bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintenance therapy with infliximab or vedolizumab in inflammatory bowel disease is not associated with increased SARS-CoV-2 seroprevalence: UK experience in the 2020 pandemic
Authors: McGregor Colleen G C , Adams Alex , Sadler Ross , Arancibia-Cárcamo Carolina V , Palmer Rebecca , Ambrose Tim , Brain Oliver , Walsh Alissa , Klenerman Paul , Travis Simon , Croft Nicholas M , Lindsay James O , Satsangi Jack 
Published: December 2020

AbstractBackgroundThere has been great concern amongst clinicians and patients that immunomodulatory treatments for IBD may increase risk of SARS-CoV-2 susceptibility or progression to severe disease.MethodsSera from 640 patients attending for maintenance infliximab or vedolizumab infusions between April and June 2020 at the John Radcliffe Hospital (Oxford, UK) and Royal London Hospital (London, UK) were tested using the Abbott SARS-CoV-2 IgG assay. Demographic and clinical data were collated from electronic patient records and research databases.ResultsSeropositivity rates of 3.0% (12/404), 7.2% (13/180), and 12.5% (7/56) were found in the Oxford and London adult IBD cohorts and London paediatric IBD cohorts respectively. Seroprevalence rates in the Oxford adult IBD cohort were lower than that seen in non-patient facing health-care workers within the same hospital (7.2%). Seroprevalence rates of the London paediatric IBD cohort were comparable to a contemporary healthy cohort collected at the same hospital (54/396, 13.6%).ConclusionsSARS-CoV-2 seropositivity rates are not elevated in patients with IBD receiving maintenance infliximab or vedolizumab infusions. There is no rationale based on these data for elective interruption of maintenance therapy, and we recommend continuation of maintenance therapy. These data do not address the efficacy of vaccination in these patients.
Deep sequencing of DNA from urine of kidney allograft recipients to estimate the donor-specific DNA fraction
Authors: Belkadi Aziz , Thareja Gaurav , Dadhania Darshana , Lee John R. , Muthukumar Thangamani , Snopkowski Catherine , Li Carol , Halama Anna , Abdelkader Sara , Mahmoud Yasmin , Malek Joel , Suthanthiran Manikkam , Suhre Karsten 
Published: December 2020

AbstractRenal transplantation is the method of choice for patients with end stage kidney failure. But transplanted allograft could be affected by viral and bacterial infections and immune rejections. The standard test for the diagnosis of acute pathologies in kidney transplants is the renal biopsy. However, noninvasive tests would be desirable. Various methods using different techniques have been developed by the transplantation community. But these methods expect improvements. We present here a cost-effective method based on estimating donor-specific DNA fraction in recipient urine based on sequencing of recipient urine DNA only. We hypothesized that in the no-pathology stage, the largest tissue types present in recipient urine are donor kidney cells and in case of rejection, a larger number of recipient immune cells would be observed. Extensive in-silico simulation was used to tune the sequencing parameters: number of variants and depth of coverage. Sequencing of DNA mixture from 2 healthy individuals showed the method high prediction accuracy (maximum error < 0.04). We then demonstrated the insignificant impact of familial relationship and ethnicity using an in-house and public database. Lastly, we performed recipient deep urine DNA sequencing in 32 samples representing two pathology groups: acute rejection (AR, 12 samples) and acute tubular injury (ATI, 11 samples) and 9 samples with no pathology. We found a significant association between the donor-specific DNA fraction in the two pathology groups compared to no pathology (P = 0.0064 for AR and P = 0.026 for ATI). We conclude that deep DNA sequencing of recipient urine offers a noninvasive means of diagnosing and prognosticating acute pathologies in the human kidney allograft.
Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation
Authors: Jolivet Geneviève , Daniel-Carlier Nathalie , Harscoёt Erwana , Airaud Eloïse , Dewaele Aurélie , Pierson Cloé , Giton Frank , Boulanger Laurent , Daniel Nathalie , Mandon-Pépin Béatrice , Pannetier Maёlle , Pailhoux Eric 
Published: December 2020

AbstractAROMATASE, encoded by theCYP19A1gene, is the cytochrome enzyme responsible for the synthesis of estrogens in vertebrates. In most mammals a peak of expression of theCYP19A1gene occurs in the fetal XX gonad when sexual differentiation starts up. To elucidate the role of this peak, we produced 3 lines of TALEN genetically editedCYP19A1KO rabbits, that were void of any production of estradiol. All KO XX rabbits developed as females, with aberrantly small sized ovaries at adulthood, an almost empty reserve of primordial follicles and very few large antrum follicles. Ovulation never occurred. Our histological, immunohistological and transcriptomic analyses showed that the surge of estradiol in the XX fetal rabbit gonad is dispensable for its determination as an ovary, or for meiosis. However, it is mandatory for the high proliferation and differentiation of both somatic and germ cells, and consequently for the establishment of the ovarian reserve.
Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products in vitro
Authors: He Chang-Long , Huang Lu-Yi , Wang Kai , Gu Chen-Jian , Hu Jie , Zhang Gui-Ji , Xu Wei , Xie You-Hua , Tang Ni , Huang Ai-Long 
Published: December 2020

AbstractCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. To screen for antiviral drugs for COVID-19 treatment, we constructed a SARS-CoV-2 spike (S) pseudovirus system using an HIV-1-based lentiviral vector with a luciferase reporter gene to screen 188 small potential antiviral compounds. Using this system, we identified nine compounds, specifically, bis-benzylisoquinoline alkaloids, that potently inhibited SARS-CoV-2 pseudovirus entry, with EC50values of 0.1–10 μM. Mechanistic studies showed that these compounds, reported as calcium channel blockers (CCBs), inhibited Ca2+-mediated membrane fusion and consequently suppressed coronavirus entry. These candidate drugs showed broad-spectrum efficacy against the entry of several coronavirus pseudotypes (SARS-CoV, MERS-CoV, SARS-CoV-2 [S-D614, S-G614, N501Y.V1 and N501Y.V2]) in different cell lines (293T, Calu-3, and A549). Antiviral tests using native SARS-CoV-2 in Vero E6 cells confirmed that four of the drugs (SC9/cepharanthine, SC161/hernandezine, SC171, and SC185/neferine) reduced cytopathic effect and supernatant viral RNA load. Among them, cepharanthine showed the strongest anti-SARS-CoV-2 activity. Collectively, this study offers new lead compounds for coronavirus antiviral drug discovery.
Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials
Authors: Follmann Dean , Fintzi Jonathan , Fay Michael P. , Janes Holly E. , Baden Lindsey , Sahly Hana El , Fleming Thomas R. , Mehrotra Devan V. , Carpp Lindsay N. , Juraska Michal , Benkeser David , Donnell Deborah , Fong Youyi , Han Shu , Hirsch Ian , Huang Ying , Huang Yunda , Hyrien Ollivier , Luedtke Alex , Carone Marco , Nason Martha , Vandebosch An , Zhou Honghong , Cho Iksung , Gabriel Erin , Kublin James G. , Cohen Myron S. , Corey Lawrence , Gilbert Peter B. , Neuzil Kathleen M. 
Published: December 2020

ABSTRACTBackgroundSeveral candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known.MethodsFollowing vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease.ResultsPost-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods.ConclusionsWe advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.
Coordinating the morphogenesis-differentiation balance by tweaking the cytokinin-gibberellin equilibrium
Authors: Israeli Alon , Burko Yogev , Shleizer-Burko Sharona , Zelnik Iris Daphne , Sela Noa , Hajirezaei Mohammad R. , Fernie Alisdair R. , Tohge Takayuki , Ori Naomi , Bar Maya 
Published: December 2020

AbstractMorphogenesis and differentiation are important stages in organ development and shape determination. However, how they are balanced and tuned during development is not fully understood. In the compound leaved tomato, an extended morphogenesis phase allows for the initiation of leaflets, resulting in the compound form. Maintaining a prolonged morphogenetic phase in early stages of compound-leaf development is dependent on delayed activity of several factors that promote differentiation, including CIN-TCP transcription factor (TF) LA, the MYB TF CLAU and the plant hormone Gibberellin (GA). Here, we investigated the genetic regulation of the morphogenesis-differentiation balance by studying the relationship between LA, CLAU and GA. Our genetic and molecular examination suggest thatLAis expressed more broadly thanCLAUand determines the spatio-temporal context of CLAU activity. We demonstrate that both LA and CLAU affect the Cytokinin/Gibberellin (CK/GA) balance. LA reduces the sensitivity of the leaf margin to CK, shown before to be also affected by CLAU. CLAU affects leaf active GA content and sensitivity, shown previously to be also influenced by LA. Therefore, LA and CLAU likely function in parallel pathways to promote leaf differentiation by converging on common downstream processes, including the CK/GA balance.
Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70
Authors: Kemp Steven A , Meng Bo , Ferriera Isabella ATM , Datir Rawlings , Harvey William T , Papa Guido , Lytras Spyros , Collier Dami A , Mohamed Ahmed , Gallo Giulia , Thakur Nazia ,   The COVID-19 Genomics UK (COG-UK) Consortium, Carabelli Alessandro M , Kenyon Julia C , Lever Andrew M , De Marco Anna , Saliba Christian , Culap Katja , Cameroni Elisabetta , Piccoli Luca , Corti Davide , James Leo C , Bailey Dalan , Robertson David L , Gupta Ravindra K. 
Published: December 2020

AbstractSARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1.1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H).In vitro, we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1.1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally.HighlightsΔH69/V70 is present in at least 28 SARS-CoV-2 lineagesΔH69/V70 does not confer escape from convalescent seraΔH69/V70 increases spike infectivity and compensates for RBD mutationsΔH69/V70 is associated with greater spike cleavageB.1.1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity
Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells
Authors: Raina Dhruv , Fabris Fiorella , Morelli Luis G. , Schröter Christian 
Published: December 2020

AbstractSignal transduction networks process extracellular signals to guide cell fate decisions such as to divide, differentiate, or die. These networks can generate characteristic dynamic activities that are shaped by their cell-type specific architecture. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, the dynamic activity of the FGF/ERK signaling network in this context remains unexplored. Here we use live cell sensors in wild type andFgf4mutant mouse embryonic stem cells to measure ERK dynamic activity in single cells, in response to defined ligand concentrations. We find that ERK activity oscillates in embryonic stem cells. Single cells can transit between oscillatory and non-oscillatory behavior, leading to heterogeneous dynamic activities in the population. Oscillations become more prevalent with increasing FGF4 dose, while maintaining a robust characteristic timescale. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells.
Utilization of the repeated squat-stand model for studying the directional sensitivity of the cerebral pressure-flow relationship
Authors: Labrecque Lawrence , Smirl Jonathan D , Brassard Patrice 
Published: December 2020

AbstractHysteresis in the cerebral pressure-flow relationship describes the superior ability of the cerebrovasculature to buffer cerebral blood flow changes when mean arterial pressure (MAP) acutely increases compared to when MAP acutely decreases. This phenomenon can be evaluated by comparing the change in middle cerebral artery mean blood velocity (MCAv) per change in MAP during either acute increases or decreases in MAP induced by repeated squat-stands (RSS). However, no real baseline can be employed for this particular protocol as there is no true stable reference point. Herein, we characterized a novel metric using the greatest MAP oscillations induced by RSS without using an independent baseline value and adjusted for time intervals (ΔMCAvT/ΔMAPT). We also examined whether this metric during each RSS transition were comparable between each other over a 5-min period. ΔMCAvT/ΔMAPTwas calculated using the minimum to maximum MCAv and MAP for each RSS performed at 0.05 Hz and 0.10 Hz. We compared averaged ΔMCAvT/ΔMAPTduring MAP increases and decreases in 74 healthy subjects [9 women; 32 ± 13 years]. ΔMCAvT/ΔMAPTwas lower for MAP increases than MAP decreases at 0.10 Hz RSS only (0.91 ± 0.34 vs. 1.01 ± 0.44 cm·s-1/mmHg; p = 0.0013). For both frequency and MAP direction, time during RSS had no effect on ΔMCAvT/ΔMAPT. This novel analytical method supports the use of the RSS model to evaluate the directional sensitivity of the pressure-flow relationship. These results contribute to the importance of considering the direction of MAP changes when evaluating dynamic cerebral autoregulation.News & NoteworthyRepeated squat-stand maneuvers are able to examine the directional sensitivity of the cerebral pressure-flow relationship. These maneuvers induce stable physiological cyclic changes where brain blood flow changes with blood pressure increases are buffered more than decreases. These results highlight the importance of considering directional blood pressure changes within cerebral autoregulation.
The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression
Authors: Gentile Alessandra , Bensimon-Brito Anabela , Priya Rashmi , Maischein Hans-Martin , Piesker Janett , Günther Stefan , Gunawan Felix , Stainier Didier Y.R. 
Published: December 2020

SummaryThe zinc finger transcription factor Snai1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3and neural crest delamination in vertebrates4. During cardiac development, Snai1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for Snai1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that Snai1b is required for myocardial wall integrity. Global loss ofsnai1bleads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions insnai1bmutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type andsnai1bmutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation ofdesmin b. We tested the role ofdesmin bin myocardial wall integrity and found that CM-specificdesmin boverexpression led to CM extrusion, recapitulating thesnai1bmutant phenotype. Altogether, these results indicate that Snai1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressingdesmin bexpression.
Corporal Punishment in Schools in the Jaffna District of Sri Lanka – A students’ view
Authors: Sathiadas M G , Antonyraja Annieston , Viswalingam Arunath , Arunthavavinajagamoorthy Shubanki 
Published: December 2020

AbstractPurpose:Corporal-punishment has been prevailing in Sri- Lanka despite the strict law against it. Objectives of this study was to find the prevalence of corporal punishment in schools and the knowledge, perceptions and actions in the children.Methods:A community based cross sectional descriptive study done among school students from Jaffna district using a pretested questionnaire containing 40 questions. Multistage stratified proportionate cluster sampling was used to recruit the students. Scoring systems were used to determine the knowledge and perception of Corporal-punishment. Data was analyzed using SPSS version 20.Results:A total of 1130 students were recruited with mean age of 17.58±0.5y. A total of 687(60.7%) said they received some form of corporal punishment at least once during the school term. Physical punishment (64.5%) was common followed by psychological (27.1%). Teachers (54.8%) were the main group involved in corporal-punishment. Mean score for the knowledge was 11.11 and a good knowledge score was seen in 37.3% of the students. Participants with good knowledge favored law against it (p value<0.05), take legal action (P value<0.05) and supported complete prohibition of it (P value<0.05). Nearly 2% (n=22) had good perception and 40.8% (n=461) had a more positive perception. Majority (86.3%) preferred an alternative way of discipline and felt it was detrimental to the future (89.5%).Conclusion:Corporal-punishment was experienced by majority of the students in school and the students were aware that it was illegal and those with good knowledge were willing to take legal action.
Robot-Assisted SpiderMass forin vivoReal-Time Topography Mass Spectrometry Imaging
Authors: Ogrinc Nina , Kruszewski Alexandre , Chaillou Paul , Saudemont Philippe , Lagadec Chann , Salzet Michel , Duriez Christian , Fournier Isabelle 
Published: December 2020

AbstractMass Spectrometry Imaging (MSI) has shown to bring invaluable information for biological and clinical applications. However, conventional MSI is generally performedex vivofrom tissue sections. Here, we develop a novel MS-based method forin vivomass spectrometry imaging. By coupling the SpiderMass technology - that providesin vivominimally invasive analysis – to a robotic arm of high accuracy, we demonstrate that images can be acquired from any surface by moving the laser probe above the surface. By equipping the robotic arm with a sensor, we are also able to both get the topography image of the sample surface and the molecular distribution, and then and plot back the molecular data, directly to the 3D topographical image without the need for image fusion. This is shown for the first time with the 3D topographic MS-Based whole-body imaging of a mouse. Enabling fast in vivo MSI bridged to topography pave the way for surgical applications to excision margins.