluctuations of the flow field. Overall, 80% of the particles were removed from the cabin in 1.3 to 2.6 minutes, depending on conditions, and 95% of the particles were removed in 2.4 to 4.6 minutes. Reducing airflow increased particle dispersion throughout the cabin but did not increase the highest exposure of nearby passengers. The highest exposure was 0.3% of the nonvolatile mass expelled by the cough, and the median exposure for seats within 3 feet of the cough discharge was 0.1%, which was in line with recent experimental testing.
Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics
Authors: Chu Xiakun , Wang Jin 
Published: February 2021

AbstractCancer reflects the dysregulation of the underlying gene network, which is intimately related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosomal structural transition during the can-cerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanded structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on chromosome. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosomal structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization, which contains initial reprogramming towards the stem cell followed by differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of cell stemness.