bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic Evolution of De Novo DNA Methyltransferases in Rodent and Primate Genomes
Authors: Molaro Antoine , Malik Harmit S , Bourc’his Deborah 
Published: February 2020

Abstract
Transcriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred ∼60 Ma in the last common ancestor of muroid rodents. Importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds have undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has instead evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result of an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo methylation enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMT3s in mammals.
Practical Speedup of Bayesian Inference of Species Phylogenies by Restricting the Space of Gene Trees
Authors: Wang Yaxuan , Ogilvie Huw A , Nakhleh Luay 
Published: February 2020

AbstractSpecies tree inference from multilocus data has emerged as a powerful paradigm in the postgenomic era, both in terms of the accuracy of the species tree it produces as well as in terms of elucidating the processes that shaped the evolutionary history. Bayesian methods for species tree inference are desirable in this area as they have been shown not only to yield accurate estimates, but also to naturally provide measures of confidence in those estimates. However, the heavy computational requirements of Bayesian inference have limited the applicability of such methods to very small data sets. In this article, we show that the computational efficiency of Bayesian inference under the multispecies coalescent can be improved in practice by restricting the space of the gene trees explored during the random walk, without sacrificing accuracy as measured by various metrics. The idea is to first infer constraints on the trees of the individual loci in the form of unresolved gene trees, and then to restrict the sampler to consider only resolutions of the constrained trees. We demonstrate the improvements gained by such an approach on both simulated and biological data.
Using miRNAs as diagnostic biomarkers for male infertility: opportunities and challenges
Authors: Vashisht A , Gahlay G K 
Published: February 2020

AbstractThe non-coding genome has been extensively studied for its role in human development and diseases. MicroRNAs (miRNAs) are small non-coding RNAs, which can regulate the expression of hundreds of genes at the post-transcriptional level. Therefore, any defects in miRNA biogenesis or processing can affect the genes and have been linked to several diseases. Male infertility is a clinical disorder with a significant number of cases being idiopathic. Problems in spermatogenesis and epididymal maturation, testicular development, sperm maturation or migration contribute to male infertility, and many of these idiopathic cases are related to issues with the miRNAs which tightly regulate these processes. This review summarizes the recent research on various such miRNAs and puts together the candidate miRNAs that may be used as biomarkers for diagnosis. The development of strategies for male infertility treatment using anti-miRs or miRNA mimics is also discussed. Although promising, the development of miRNA diagnostics and therapeutics is challenging, and ways to overcome some of these challenges are also reviewed.
Quantitative comparison of within-sample heterogeneity scores for DNA methylation data
Authors: Scherer Michael , Nebel Almut , Franke Andre , Walter Jörn , Lengauer Thomas , Bock Christoph , Müller Fabian , List Markus 
Published: February 2020

AbstractDNA methylation is an epigenetic mark with important regulatory roles in cellular identity and can be quantified at base resolution using bisulfite sequencing. Most studies are limited to the average DNA methylation levels of individual CpGs and thus neglect heterogeneity within the profiled cell populations. To assess this within-sample heterogeneity (WSH) several window-based scores that quantify variability in DNA methylation in sequencing reads have been proposed. We performed the first systematic comparison of four published WSH scores based on simulated and publicly available datasets. Moreover, we propose two new scores and provide guidelines for selecting appropriate scores to address cell-type heterogeneity, cellular contamination and allele-specific methylation. Most of the measures were sensitive in detecting DNA methylation heterogeneity in these scenarios, while we detected differences in susceptibility to technical bias. Using recently published DNA methylation profiles of Ewing sarcoma samples, we show that DNA methylation heterogeneity provides information complementary to the DNA methylation level. WSH scores are powerful tools for estimating variance in DNA methylation patterns and have the potential for detecting novel disease-associated genomic loci not captured by established statistics. We provide an R-package implementing the WSH scores for integration into analysis workflows.
Real-world Effectiveness of Sofosbuvir/Velpatasvir for Treatment of Chronic Hepatitis C in British Columbia, Canada: A Population-Based Cohort Study
Authors: Wilton James , Wong Stanley , Yu Amanda , Ramji Alnoor , Cook Darrel , Butt Zahid A , Alvarez Maria , Binka Mawuena , Darvishian Maryam , Jeong Dahn , Bartlett Sofia R , Pearce Margo E , Adu Prince A , Yoshida Eric M , Krajden Mel , Janjua Naveed Z 
Published: February 2020

Abstract

Background
Clinical trials show high efficacy of sofosbuvir/velpatasvir (SOF/VEL), but there are limited data from “real-world” settings. We aimed to evaluate SOF/VEL effectiveness for all hepatitis C virus (HCV) genotypes (GTs) in British Columbia (BC), Canada.

Methods
We used the BC Hepatitis Testers Cohort, which includes all HCV cases in the province (1990–2015) linked to administrative databases, including prescriptions to end of 2018. We measured sustained virologic response (SVR; negative RNA ≥10 weeks after treatment end) and identified characteristics associated with non-SVR. Conservatively, we excluded individuals with no assessment for SVR if their last RNA test after treatment initiation was negative (but included if positive).

Results
Of 2821 eligible participants, most were infected with GT1 (1076, 38.1%) or GT3 (1072, 38.0%), and a minority (278, 9.9%) were treated with RBV. SVR was 94.6% (2670/2821) overall and 94.5% (1017/1076) for GT1, 96.4% (512/531) for GT2, and 93.7% (1004/1072) for GT3. When disaggregated by GT, treatment regimen, and cirrhosis/treatment experience, SVR was lowest (30/40, 75.0%) among treatment-experienced GT3 individuals treated with RBV. Characteristics associated with non-SVR in multivariable analysis included younger age, RBV addition, and being a person with HIV (PWH) or who injects/injected drugs (PWID). When treatment regimen (±RBV) was removed from multivariable model, treatment experience was associated with non-SVR for GT3. Of 151 non-SVR individuals, 56.3% were nonvirological failures (treatment incomplete/no assessment for SVR) and 43.7% were virological failures (nonresponse/relapse). A disproportionately high percentage of non-SVR among PWID was due to nonvirological failure.

Conclusions
SOF/VEL was highly effective in this “real-world” population-based cohort. Additional support is required for PWID/PWH to reach SVR.
The Role of Healthcare Worker-Mediated Contact Networks in the Transmission of Vancomycin-Resistant Enterococci
Authors: Klein Eili Y , Tseng Katie K , Hinson Jeremiah , Goodman Katherine E , Smith Aria , Toerper Matt , Amoah Joe , Tamma Pranita D , Levin Scott R , Milstone Aaron M 
Published: February 2020

Abstract

Background
User- and time-stamped data from hospital electronic health records (EHRs) present opportunities to evaluate how healthcare worker (HCW)-mediated contact networks impact transmission of multidrug-resistant pathogens, such as vancomycin-resistant enterococci (VRE).

Methods
This is a retrospective analysis of incident acquisitions of VRE between July 1, 2016 and June 30, 2018. Clinical and demographic patient data were extracted from the hospital EHR system, including all recorded HCW contacts with patients. Contacts by an HCW with 2 different patients within 1 hour was considered a “connection”. Incident VRE acquisition was determined by positive clinical or surveillance cultures collected ≥72 hours after a negative surveillance culture.

Results
There were 2952 hospitalizations by 2364 patients who had ≥2 VRE surveillance swabs, 112 (4.7%) patients of which had incident nosocomial acquisitions. Patients had a median of 24 (interquartile range [IQR], 18–33) recorded HCW contacts per day, 9 (IQR, 5–16) of which, or approximately 40%, were connections that occurred &lt;1 hour after another patient contact. Patients that acquired VRE had a higher average number of daily connections to VRE-positive patients (3.1 [standard deviation {SD}, 2.4] versus 2.0 [SD, 2.1]). Controlling for other risk factors, connection to a VRE-positive patient was associated with increased odds of acquiring VRE (odds ratio, 1.64; 95% confidence interval, 1.39–1.92).

Conclusions
We demonstrated that EHR data can be used to quantify the impact of HCW-mediated patient connections on transmission of VRE in the hospital. Defining incident acquisition risk of multidrug-resistant organisms through HCWs connections from EHR data in real-time may aid implementation and evaluation of interventions to contain their spread.
Issues and Perspectives in Designing Clinical Trials for Negative Symptoms in Schizophrenia: Consensus Statements
Authors: Marder Stephen R , Davidson Michael , Zaragoza Silvia , Kott Alan , Khan Anzalee , Wang Xingmei , Velligan Dawn I , Umbricht Daniel , Luthringer Remy , Daniel David 
Published: February 2020

Abstract
Individuals from academia, the pharmaceutical industry, and regulators reevaluated earlier recommendations for the design of clinical trials for negative symptoms based on data from recent large trials. A session in February, 2018 at the International Society of CNS Clinical Trails and Methodology (ISCTM) annual meeting reviewed results from selected trials that reported findings between 2013 and 2018. The group reached a consensus on prior recommendations that should be reconsidered in future trials which included: (1) How can placebo effects be minimized? (2) Should global measures of negative symptoms be included? (3) Should a new drug targeting negative symptoms be tested in a monotherapy design or in an add-on design? (4) Can new information from negative symptom trials inform the selection of clinical outcome assessments (COA’s) for future trials? For each of these issues new data was evaluated, discussed by the group, and in some cases the earlier recommendations were revised.
A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys
Authors: Mitra Mayur S , Lancaster Karla , Adedeji Adeyemi O , Palanisamy Gopinath S , Dave Rutwij A , Zhong Fiona , Holdren Matthew S , Turley Shannon J , Liang Wei-Ching , Wu Yan , Meng Y Gloria , Vernes Jean-Michel , Schutten Melissa M 
Published: February 2020

Abstract
Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb.
Hide-and-seek with hoverflies: Merodon aureus – a species, a complex or a subgroup?
Authors: Vujić Ante , Šašić Zorić Ljiljana , Ačanski Jelena , Likov Laura , Radenković Snežana , Djan Mihajla , Milić Dubravka , Šebić Anja , Ranković Milica , Khaghaninia Samad 
Published: February 2020

AbstractIn order to disentangle the currently confused interpretations and nomenclature of Merodon aureus and M. aeneus, we have reviewed all existing type material and species names known to us as assigned synonyms of these taxa. We resolve M. aeneus as being a junior synonym of M. aureus. We designate a lectotype for M. aureus and a neotype for M. aeneus. Additionally, we provide evidence that M. aureus, together with two newly discovered taxa (M. calidus sp. nov. and M. ortus sp. nov.), represent a complex of cryptic species named the M. aureus species complex. This complex, together with the M. unicolor species complex and the species M. pumilus, is part of the M. aureus subgroup. The M. unicolor species complex comprises two cryptic species: M. unicolor and M. albidus sp. nov. The new species are described by applying an integrative taxonomic approach using several data types (COI and 28S rRNA genes, geometric morphometry of the wings, ecological and distributional data). Based on the COI gene sequence analysis and distributional data, the pupa previously described as an immature stage of the species M. aureus is redefined as an immature stage of the new species M. calidus. Speciation within the M. aureus subgroup is discussed in the context of the phylogeographic history in the studied region.
STAT1-dependent tolerance of intestinal viral infection
Authors: Filyk Heather A , Sharon Andrew J , Fonseca Nicolette M , Simister Rachel L , Yuen Wallace , Hardman Blair K , Robinson Hannah G , Seo Jung Hee , Rocha-Pereira Joana , Welch Ian , Neyts Johan , Crowe Sean A , Osborne Lisa C 
Published: February 2020

AbstractRecent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4+and CD8+T cell responses. In contrast to systemic viral pathogens that drive T cell mediated immunopathology in STAT1-deficient mice, our data indicates that loss of CD4+or CD8+T cells and their associated effector functions has no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound to limit viral replication prevented viral-induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell responses from innate immune-mediated restriction of viral replication that is necessary for intestinal viral tolerance.
Dopaminergic modulation of human inter-temporal choice: a diffusion model analysis using the D2-receptor-antagonist haloperidol
Authors: Wagner Ben , Clos Mareike , Sommer Tobias , Peters Jan 
Published: February 2020

AbstractThe neurotransmitter dopamine is implicated in diverse functions, including reward processing, reinforcement learning and cognitive control. The tendency to discount future rewards in value over time has long been discussed in the context of potential dopaminergic modulation. Here we examined the effect of a single dose of the D2 receptor antagonist Haloperidol (2mg) on temporal discounting. Our approach extends previous human pharmacological studies in two ways. First, we applied state-of-the-art computational modeling based on the drift diffusion model to comprehensively examine choice dynamics. Second, we examined dopaminergic modulation of reward magnitude effects on temporal discounting. Drift diffusion modeling revealed reduced temporal discounting and substantially faster non-decision times under Haloperidol. Temporal discounting was substantially increased for low vs. high reward magnitudes, but this magnitude effect was largely unaffected by Haloperidol. These results were corroborated by model-free analyses as well as modeling via more standard approaches using softmax action selection. We previously reported elevated caudate activation under Haloperidol in this sample of participants, supporting the idea that Haloperidol elevated dopamine neurotransmission, e.g. by blocking inhibitory feedback via presynaptic D2 autoreceptors. The present modeling results show that during inter-temporal choice, this leads to attenuated temporal discounting and increased response vigor (shorter non-decision times).
RNA binding protein hnRNP-U is required for physiological hypertrophy of skeletal muscle
Authors: Bagchi Debalina , Mason Benjamin D , Baldino Kodilichi , Li Bin , Lee Eun-Joo , Zhang Yuteng , Chu Linh Khanh , el Raheb Sherif , Sinha Indranil , Neppl Ronald L 
Published: February 2020

AbstractSkeletal muscle has the remarkable ability to modulate its mass in response to physiological changes associated with nutritional input, functional utilization, systemic disease, and age. A decreased responsiveness to anabolic stimuli is thought to contribute significantly to the loss of skeletal muscle mass and strength associated with sarcopenia, however the molecular mechanisms precipitating this are unclear. The signal transduction pathways that control the relative balance between anabolic and catabolic processes are tightly regulated at the transcriptional and post-transcriptional levels. Alternative splicing produces multiple protein isoforms from a single gene in a cell-type-specific manner and in response to environmental cues. We show that sustained activation of Akt1 inHnrnpudeficient mice leads to premature muscle wasting, in part, through impaired autophagy while providing mechanistic insights into the development of anabolic resistance.
Amphibians in the Brazilian Cerrado: diversity, research effort and conservation
Authors: Alves Enne Gomes , Pelicice Fernando Mayer 
Published: February 2020

AbstractIn order to investigate the relationship among amphibian diversity, research effort and conservation status across the Brazilian Cerrado, we carried out a scientometric analysis. Scientific publications were searched in international databases, totaling 72 studies, with 177 taxa recorded. Most studies occurred in the Southeast and Midwest regions of the country, followed by Northeast and North. The first two regions summed almost all taxa; controlling for sampling effort, however, northern regions appeared more diverse. Moreover, northern regions still preserve much of the original vegetation, while savanna in Southeast and Midwest regions has been significantly suppressed. These differences indicate particular geographical needs: immediate conservation efforts to protect diversity and restore savannas in Southeast and Midwest regions; and basic research effort (inventory) to uncover biodiversity in northern Cerrado areas.
Gut bacterial deamination of residual levodopa medication for Parkinson’s disease
Authors: van Kessel Sebastiaan P. , de Jong Hiltje R. , Winkel Simon L. , van Leeuwen Sander S. , Nelemans Sieger A. , Permentier Hjalmar , Keshavarzian Ali , Aidy Sahar El 
Published: February 2020

AbstractAromatic bacterial metabolites are attracting considerable attention due to their impact on gut homeostasis and host’s physiology.Clostridium sporogenesis a key contributor to the production of these bioactive metabolites in the human gut. Here, we show thatC. sporogenesdeaminates levodopa, the main treatment in Parkinson’s disease, and identify the aromatic aminotransferase responsible for the initiation of the deamination pathway. The deaminated metabolite from levodopa, 3-(3,4-dihydroxyphenyl)propionic acid, elicits an inhibitory effect on ileal motility in anex vivomodel. 3-(3,4-dihydroxyphenyl)propionic acid is detected in fecal samples of Parkinson’s disease patients on levodopa medication. Our data are of significant impact to the treatment of Parkinson’s disease, where constipation is reported as the most common gastrointestinal symptom. Overall, this study underpins the importance of the metabolic pathways of the gut microbiome involved in drug metabolism not only to preserve drug effectiveness, but also to avoid potential side effects of bacterial breakdown products of the unabsorbed residue of medication.
Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1
Authors: Casalino-Matsuda S. Marina , Chen Fei , Gonzalez-Gonzalez Francisco J. , Nair Aisha , Dib Sandra , Yemelyanov Alex , Gates Khalilah , Budinger G. R. Scott , Beitel Greg J. , Sporn Peter H. S. 
Published: February 2020

AbstractHypercapnia, elevation of the partial pressure of CO2in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO2increased IAV replication and inhibited antiviral gene and protein expression in macrophagesin vivoandin vitro. Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnia’s effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO2signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.