bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of histone acetyltranserase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a novel gain of function
Authors: Kumar Manish , Molkentine David , Molkentine Jessica , Bridges Kathleen , Xie Tongxin , Yang Liang , Hefner Andrew , Gao Meng , Frederick Mitchell J. , Seth Sahil , Abdelhakiem Mohamed , Beadle Beth M. , Johnson Faye , Wang Jing , Shen Li , Heffernan Timothy , Sheth Aakash , Ferris Robert , Myers Jeffrey N. , Pickering Curtis R. , Skinner Heath D. 
Published: April 2020

AbstractDespite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiation sensitizers for clinical use. We performedin vivoshRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identified the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Furtherin vitroandin vivostudies confirmed this phenomenon was due to repression of homologous recombination following DNA damage and can be reproduced using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targets by HAT inhibition. Additionally, mutations in CREBBP/EP300 were associated with recurrence following radiation, in several squamous cell carcinoma cohorts. These findings represent both a novel mechanism of treatment resistance and the potential for genomically-driven treatment.
Mapping the unique and shared functions of oncogenic KRAS and RIT1 with proteome and transcriptome profiling
Authors: Lo April , Holmes Kristin , Mundt Filip , Moorthi Sitapriya , Fung Iris , Fereshetian Shaunt , Watson Jackie , Carr Steven A. , Mertins Philipp , Berger Alice H. 
Published: April 2020

AbstractAberrant activation of RAS oncogenes is prevalent in lung adenocarcinoma, with somatic mutation ofKRASoccurring in ∼30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPaseRIT1in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present quantitative proteomic and transcriptomic profiles fromKRAS-mutant andRIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene. We find that both mutant KRAS and mutant RIT1 promote S6 kinase, AKT, and RAF/MEK signaling, and promote epithelial-to-mesenchymal transition and immune evasion via HLA protein loss. However, KRAS and RIT1 diverge in regulation of phosphorylation sites on EGFR, USO1, and AHNAK proteins. The majority of the proteome changes are related to altered transcriptional regulation, but a small subset of proteins are differentially regulated by both oncoproteins at the post-transcriptional level, including intermediate filament proteins, metallothioneins, and MHC Class I proteins. These data provide the first global, unbiased characterization of oncogenic RIT1 network and identify the shared and divergent functions of oncogenic RIT1 and KRAS GTPases in lung cancer.
Measuring antimicrobial use on dairy farms: a longitudinal method comparison study
Authors: Rees G. M. , Barrett D. C. , Sánchez-Vizcaíno F. , Reyher K. K. 
Published: April 2020

ABSTRACTAntimicrobial use on UK dairy farms is measured for surveillance purposes and utilizes veterinary sales data as a proxy for use. Two other methods of recording use have been used commonly on-farm: medicine waste bins and farm medicine records. However, none of these methods have been validated to measure antimicrobial use. The objectives of this research are to assess agreement between the 3 most common methods for measuring on-farm antimicrobial use with a pre-determined “gold standard” measure. Antimicrobial use was measured prospectively on 26 UK dairy farms using medicine waste bins into which participants placed all discarded medicine packaging for a 12-month period. At the end of 12 months, farm medicine records and veterinary sales data were obtained retrospectively for participating farms. The systematic difference between the mean on-farm antimicrobial use measured by each of the 3 methods with a gold standard measure was investigated using one-way repeated measures ANOVAs. Reliability and clinical relevance of the agreement between each pair of methods was quantified using the concordance correlation coefficient and the Bland-Altman method, respectively. Veterinary sales data shows excellent reliability for all forms of antimicrobial when compared with the gold standard. Medicine waste bins show moderate to excellent reliability for injectables, poor to good reliability for intramammaries and no agreement for other forms of antimicrobial. Farm medicine records do not show agreement for any form of antimicrobial when compared with the gold standard. The use of veterinary sales data as a proxy for on-farm antimicrobial use in the UK represents excellent statistical reliability and offers a clinically acceptable agreement with a gold standard method when used to measure both injectable antimicrobials and intramammary antimicrobials. These results have policy implications both nationally and internationally and are essential in quantifying the actual impact of agricultural antimicrobial use on both animal and human health.
Mouse Classical and Non-Classical Monocytes Express Comparable Levels of Chemokine Receptor CX3CR1
Authors: Cassetta Luca , Heideveld Esther , Matilionyte Gabriele , Fragkogianni Stamatina , van der Akker Emile , Kippen Nicolle , Kitamura Takanori , Pollard Jeffrey W. 
Published: April 2020

ABSTRACTHuman and mouse monocytes are divided into two subpopulations, classical (C-Mo) and non-classical (NC-Mo) monocytes. CC-chemokine receptor 2 (CCR2) and CX3C-chemokine receptor 1 (CX3CR1) are common features of monocyte subsets between humans and mice, i.e., C-Mo and NC-Mo are characterized as CCR2highCX3CR1lowand CCR2lowCX3CR1high. Since many studies utilize mouse models to investigate roles of monocytes in human diseases, it is important to understand the similarities and differences between human and mouse monocytic subsets. In this study, we show that the expression ofCx3cr1mRNA and CX3CR1 cell surface protein are different between circulating monocytic subsets in human but not in mice. We analyzed monocyte subsets in the blood using wild type C57BL/6 andCx3cr1-GFP knock-in (Cx3cr1GFP/+) reporter mice. We observed higherCx3cr1promoter activity indicated by GFP expression in NC-Mo compared to C-Mo. However, there were no differences between the subsets in CX3CR1 mRNA nor surface protein expression determined by anti-CX3CR1 antibody or binding of fluorophore-conjugated ligand. However in the bone marrow ofCx3cr1GFP/+mice, CX3CR1 expression was higher in NC-Mo compared to C-Mo, suggesting that mouse NC-Mo express higher level of CX3CR1 than C-Mo in the bone but this difference disappears in the blood. In contrast, human NC-Mo differentially expressed CX3CR1 compared to C-Mo in both blood and bone marrow. Given these findings, the discrepancy between promoter activity and protein levels should be considered when the roles of CX3CR1 are investigated in mouse models of human diseases.Summary sentenceIn this study, we show that the expression ofCx3cr1mRNA is different between circulating monocytic subsets in human but not in mice.
Morphology and Blood Metabolites Reflect Recent Spatial Differences Among Lake Winnipeg Walleye,Sander vitreus
Authors: Thorstensen Matt J. , Wiens Lilian M. , Jeffrey Jennifer D. , Klein Geoffrey M. , Jeffries Ken M. , Treberg Jason R. 
Published: April 2020

AbstractThe invasive rainbow smelt (Osmerus mordax) was an abundant food source for Lake Winnipeg walleye (Sander vitreus), especially in the north basin of the lake, until the smelt’s collapse in approximately 2013. We quantified changing length-at-age (≈ growth rates) and relative mass (≈ body condition) in Lake Winnipeg walleye caught for a gillnet index data set. Here, walleye showed smaller length-at-age, particularly in the north basin with young fish, over time. This approach to assessing growth suggests a constraint in the north basin fish, possibly a nutritional limitation between 2017 and 2018, that was not present in the south. We then analyzed a separate group of walleye (≥452 mm in fork length) sampled in 2017 as part of a large-scale tracking study, which had a similar slope in length-mass relationship to large walleye caught in that year for the gillnet index data. A panel of metabolites associated with amino acid metabolism and protein turnover was compared in whole blood. These metabolites revealed elevated essential amino acids and suggest protein degradation may be elevated in north basin walleye. Therefore, based on both growth estimates and metabolites associated with protein balance, we suggest there were spatially distinct separations affecting Lake Winnipeg walleye with decreased nutritional status of walleye in the north basin of Lake Winnipeg being of particular concern.
Structural interactions between pandemic SARS-CoV-2 spike glycoprotein and human Furin protease
Authors: Vankadari Naveen 
Published: April 2020

AbstractThe SARS-CoV-2 pandemic is an urgent global public health emergency and warrants investigating molecular and structural studies addressing the dynamics of viral proteins involved in host cell adhesion. The recent comparative genomic studies highlight the insertion of Furin protease site in the SARS-CoV-2 spike glycoprotein alerting possible modification in the viral spike protein and its eventual entry to host cell and presence of Furin site implicated to virulence. Here we structurally show how Furin interacts with the SARS-CoV-2 spike glycoprotein homotrimer at S1/S2 region, which underlined the mechanism and mode of action, which is a key for host cell entry. Unravelling the structural features of biding site opens the arena in rising bonafide antibodies targeting to block the Furin cleavage and have great implications in the development of Furin inhibitors or therapeutics.
Efficacy and Safety of Tradipitant in Diabetic and Idiopathic Gastroparesis: A Randomized, Placebo-Controlled Study
Authors: Carlin Jesse L. , Lieberman V. Rose , Dahal Arya , Keefe Madison S. , Xiao Changfu , Birznieks Gunther , Abell Thomas L. , Lembo Anthony , Parkman Henry P. , Polymeropoulos Mihael H. 
Published: April 2020

AbstractBackground and AimsThere is a high unmet need for the treatment of gastroparesis and studies of NK1-R antagonists suggest potential benefit in reducing the symptoms of nausea and vomiting. We hypothesized that tradipitant, an NK1-R antagonist, would be effective in treating patients with idiopathic or diabetic gastroparesis.MethodsIn a randomized, double-blind, placebo-controlled study across 47 U.S. sites, 152 gastroparesis patients were randomized to receive oral 85mg BID tradipitant (n=77) or placebo (n=75) daily for four weeks. Symptoms were assessed using a daily symptom dairy, Gastroparesis Cardinal Symptom Index (GCSI), and other patient reported questionnaires.ResultsPatients receiving tradipitant had a significant decrease in nausea score at Week 4 compared to placebo (−1.2 improvement vs −0.7, respectively, p=0.0099), and a significant increase in nausea-free days (28.8% increase on tradipitant vs 15.0% on placebo p=0.0160). Patients with both nausea and vomiting at baseline (n=101) showed an even greater decrease in nausea score (−1.4 improvement on tradipitant vs −0.4 on placebo p<0.0001) and an increase in nausea free days (32.3% improvement on tradipitant vs 7.6% on placebo p=0.0003). 32.9% of patients treated with tradipitant were nausea responders (average nausea score ≤ 1 at week 4) compared to 11.8% of patients on placebo (p=0.0013). 46.6% of patients treated with tradipitant had a greater than 1-point improvement in GCSI score compared to 23.5% of patients on placebo (p=0.0053).ConclusionsTradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. These robust efficacy results suggest tradipitant has the potential to become a useful pharmacological treatment for gastroparesis.
Cell-Type-Specific Expression of Renin-Angiotensin-System Components in the Human Body and Its Relevance to SARS-CoV-2 Infection
Authors: Suryawanshi Hemant , Morozov Pavel , Muthukumar Thangamani , tenOever Benjamin R. , Yamaji Masashi , Williams Zev , Tuschl Thomas 
Published: April 2020

AbstractWe have analyzed the cell-type-specific expression of the renin-angiotensin system (RAS) components across 141 cell types or subtypes as defined by single-cell RNA-seq (scRNA-seq) analysis. ACE2, one of the components of RAS, also facilitates SARS-CoV-2 entry into cells in cooperation with its associated protease TMPRSS2. Therefore, our analysis also contributes to the understanding of SARS-CoV-2 infection, spreading of the virus throughout the body, and potential viral interference with RAS in COVID-19 patients.
Evaluation of heating and chemical protocols for inactivating SARS-CoV-2
Authors: Pastorino Boris , Touret Franck , Gilles Magali , de Lamballerie Xavier , Charrel Remi N. 
Published: April 2020

AbstractClinical samples collected in COVID-19 patients are commonly manipulated in BSL-2 laboratories for diagnostic purpose. We used the French norm NF-EN-14476+A2 derived from the European standard EN-14885. To avoid the risk of exposure of laboratory workers, we showed that Triton-X100 must be added to guanidinium thiocyanate-lysis buffers to obtain a 6-log reduction of infectious virus. Although heating protocol consisting of 92°C-15min was more effective rather than 56°C-30min and 60°C-60min to achieve 6-log reduction, it is not amenable for molecular detection on respiratory specimens because of important decrease of detectable RNA copies in the treated samplevsuntreated sample. The 56°C-30min and 60°C-60min should be used for inactivation of serum / plasma samples for serology because of the 5log10 reduction of infectivity and low viral loads in blood specimens.
Cdk5 and GSK3β inhibit Fast Endophilin-Mediated Endocytosis
Authors: Ferreira Antonio P. A. , Casamento Alessandra , Roas Sara Carrillo , Panambalana James , Subramaniam Shaan , Schützenhofer Kira , Halff Els F. , Wah Hak Laura Chan , McGourty Kieran , Kittler Josef T. , Thalassinos Konstantinos , Martinvalet Denis , Boucrot Emmanuel 
Published: April 2020

ABSTRACTEndocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Parallel to Clathrin-mediated endocytosis, additional Clathrin-independent endocytic routes exist, including fast Endophilin-mediated endocytosis (FEME). The latter is not constitutively active but requires the activation of selected receptors. In cell culture, however, the high levels of growth factors in the regular culture media induce spontaneous FEME, which can be suppressed upon serum starvation. Thus, we predicted a role for protein kinases in this growth factor receptor-mediated regulation of the pathway. Using chemical and genetic inhibition, we found that Cdk5 and GSK3β are negative regulators of FEME. Their inhibition was sufficient to activate FEME promptly in resting cells and boosted the production of endocytic carriers containing β 1-adrenergic receptor, following dobutamine addition. We established that the kinases suppress FEME at several levels. They control Dynamin-1 and Dynein recruitment and sorting of cargo receptors such as Plexin A1 and ROBO1 into FEME carriers. They do so by antagonizing the binding of Endophilin to Dynamin-1 as well as to Collapsin response mediator protein 4 (CRMP4), a Plexin A1 adaptor. Cdk5 and GSK3β also hamper the binding and recruitment of Dynein onto FEME carriers by Bin1. Interestingly, we found that GSK3β binds to Endophilin, thus imposing a local regulation of FEME. Collectively, these findings place the two kinases as key regulators of FEME, licensing cells for rapid uptake by the pathway only upon when Cdk5 and GSK3β activity is low.
Noradrenergic circuits in the forebrain control affective responses to novelty
Authors: Lustberg Daniel , Tillage Rachel P. , Bai Yu , Pruitt Molly , Liles L. Cameron , Weinshenker David 
Published: April 2020

AbstractRationaleIn rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.ObjectiveWe sought to define the role of central NE transmission in neophilic and neophobic behaviors.MethodsWe assessed dopamine β-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions.ResultsDbh -/-mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued inDbh -/-mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL,Dbh -/-mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala.ConclusionThese findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.
Proliferation control of kidney interstitial cells
Authors: McCarthy Sarah S. , Gower Lindsey , Karolak Michele , England Alicia , Carroll Thomas , Oxburgh Leif 
Published: April 2020

ABSTRACTExpansion of interstitial cells in the adult kidney is a hallmark of chronic disease, whereas their proliferation during fetal development is necessary for organ formation. An intriguing difference between adult and neonatal kidneys is that the neonatal kidney has the capacity to control interstitial cell proliferation when the target number has been reached. In this study, we define the consequences of inactivating the TGFβ/Smad response in the interstitial cell lineage. We find that pathway inactivation through loss ofSmad4leads to over-proliferation of interstitial cells regionally in the kidney medulla. Genetic and molecular interaction studies showed that Smad3/4 participates in the Wnt/β-catenin signaling pathway, which is responsible for promoting proliferation of interstitial cells. Specifically,Smad4is required for the expression of the Wnt feedback inhibitorApcdd1, and based on these findings we propose a model for interstitial cell proliferation control in which the Wnt/β-catenin proliferative signal is attenuated by TGFβ/Smad signaling to ensure that proliferation ceases when the target number of interstitial cells has been reached in the neonatal medulla.Summary statementThis study describes a novel function for TGFβ signaling in the developing renal interstitium. Mice with Foxd1-Cre-mediated deletion of Smad4 have interstitial expansion and activated Wnt signaling.
Disentangling the determinants of transposable elements dynamics in vertebrate genomes using empirical evidences and simulations
Authors: Bourgeois Yann , Ruggiero Robert , Hariyani Imtiyaz , Boissinot Stéphane 
Published: April 2020

AbstractBackgroundThe interactions between transposable elements (TEs) and their hosts constitute one of the most profound co-evolutionary processes found in nature. The population dynamics of TEs depends on factors specific to each TE families, such as the rate of transposition and insertional preference, the demographic history of the host and the genomic landscape. How these factors interact has yet to be investigated holistically. Here we are addressing this question in the green anole (Anolis carolinensis) whose genome contains an extraordinary diversity of TEs (including non-LTR retrotransposons, SINEs, LTR-retrotransposons and DNA transposons).ResultsWe observe a positive correlation between recombination rate and TEs frequencies and densities for LINEs, SINEs and DNA transposons. For these elements, there was a clear impact of demography on TE frequency and abundance, with a loss of polymorphic elements and skewed frequency spectra in recently expanded populations. On the other hand, some LTR-retrotransposons displayed patterns consistent with a very recent phase of intense amplification. To determine how demography, genomic features and intrinsic properties of TEs interact we ran simulations using SLiM3. We determined that i) short TE insertions are not strongly counter-selected, but long ones are, ii) neutral demographic processes, linked selection and preferential insertion may explain positive correlations between average TE frequency and recombination, iii) TE insertions are unlikely to have been massively recruited in recent adaptation..ConclusionsWe demonstrate that deterministic and stochastic processes have different effects on categories of TEs and that a combination of empirical analyses and simulations can disentangle the effects of these processes.
Recruitment methods, recruitment outcomes and information credibility and sufficiency
Authors: Muduli Ashutosh , Trivedi Jeegnesh J. 
Published: April 2020

PurposeRecruiters’ decision to use recruitment methods (RMs) depends on several expected outcomes such as number applications, quality of applicants, speed of filling up vacancy, post joining job performance, absenteeism, commitment and satisfaction of the applicants. RMs may vary from each other in terms of its capability to communicate different type of information. The current research aims at exploring recruiter's intention to use RMs like job advertisement (JA), online recruitment (OLR) and social media in reference to several recruitment outcomes (ROs). Further, the role of information credibility and sufficiency (ICS) on recruiter's intention to use has been studied.Design/methodology/approachData were collected from 242 recruiters from the manufacturing and service sector of India. The survey instrument consists of RMs, recruitment outcome and credibility and satisfaction that are identified following the theory of planned behavior (TPB). Confirmatory factor analysis (CFA) was used for a simultaneous assessment of overall and specific elements of measurement validity and reliability. Structural equation modeling (SEM) is used to test the hypothesized model.FindingsThe result shows that RMs significantly relates with ROs. In detail, social media recruitment (SMR) significantly relates with pre ROs and post ROs; OLR significantly relates with pre ROs and post ROs and JA significantly relates post ROs. Only JA insignificantly relates with pre ROs. The result also supports the hypothesis that ICS acts as a mediator between the influences of RMs on ROs.Research limitations/implicationsThe result of the study has important theoretical and managerial implications. The theoretical implication is explained from the perspective of signaling theory (ST) and elaboration likelihood model (ELM) theory.Originality/valueThe study is unique as multiple RMs have been studied with reference to both pre and post ROs using the data collected from the recruiters.