bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Specific Inhibitory Antibodies for P450 Reaction Phenotyping of Investigational Drugs
Authors: Lasker Jerome Michael 
Published: April 2020

Identifying the CYP450 enzymes underlying metabolism of investigational drugs (i.e., P450 reaction phenotyping; PRP) is critical to the development of effective therapeutics. Information gained from such studies can: a) provide insight into structural modifications of test drugs in order to improve metabolic stability and; b) specify an estimate of drug‐drug interaction potential as well as that of interindividual and species differences in oxidative metabolism. CYP450 chemical inhibitors (e.g., a‐naphthoflavone and sulfaphenazole) are often used in reaction phenotyping studies but the outcome is sometimes equivocal due to the non‐specific effects of these chemical agents plus their capacity to undergo P450‐dependent catabolism. In contrast, inhibitory P450 antibodies offer high specificity and irreversibility, and may thus represent a superior approach for characterizing individual P450 enzyme involvement in drug metabolism. We recently developed a compilation of highly‐specific polyclonal and monoclonal antibodies to the CYP450s comprising the major oxidative drug‐metabolizing enzymes in human liver, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (aka CYP ImmunoInhibit antibodies). As shown here, each of these antibodies proved capable of eliciting > 80% inhibition of probe drug metabolism by the cognate P450 antigens in human liver microsomes (HLMx), while giving insignificant effects on different CYP450s (Figure
1). The inhibition observed with each of the six CYP450 antibodies was not only highly‐specific but was also dose‐dependent, with maximal inhibition (80–90%) achieved at IgG:microsomal protein ratios ranging from 0.1 mg/mg to 3 mg/mg (Figure
2). Control (pre‐immune) antibodies had no effect on substrate metabolism. Such results show that inhibitory antibodies coupled with HLMx represent an alternative and powerful approach to chemical inhibitors for evaluating involvement of specific P450 enzymes in the hepatic metabolism of investigational drugs. Interestingly, studies ongoing with CYP ImmunoInhibit antibodies and MetMax™ cryopreserved human hepatocytes, which are liver cells that have been permeabilized and cryopreserved, have given analogous results to those achieved with HLMx. The utilization of inhibitory antibodies with HLMx represents an accurate model for PRP of new therapeutics due to the specificity of these immunoreagents, and the irreversible nature of the inhibition achieved, an important benefit when working with metabolically‐stable test agents.Specific Inhibition of Microsomal Drug Metabolism by CYP ImmunoInhibit AntibodiesFigure 1Dose‐Response Inhibition of Microsomal Drug Metabolism by CYP ImmunoInhibit AntibodiesFigure 2
White angico gum reduces the mast cell count in the duodenum and jejunum of mice subjected to intestinal mucositis
Authors: Pimenta Helder Bindá , Menslin Kimberlly , Cunha João Luiz , Nunes João Victor , Oliveira Ana Carolina , da Silva Stephany Caroline , Biason Giovanna , ALVES Ronny Helson , Vidinha Alice Cristina , Lopes Matheus , Santos Victor Rodrigo , Queiroz Herdeson Araújo , de Farias Sérgio Augusto , Nicolau Júlia Fernanda Alencar , de Carvalho Vale Larice , Barbosa Maria Lucianny Lima , Cerqueira Gilberto Santos 
Published: April 2020

Intestinal mucositis was induced by the administration of 5‐FU in a single dose of 450mg/kg on the first day of the protocol in Swiss mice, and groups of animals that received dosages of angico branco were treated between the second and the fifth day, culminating in euthanasia and removal of intestinal segments for further analysis. Initially, through histopathological and morphometric findings, the severity of mucositis was demonstrated in this study, through aspects related to tissue architecture, focusing on the reduction and vacuolization of intestinal villi, crypt necrosis, infiltration of inflammatory cells, loss of inflammation cell architecture, decreased villus/crypt ratio, caused in the group of animals that received the 5‐FU dose. However, the group of animals that were treated with angico branco gum at a dose of 400mg/kg, after induction of intestinal mucositis, attenuation of these deleterious effects promoted by 5‐FU was observed, among which we can mention: less inflammatory infiltrate, maintenance of cellular architecture, attenuation of villus shortening and crypt depth, decrease of crypt necrosis, also evidenced by the better villus/crypt ratio. These effects, however, were not seen in the ileum. Treatment with white angelic gum at doses of 100 mg/kg; 200 mg/kg and 400 mg/kg promoted a statistically significant reduction (p <0.05) in the number of mast cells when confronted with the 5‐FU group in the duodenum and jejunum. In contrast, treatment with white angico gum reversed the mastocytosis observed by the increase in mast cell count in the intestinal segments of animals submitted to mucositis. In addition, the saline group did not show an increase in mast cells when compared to the group with 5‐FU. Studies that evaluated the role of mast cells in mucositis also revealed the participation of these substances in the course of intestinal mucositis (PEREIRA JUNIOR, 2017; MIRANDA, 2018). The study by Nogueira et al. (2017) also demonstrated a significant increase in the number of total and degranulated mast cells in the intestinal segments of animals subjected to irinotecan‐induced intestinal mucositis, with a release of pro‐inflammatory mediators in the inflammatory condition. Through the results found in this study it can be concluded that the gum of angico reduced the mast cell count and preserved the number of goblet cells after induction of intestinal mucositis induced by 5‐FU in mice.White angico gum reduces the mast cell count in the duodenum, jejunum of mice subjected to intestinal mucositis induced by 5‐FU.Figure 1
Exercise‐induced Extracellular Vesicles’ Effect on Stress.
Authors: Yoon Kyeong Jin , Cho Hae-Sung , Lee WonSang , Moon HyoYoul 
Published: April 2020

Modern society changes faster and more complicated. It causes stress on mentally and physically. Especially stress can increase anxiety. The evidence that anxiety is associated with mental disorder such as depression and suicide is increasing. This phenomenon elevates social burden in public health.Exercise induces releasing extracellular vesicles (EVs) into circulation system that can be signaling molecules between organs. EVs have micro RNAs (miRNA) that regulate genes through inhibiting translation or degrading messenger RNA. Also, previous studies found that EVs can cross the blood‐brain barrier and it may be the role of neurotransmitters. However, the underlying mechanism of EVs on stress is not fully elucidated.To investigate the direct role of exercise‐derived EVs on brain function, we isolated the EVs from serum of sedentary or voluntary exercised mice. Then we analyzed the behavioral changes with chronic unpredictable mild stress (CUMS) induced anxiety mice after administration of total 0.3 ug of exercise or sedentary derived EVs into the left cerebral ventricle. We found that exercise derived EVs reduced the symptom of anxiety in a nest building test compared to control groups while there were no differences in the rotarod test or oft between groups. Furthermore, we observed that exercise‐derived EVs enhanced the neurogenic markers such as NOR1 and PAX6.We further characterized the changes of miRNA profile packaged in serum EVs after 4 weeks of voluntary exercise. miRNA sequencing results showed that 82 miRNAs (46 genes up and 36 genes down) changed by exercise. Using bioinformatics tools, we found that 17 miRNAs were commonly related with response to oxygen level. Among 8353 predicted targeting genes regulated by these 17 miRNAs, we selected 190 genes which were overlapped above 4 miRNAs. 13.04% of 190 genes were related with central nervous system neuron differentiation and TOR signaling, respectively and 8.7% of genes connected with sarcoplasmic reticulum.These results suggest that exercise‐derived EVs may be involved in anti‐anxiety like effect of exercise partially via neurogenesis. We believe our findings can propose the possibility of therapeutic strategy through exercise‐derived EVs in anxiety disorder.Support or Funding InformationThis work was supported by the National Research Foundation (NRF, 700‐20190019), Korea Mouse Phenotype Center (NRF, 2019M3A9D5A01102794) and Research Resettlement Fund for the new faculty of Seoul National University.Characters of Extracellular vehicles.Figure 1Injection of EVs in stress treated mice.Figure 2
Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City Region
Authors: Maurano Matthew T. , Ramaswami Sitharam , Zappile Paul , Dimartino Dacia , Boytard Ludovic , Ribeiro-dos-Santos André M. , Vulpescu Nicholas A. , Westby Gael , Shen Guomiao , Feng Xiaojun , Hogan Megan S. , Ragonnet-Cronin Manon , Geidelberg Lily , Marier Christian , Meyn Peter , Zhang Yutong , Cadley John , Ordoñez Raquel , Luther Raven , Huang Emily , Guzman Emily , Arguelles-Grande Carolina , Argyropoulos Kimon V. , Black Margaret , Serrano Antonio , Call Melissa E. , Kim Min Jae , Belovarac Brendan , Gindin Tatyana , Lytle Andrew , Pinnell Jared , Vougiouklakis Theodore , Chen John , Lin Lawrence H. , Rapkiewicz Amy , Raabe Vanessa , Samanovic Marie I. , Jour George , Osman Iman , Aguero-Rosenfeld Maria , Mulligan Mark J. , Volz Erik M. , Cotzia Paolo , Snuderl Matija , Heguy Adriana 
Published: April 2020

AbstractEffective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.
Dynamic Detection of Delayed Cerebral Ischemia Using Machine Learning
Authors: Megjhani Murad , Terilli Kalijah , Alkhachroum Ayham , Roh David J. , Agarwal Sachin , Connolly E. Sander , Velazquez Angela , Boehme Amelia , Claassen Jan , Park Soojin 
Published: April 2020

AbstractObjectiveTo develop a machine learning based tool, using routine vital signs, to assess delayed cerebral ischemia (DCI) risk over time.MethodsIn this retrospective analysis, physiologic data for 540 consecutive acute subarachnoid hemorrhage patients were collected and annotated as part of a prospective observational cohort study between May 2006 and December 2014. Patients were excluded if (i) no physiologic data was available, (ii) they expired prior to the DCI onset window (< post bleed day 3) or (iii) early angiographic vasospasm was detected on admitting angiogram. DCI was prospectively labeled by consensus of treating physicians. Occurrence of DCI was classified using various machine learning approaches including logistic regression, random forest, support vector machine (linear and kernel), and an ensemble classifier, trained on vitals and subject characteristic features. Hourly risk scores were generated as the posterior probability at timet. We performed five-fold nested cross validation to tune the model parameters and to report the accuracy. All classifiers were evaluated for good discrimination using the area under the receiver operating characteristic curve (AU-ROC) and confusion matrices.ResultsOf 310 patients included in our final analysis, 101 (32.6%) patients developed DCI. We achieved maximal classification of 0.81 [0.75-0.82] AU-ROC. We also predicted 74.7 % of all DCI events 12 hours before typical clinical detection with a ratio of 3 true alerts for every 2 false alerts.ConclusionA data-driven machine learning based detection tool offered hourly assessments of DCI risk and incorporated new physiologic information over time.
COVID-19-Associated Acute Disseminated Encephalomyelitis – A Case Report
Authors: Zhang Tianshu , Rodricks Michael B. , Hirsh Ellen 
Published: April 2020

AbstractWe present the first described case of acute disseminated encephalomyelitis (ADEM) in a COVID-19 patient. The clinical features with head CT and brain MRI changes were described. Our described case is an atypical presentation of the novel coronavirus in a young patient and is illustrative of the possible approaches to explore the treatable differential etiologies.
Smoking does not alter treatment effect of intravenous thrombolysis in mild to moderate acute ischemic stroke – a Dutch String-of-Pearls Institute (PSI) Stoke Study
Authors: Kufner Anna , Ebinger Martin , Luijckx Gert Jan , Endres Matthias , Siegerink Bob ,   Dutch String-of-Pearls Stroke Study Group
Published: April 2020

AbstractBackgroundThe smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject have yielded contradictory results and an interaction analysis of exposure to smoking and thrombolysis in a large, multicenter database is lacking.MethodsConsecutive AIS patients admitted within 12 hours of symptom onset between 2009 and 2014 from the prospective, multicenter stroke registry (Dutch String-of-Pearls Stroke Study) were included for this analysis. We performed a generalized linear model for functional outcome three months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: smoking, hypertension, atrial fibrillation, stroke severity, and stroke etiology.ResultsOut of 468 patients, 30.6% were smokers and median baseline NIHSS was 3 (interquartile range 1-6). Smoking alone had a crude and adjusted relative risk (RR) of 0.99 (95% CI 0.89-1.10) and 0.97 (95%CI 0.87-1.01) for good outcome (modified Rankin Score ≤2), respectively. A combination of exposure variables (smoking and thrombolysis) did not change the results significantly (crude RR 0.87 [95% CI 0.74-1.03], adjusted RR 1.1 [95%CI 0.93-1.33]). Smoking alone had an adjusted RR of 1.2 (95% CI 0.6-2.7) for recanalization following thrombolysis (N=88).ConclusionsIn patients with mild to moderate AIS admitted within 12 hours of symptom onset, smoking did not modify treatment effect of thrombolysis.
A scientometric overview of CORD-19
Authors: Colavizza Giovanni , Costas Rodrigo , Traag Vincent A. , van Eck Nees Jan , van Leeuwen Thed , Waltman Ludo 
Published: April 2020

AbstractAs the COVID-19 pandemic unfolds, researchers from all disciplines are coming together and contributing their expertise. CORD-19, a dataset of COVID-19 and coronavirus publications, has been made available along-side calls to help mine the information it contains and to create tools to search it more effectively. We analyse the delineation of the publications included in CORD-19 from a scientometric perspective. Based on a comparison to the Web of Science database, we find that CORD-19 provides an almost complete coverage of research on COVID-19 and coronaviruses. CORD-19 contains not only research that deals directly with COVID-19 and coronaviruses, but also research on viruses in general. Publications from CORD-19 focus mostly on a few well-defined research areas, in particular: coronaviruses (primarily SARS-CoV, MERS-CoV and SARS-CoV-2); public health and viral epidemics; molecular biology of viruses; influenza and other families of viruses; immunology and antivirals; clinical medicine. CORD-19 publications that appeared in 2020, especially editorials and letters, are disproportionately popular on social media. While we fully endorse the CORD-19 initiative, it is important to be aware that CORD-19 extends beyond research on COVID-19 and coronaviruses.
Harmful DNA:RNA hybrids are formedin cisand in a Rad51-independent manner
Authors: Lafuente-Barquero Juan , Martin-Alonso Marta San , Gómez-González Belén , Aguilera Andrés 
Published: April 2020

ABSTRACTDNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule producedin ciswith its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules producedin transin a Rad51-mediated reaction. Here, we tested the possibility that such DNA:RNA hybrids producedin transconstitute a source of recombinogenic DNA damage taking advantage of Rad51-independent single-strand annealing recombination assays and new constructs designed to induce expression of mRNA transcriptsin transin the yeastSaccharomyces cerevisiae.We show that unscheduled and recombinogenic DNA:RNA hybrids are formed incisduring transcription and in a Rad51-independent manner.
Surface electrostatics govern the emulsion stability of biomolecular condensates
Authors: Welsh Timothy J. , Krainer Georg , Espinosa Jorge R. , Joseph Jerelle A. , Sridhar Akshay , Jahnel Marcus , Arter William E. , Saar Kadi L. , Alberti Simon , Collepardo-Guevara Rosana , Knowles Tuomas P.J. 
Published: April 2020

AbstractLiquid–liquid phase separation underlies the formation of biological condensates. Physically, such systems are microemulsions which have a general propensity to fuse and coalesce; however, many condensates persist as independent droplets inside cells. This stability is crucial for their functioning, but the physicochemical mechanisms that control the emulsion stability of condensates remain poorly understood. Here, by combining single-condensate zeta potential measurements, optical microscopy, tweezer experiments, and multiscale molecular modelling, we investigate how the forces that sustain condensates impact their stability against fusion. By comparing PR25:PolyU and FUS condensates, we show that a higher condensate surface charge correlates with a lower fusion propensity, and that this behavior can be inferred from their zeta potentials. We reveal that overall stabilization against fusion stems from a combination of repulsive forces between condensates and the effects that surface electrostatics have on lowering surface tension, thus shedding light on the molecular determinants of condensate coalescence.
A method for validating the accuracy of NMR protein structures
Authors: Fowler Nicholas J. , Sljoka Adnan , Williamson Mike P. 
Published: April 2020

AbstractWe present a method, Accuracy of NMR Structures using Random Coil Index and Rigidity (ANSURR), that measures the accuracy of NMR protein structures. It provides a residue-by-residue comparison of two measures of local rigidity: the Random Coil Index [RCI] (a measure of the extent to which backbone chemical shifts adopt random coil values); and local rigidity predicted by mathematical rigidity theory using the computational method Floppy Inclusion and Rigid Substructure Topology [FIRST], calculated from an NMR structural model. We compare RCI and FIRST using acorrelation score(which assesses the location of secondary structure), and anRMSD score(which measures overall rigidity, and mainly assesses hydrogen bond correctness). We test the performance of ANSURR using: (a) structures refined in explicit solvent, which have much better RMSD score than unrefined structures, though similar correlation; (b) decoy structures generated for 89 NMR structures. The experimental NMR structures are usually better, though helical and sheet structures behave differently; (c) conventional predictors of structural accuracy such as number of restraints per residue, restraint violations, energy of structure, RMSD of the ensemble (precision of the calculation), Ramachandran distribution, and clashscore. Comparisons of NMR to crystal structures show that secondary structure is equally accurate in both, but crystal structures tend to be too rigid in loops, whereas NMR structures tend to be too floppy overall.
SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology
Authors: Ogando Natacha S. , Dalebout Tim J. , Zevenhoven-Dobbe Jessika C. , Limpens Ronald W. , van der Meer Yvonne , Caly Leon , Druce Julian , de Vries Jutte J. C. , Kikkert Marjolein , Bárcena Montserrat , Sidorov Igor , Snijder Eric J. 
Published: April 2020

ABSTRACTThe sudden emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 from the Chinese province of Hubei and its subsequent pandemic spread highlight the importance of understanding the full molecular details of coronavirus infection and pathogenesis. Here, we compared a variety of replication features of SARS-CoV-2 and SARS-CoV and analysed the cytopathology caused by the two closely related viruses in the commonly used Vero E6 cell line. Compared to SARS-CoV, SARS-CoV-2 generated higher levels of intracellular viral RNA, but strikingly about 50-fold less infectious viral progeny was recovered from the culture medium. Immunofluorescence microscopy of SARS-CoV-2-infected cells established extensive cross-reactivity of antisera previously raised against a variety of nonstructural proteins, membrane and nucleocapsid protein of SARS-CoV. Electron microscopy revealed that the ultrastructural changes induced by the two SARS viruses are very similar and occur within comparable time frames after infection. Furthermore, we determined that the sensitivity of the two viruses to three established inhibitors of coronavirus replication (Remdesivir, Alisporivir and chloroquine) is very similar, but that SARS-CoV-2 infection was substantially more sensitive to pre-treatment of cells with pegylated interferon alpha. An important difference between the two viruses is the fact that - upon passaging in Vero E6 cells - SARS-CoV-2 apparently is under strong selection pressure to acquire adaptive mutations in its spike protein gene. These mutations change or delete a putative ‘furin-like cleavage site’ in the region connecting the S1 and S2 domains and result in a very prominent phenotypic change in plaque assays.
Consumption of artificially sweetened beverages during pregnancy impacts infant gut microbiota and body mass index
Authors: Laforest-Lapointe Isabelle , Becker Allan B. , Mandhane Piushkumar J. , Turvey Stuart E. , Moraes Theo J. , Sears Malcolm R. , Subbarao Padmaja , Sycuro Laura K. , Azad Meghan B. , Arrieta Marie-Claire 
Published: April 2020

ABSTRACTArtificial sweetener consumption by pregnant women has been associated with an increased risk of infant obesity, but the underlying mechanisms are unknown. We aimed to determine if maternal consumption of artificially sweetened beverages (ASB) during pregnancy is associated with modifications of infant gut bacterial community composition during the first year of life, and whether these alterations are linked with infant body mass index (BMI) at one year of age. This research included 100 infants from the prospective Canadian CHILD Cohort Study, selected based on maternal ASB consumption during pregnancy (50 non-consumers and 50 daily consumers). We identified four microbiome clusters, of which two recapitulated the maturation trajectory of the infant gut bacterial communities from immature to mature and two deviated from this trajectory. Maternal ASB consumption was associated with the depletion of several Bacteroides sp. and higher infant BMI. As we face an unprecedented rise in childhood obesity, future studies should evaluate the causal role of gut microbiota in the association between maternal ASB consumption, infant development and metabolism, and body composition.