bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpreting Mendelian randomization estimates of the effects of categorical exposures such as disease status and educational attainment
Authors: Howe Laurence J , Tudball Matthew , Smith George Davey , Davies Neil M 
Published: December 2020

AbstractMendelian randomization has been previously used to estimate the effects of binary and ordinal categorical exposures - e.g. type 2 diabetes or educational attainment defined by qualification - on outcomes. Binary and categorical phenotypes can be modelled in terms of liability, an underlying latent continuous variable with liability thresholds separating individuals into categories. Genetic variants typically influence an individual’s categorical exposure via their effects on liability, thus Mendelian randomization analyses with categorical exposures will capture effects of liability which act independent of exposure category.We discuss how groups where the categorical exposure is invariant can be used to detect liability effects acting independently of exposure category. For example, associations between an adult educational attainment polygenic score (PGS) and BMI measured before the minimum school leaving age (e.g. age 10), cannot indicate the effects of years in full-time education on this outcome. Using UK Biobank data, we show that a higher education PGS is strongly associated with lower smoking initiation and higher glasses use at age 15. These associations were replicated in sibling models. An orthogonal approach using the raising of the school leaving age (ROSLA) policy change found that individuals who chose to remain in education to age 16 before the reform likely had higher liability to educational attainment than those who were compelled to remain in education to 16 after the reform, and had higher income, decreased cigarette smoking, higher glasses use and lower deprivation in adulthood. These results suggest that liability to educational attainment associates with health and social outcomes independent of years in full-time education.Mendelian randomization studies with non-continuous exposures should be interpreted in terms of liability, which may affect the outcome via changes in exposure category and/or independently.
A gene regulatory network critical for axillary bud dormancy directly controlled by Arabidopsis BRANCHED1
Authors: van Es Sam W. , Muñoz-Gasca Aitor , Romero-Campero Francisco J. , González-Grandío Eduardo , de los Reyes Pedro , Tarancón Carlos , van Dijk Aalt D.J. , van Esse Wilma , Angenent Gerco C. , Immink Richard , Cubas Pilar 
Published: December 2020

AbstractThe control of branch outgrowth is critical for plant fitness, stress resilience and crop yield. The Arabidopsis thaliana transcription factor BRANCHED1 (BRC1) plays a pivotal role in this process as it integrates signals that inhibit axillary bud growth to control shoot branching. Despite the remarkable activity of BRC1 as a potent growth inhibitor, the mechanisms by which it promotes and maintains bud dormancy are still largely unknown.Here we combine ChIP-seq, transcriptomic and systems biology approaches to characterise the BRC1-regulated gene network. We identify a group of BRC1 direct target genes encoding transcription factors (BTFs) that orchestrate, together with BRC1, an intricate transcriptional network enriched in abscisic acid signalling components. The BRC1 network is enriched in feed-forward loops and feed-back loops, robust against noise and mutation, reversible in response to stimuli, and stable once established. This knowledge is fundamental to adapt plant architecture and crop production to ever-changing environmental conditions.
Genomic surveillance framework and global population structure forKlebsiella pneumoniae
Authors: Lam Margaret M. C. , Wick Ryan R. , Watts Stephen C. , Cerdeira Louise T. , Wyres Kelly L. , Holt Kathryn E. 
Published: December 2020

ABSTRACTK. pneumoniaeis a leading cause of antimicrobial-resistant (AMR) healthcare-associated infections, neonatal sepsis and community-acquired liver abscess, and is associated with chronic intestinal diseases. Its diversity and complex population structure pose challenges for analysis and interpretation ofK. pneumoniaegenome data. Here we introduce Kleborate, a tool for analysing genomes ofK. pneumoniaeand its associated species complex, which consolidates interrogation of key features of proven clinical importance. Kleborate provides a framework to support genomic surveillance and epidemiology in research, clinical and public health settings. To demonstrate its utility we apply Kleborate to analyse publicly availableKlebsiellagenomes, including clinical isolates from a pan-European study of carbapenemase-producingKlebsiella, highlighting global trends in AMR and virulence as examples of what could be achieved by applying this genomic framework within more systematic genomic surveillance efforts. We also demonstrate the application of Kleborate to detect and typeK. pneumoniaefrom gut metagenomes.
Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain
Authors: Playfoot Christopher J. , Duc Julien , Sheppard Shaoline , Dind Sagane , Coudray Alexandre , Planet Evarist , Trono Didier 
Published: December 2020

AbstractTransposable elements (TEs) constitute 50% of the human genome and many have been co-opted throughout human evolution due to gain of advantageous regulatory functions controlling gene expression networks. Several lines of evidence suggest these networks can be fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed ‘transposcription’) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking.In order to elucidate the spatiotemporal transposcriptome of the developing human brain, we have analysed two independent RNA-seq datasets encompassing 16 distinct brain regions from eight weeks post-conception into adulthood. We reveal an anti-correlated, KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. We also demonstrate experimentally that a co-opted antisense L2 element drives temporal protein re-localisation away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its potential importance throughout neurotypical human brain development.
Deep learning classification of canine behavior using a single collar-mounted accelerometer: Real-world validation
Authors: Chambers Robert D. , Yoder Nathanael C. , Carson Aletha B. , Junge Christian , Allen David E. , Prescott Laura M. , Bradley Sophie , Wymore Garrett , Lloyd Kevin , Lyle Scott 
Published: December 2020

AbstractCollar-mounted canine activity monitors can use accelerometer data to estimate dog activity levels, step counts, and distance traveled. With recent advances in machine learning and embedded computing, much more nuanced and accurate behavior classification has become possible, giving these affordable consumer devices the potential to improve the efficiency and effectiveness of pet healthcare. Here we describe a novel deep learning algorithm that classifies dog behavior at sub-second resolution using commercial pet activity monitors. We built machine learning training databases from over 5,000 videos of over 2,500 dogs and ran the algorithms in production on over 11 million days of device data. We then surveyed project participants representing 10,550 dogs, they provided us 163,110 event responses to validate real-world detection of eating and drinking behavior. The resultant algorithm displayed a sensitivity and specificity for detecting drinking behavior (0.949 and 0.999, respectively) and eating behavior (0.988, 0.983). We also demonstrated detection of licking, petting, rubbing, scratching, and sniffing. We show that the devices’ position on the collar has no measurable impact on performance. In production, users reported a true positive rate of 95.3% for eating (among 1,514 users), and of 94.9% (among 1,491 users) for drinking. The study demonstrates the accurate detection of important health-related canine behaviors using a collar-mounted accelerometer. We trained and validated our algorithms on a large and realistic training dataset, and we assessed and confirmed accuracy in production via user validation.
A high-throughput metabolic microarray assay reveals antibacterial effects of black and red raspberries and blackberries againstHelicobacter pyloriinfection
Authors: Goodman Candace , Lyon Katrina , Scotto Aitana , Roe Mandi M. , Moghimpour Farimah , Sebrell T. Andrew , Gentry Andrew B. , Bala Ganesh , Stoner Gary , Bimczok Diane 
Published: December 2020

AbstractHelicobacter pyloriis an important bacterial pathogen that causes chronic infection of the human stomach, leading to gastritis, peptic ulcer disease and gastric cancer. Treatment with appropriate antibiotics can eliminateH. pyloriinfection and reduce the risk for severe disease outcomes. However, sinceH. pyloriis becoming increasingly resistant to standard antibiotic regimens, novel treatment strategies are needed. Previous studies have demonstrated that black and red berries may have antibacterial properties. Therefore, we analyzed organic extracts and powders from black and red raspberries and blackberries and determined their antibacterial effects on multipleH. pyloristrains. We used high-performance liquid chromatography to measure berry anthocyanins, which are considered the major active ingredients. To monitor antibiotic effects of the berry preparations onH. pylori, we developed a high-throughput metabolic growth assay based on the OmniLog™ system. All berry preparations tested had significant bactericidal effectsin vitro, with MIC90values ranging from 0.49 to 4.17%. We next used human gastric epithelial organoids to evaluate biocompatibility of the berry preparations and showed that black raspberry extract, which had the strongest antimicrobial activity, was non-toxic at the concentration required for complete bacterial growth inhibition. To determine whether dietary black raspberry application could eliminateH. pyloriinfectionin vivo, mice were infected withH. pyloriand then were placed on a diet containing 10% black raspberry powder. However, this treatment did not significantly impact bacterial infection rates or gastric pathology. In summary, our data indicate that black and red raspberry and blackberry products have potential applications in the treatment and prevention ofH. pyloriinfection, because of their antibacterial effects and good biocompatibility. However, delivery and formulation of berry compounds needs to be optimized to achieve significant antibacterial effectsin vivo.
Exposure to Renin-Angiotensin System Inhibitors Is Associated with Reduced Mortality of Older Hypertensive Covid-19 Patients
Authors: Gori Mauro , Berzuini Carlo , D’Elia Emilia , Ghirardi Arianna , Bernardinelli Luisa , Gavazzi Antonello , Balestrieri Giulio , Giammarresi Andrea , Trevisan Roberto , Di Marco Fabiano , Bellasi Antonio , Amoroso Mariangela , Raimondi Federico , Novelli Luca , Magro Bianca , Mangia Gianpaolo , Lorini Ferdinando L. , Guagliumi Giulio , Fagiuoli Stefano , Parati Gianfranco , Senni Michele 
Published: December 2020

Abstract
From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied 688 patients with arterial hypertension (254 deaths) to assess whether use of renin-angiotensin system inhibitors (RASIs) prior to hospital admission affects mortality from Covid-19. Prior use of RASIs was associated with a lower mortality in the over-68 group of patients, whereas no evidence of a similar effect (whether protective or adverse) was found in the younger group. There was positive relative excess due to a statistically significant (p =0.001) interaction between prior RASI exposure and an age greater than 68 years, corresponding to a positive relative excess risk. Next we used the subgroup of 411 hypertensive patients older than 68 yrs to separately assess the effects prior use of two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs) and angiogiotensin receptor blockers (ARBs), by comparing these two exposures with no exposure to RASIs. We found both prior use of ACEIs and prior use of ARBs to be associated with a lower Covid-19 mortality, after adjusting for 32 medical history variables via propensity score matching. (ORACEI = 0.57, 95%CI 0.36 to 0.91, p =0.018) (ORARB = 0.49, 95%CI 0.29 to 0.82, p =0.006).
Quantifying the importance and location of SARS-CoV-2 transmission events in large metropolitan areas
Authors: Aleta Alberto , Martín-Corral David , Bakker Michiel A. , y Piontti Ana Pastore , Ajelli Marco , Litvinova Maria , Chinazzi Matteo , Dean Natalie E. , Halloran M. Elizabeth , Longini Ira M. , Pentland Alex , Vespignani Alessandro , Moreno Yamir , Moro Esteban 
Published: December 2020

ABSTRACTDetailed characterization of SARS-CoV-2 transmission across different settings can help design less disruptive interventions. We used real-time, privacy-enhanced mobility data in the New York City and Seattle metropolitan areas to build a detailed agent-based model of SARS-CoV-2 infection to estimate the where, when, and magnitude of transmission events during the pandemic’s first wave. We estimate that only 18% of individuals produce most infections (80%), with about 10% of events that can be considered super-spreading events (SSEs). Although mass-gatherings present an important risk for SSEs, we estimate that the bulk of transmission occurred in smaller events in settings like workplaces, grocery stores, or food venues. The places most important for transmission change during the pandemic and are different across cities, signaling the large underlying behavioral component underneath them. Our modeling complements case studies and epidemiological data and indicates that real-time tracking of transmission events could help evaluate and define targeted mitigation policies.
Cyclic gallium-68 labeled peptides for specific detection of human angiotensin-converting enzyme 2
Authors: Parker Matthew F. L. , Blecha Joseph , Rosenberg Oren , Ohliger Michael , Flavell Robert R. , Wilson David M. 
Published: December 2020

AbstractIn this study, we developed ACE2-specific, peptide-derived68Ga-labeled radiotracers, motivated by the hypotheses that (1) ACE2 is an important determinant of SARS-CoV-2 susceptibility, and (2) that modulation of ACE2 in COVID-19 drives severe organ injury.MethodsA series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears two cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with68Ga to generate peptide radiotracers ([68Ga]NOTA-PEP). The aminocaproate-derived radiotracer [68Ga]NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model.ResultsCyclic DX-600 derived peptides had markedly lower IC50’s than their linear counterparts. The three cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated IC50’s similar to, or lower than the parent DX600 molecule. Peptides were readily labeled with68Ga, and the biodistribution of [68Ga]NOTA-PEP4 was determined in a hACE2 transgenic murine cohort. Pharmacologic concentrations of co-administered NOTA-PEP (“blocking”) showed significant reduction of [68Ga]NOTA-PEP4 signals in the in the heart, liver, lungs, and small intestine.Ex vivohACE2 activity in these organs was confirmed as a correlate toin vivoresults.ConclusionsNOTA-conjugated, cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for68Ga chelation.In vivostudies in a transgenic hACE2 murine model using the lead tracer [68Ga]NOTA-PEP4 showed specific binding in the heart, liver, lungs and intestine - organs known to be affected in SARS-CoV-2 infection. These results suggest that [68Ga]NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2 infected murine models and COVID-19 patients.TOC figureFor Table of Contents use only
Do Motoneurons’ Discharge Rate Slow With Aging? A Systematic Review And Meta-Analysis
Authors: Orssatto Lucas B. R. , Borg David N. , Pendrith Linda , Blazevich Anthony J. , Shield Anthony J. , Trajano Gabriel S. 
Published: December 2020

AbstractNervous system maladaptation is linked to the loss of maximal strength production and motor control with aging. Motor unit discharge rates are a critical determinant of force production; thus, lower discharge rates could be a mechanism underpinning maximal strength and motor control losses during aging. This meta-analysis summarized the findings of studies comparing motor unit discharge rates between young and older adults, and examined the effect of distinct muscles and contraction intensities on the magnitude of discharge rates difference between these two groups. Eligible studies were combined in a meta-analysis, including tested contraction intensities and muscles in different levels, to investigate whether there were differences in discharge rates between younger and older adults. Motor unit discharge rates were higher in younger adults compared to older adults, with a pooled standardized mean difference (SMD) for all studies of 0.63 (95%CI= 0.27 to 0.99). Contraction intensity had a significant effect on the pooled SMD, with a 1% increase in intensity associated with a 0.009 (95%CI= 0.003 to 0.015) change in the pooled SMD. These findings suggest that the reductions in motor unit discharge rates, especially at higher contraction intensities, may be an important mechanism underpinning age-related losses in maximal strength production.
Varia: Prediction, analysis and visualisation of variable genes
Authors: Mackenzie Gavin , Jensen Rasmus W. , Lavstsen Thomas , Otto Thomas D. 
Published: December 2020

SummaryAssessing the diversity or expression of variable gene families in pathogens can inform about immune escape mechanisms or host interaction phenotypes of clinical relevance. However, obtaining the sequences and quantifying their expression is a challenge. Here, we present a tool, which based on unique sequence tag similarity between members of a gene family, predicts the domains encoded by the queried gene. As an example, we are using thevargene family, encoding the major virulence proteins (PfEMP1) of the human malaria parasite,Plasmodium falciparum. We developed Varia, which predicts the likelyvargene sequence and encoded protein domain composition of a gene from short sequence tags. We provide a new extended annotatedvargenome database, in which Varia identifies genes with identical tag sequences and compares these to return the most probable domain composition of the query gene. Varia’s ability to predict correct PfEMP1 domain compositions from shortvarsequence tags was tested in two complementary pipelines to (a) return the putative gene sequences and domain compositions of the query gene from any partial sequence provided, thereby enabling detailed assessment of specific genes’ putative function and experimental validation of these (b) to accommodate rapid profiling ofvargene expression in complex patient samples, by compiling the overall domain prevalence amongvartranscripts predicted identified and quantified by next generation sequencing of so-calledvarDBLα-sequence tags.Availability and implementationVaria is available on GitHub (https://github.com/GCJMacken-zie/Varia) under the MIT license.Contactthomasl@sund.ku.dk,thomasdan.otto@glasgow.ac.uk
The 3'tsRNAs are aminoacylated: Implications for their biogenesis
Authors: Liu Ziwei , Kim Hak kyun , Xu Jianpeng , Kay Mark A. 
Published: December 2020

AbstractEmerging evidence indicates that tRNA-derived small RNAs (tsRNAs) are involved in fine-tuning gene expression and become dysregulated in various cancers. We recently showed that the 22nt LeuCAG tsRNA from 3’ end of tRNALeuis required for efficient translation of a ribosomal protein mRNA and ribosome biogenesis. Inactivation of this tsRNA induced apoptosis in rapidly dividing cells and suppressed the growth of a patient derived orthotopic hepatocellular carcinoma in mice. The mechanism involved in the generation of the 3’-tsRNAs remains elusive and it is unclear if the 3’-ends of 3’-tsRNAs are aminoacylated. Here we report an enzymatic method utilizing exonuclease T to determine the 3’charging status of tRNAs and tsRNAs. Our results showed that the LeuCAG 3’-tsRNA is fully charged and originated solely from charged mature tRNA. When the leucyl-tRNA synthetase was knocked down, less tsRNA was generated while the mature tRNA was not reduced further supporting that tsRNA generation is regulated. The fact that the 3’-tsRNA is aminoacylated has implications for their biogenesis and provides additional insights into their biological role in post-transcriptional gene regulation.
Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys
Authors: Srivastava Swayam Prakash , Li Jinpeng , Takagaki Yuta , Kitada Munehiro , Goodwin Julie , Kanasaki Keizo , Koya Daisuke 
Published: December 2020

SummaryDefects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain-of-function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis; while its loss-of-function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked-activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-depandent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial cell SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney.Context and significanceThe present study describes that endothelial cell SIRT3 protects against renal fibrosis by mitigating the metabolic reprogramming and associated mesenchymal transformations in diabetes. Accordingly, amelioration of endothelial cell SIRT3 and targeting the defective metabolism offer a potential therapeutic approach to treat or prevent the progression of diabetic kidney disease. Further investigation would delineate the mechanisms of SIRT3 up-regulation in diabetic kidney disease and discover small molecules to increase the expression of the SIRT3. In addition, this study describes the biology of SIRT3 in the health and disease processes of kidney endothelial cells.