bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empirical evaluation of the sensitivity of background incidence rate characterization for adverse events across an international observational data network
Authors: Ostropolets Anna , Li Xintong , Makadia Rupa , Rao Gowtham , Rijnbeek Peter R. , Duarte-Salles Talita , Sena Anthony G. , Shaoibi Azza , Suchard Marc A. , Ryan Patrick B. , Prieto-Alhambra Daniel , Hripcsak George 
Published: July 2021

ABSTRACTBackground incidence rates are routinely used in safety studies to evaluate the association of an exposure and an outcome. Systematic research on the sensitivity of background rates to the choice of the study parameters is lacking. We used 12 electronic health record and administrative claims data sources to calculate incidence rates of 15 adverse events. We examined the influence of age, race, sex, database, time-at-risk start (anchoring) event and duration, season and year, prior observation and clean window. For binary comparisons, we calculated incidence rate ratios and performed random-effect model meta-analysis. Background rates were highly sensitive to demographic characteristics of the population, especially age, with rates varying up to a factor of 1,000 across age groups. Rates varied by up to a factor of 100 by database. Incidence rates were highly influenced by the choice of anchoring (e.g., health visit, vaccination, or arbitrary date) for the time-at-risk start, especially at short times at risk, and less influenced by secular or seasonal trends. Therefore, comparing background to observed rates requires appropriate adjustment, and results should be interpreted in the context of design choices.Short Figure
Effects of supervised high-intensity hardstyle kettlebell training on grip strength and health-related physical fitness in insufficiently active older adults: The BELL pragmatic controlled trial
Authors: Meigh Neil J. , Keogh Justin W.L. , Schram Ben , Hing Wayne , Rathbone Evelyne N. 
Published: July 2021

ABSTRACTThe Ballistic Exercise of the Lower Limb (BELL) trial examined efficacy and safety of a pragmatic hardstyle kettlebell training program in older adults. Insufficiently active men and women aged 59-79 years, were recruited to a 6-month repeated measures study, involving 3-months usual activity and 3-months progressive hardstyle kettlebell training. Health-related physical fitness outcomes included: grip strength [GS], 6-min walk distance [6MWD], resting heart rate [HR], stair-climb [SC], leg extensor strength [LES], hip extensor strength [HES], Sit-To-Stand [STS], vertical jump [CMVJ], five-times floor transfer [5xFT], 1RM deadlift, body composition (DXA), attendance, and adverse events. Sixteen males (68.8 ± 4.6 yrs, 176.2 ± 7.8 cm, 90.7 ± 11.0 kg, 29.2 ± 2.6 kg/m2) and sixteen females (68.6 ± 4.7 yrs, 163.9 ± 5.4 cm, 70.4 ± 12.7 kg, 26.3 ± 4.9 kg/m2) were recruited. Compliance to the supervised exercise program was very high (91.5%). Kettlebell training increased GS (R: MD = 7.1 kg 95% CI [4.9, 9.3],p< 0.001, L: MD = 6.3 kg 95% CI [4.1, 8.4],p< 0.001), 6MWD (41.7 m, 95% CI [17.9, 65.5],p< .001), 1RM (16.2 kg, 95% CI [2.4, 30.0],p= 0.013), 30s STS (3.3 reps, 95% CI [0.9, 5.7],p= 0.003), LES (R: MD = 61.6 N, 95% CI [4.4, 118.8],p= 0.028), HES (L: MD = 21.0 N, 95% CI [4.2, 37.8],p= 0.007), appendicular skeletal lean mass (MD = 0.65 kg, 95% CI [0.08, 1.22],p= 0.016), self-reported health change (17.1%, 95% CI [4.4, 29.8],p= 0.002) and decreased SC time (2.7 sec, 95% CI [0.2, 5.2],p= 0.025), 5xFT time (6.0 sec, 95% CI [2.2, 9.8],p< 0.001) and resting HR (7.4 bpm, 95% CI [0.7, 14.1],p= 0.032). There were four non-serious adverse events. Mean individual training load for group training sessions during the trial was 100,977 ± 9,050 kg. High-intensity hardstyle kettlebell training was well tolerated and improved grip strength and measures of health-related physical fitness in insufficiently active older adults.
An improved codon modeling approach for accurate estimation of the mutation bias
Authors: Latrille T. , Lartillot N. 
Published: July 2021

AbstractNucleotide composition in protein-coding sequences is the result of the equilibrium between mutation and selection. In particular, the nucleotide composition differs between the three coding positions, with the third position showing more extreme composition than the first and the second positions. Yet, phylogenetic codon models do not correctly capture this phenomenon and instead predict that the nucleotide composition should be the same for all 3 positions of the codons. Alternatively, some models allow for different nucleotide rates at the three positions, a problematic approach since the mutation process should in principle be blind to the coding structure and homogeneous across coding positions. Practically, this misconception could have important consequences in modelling the impact of GC-biased gene conversion (gBGC) on the evolution of protein-coding sequences, a factor which requires mutation and fixation biases to be carefully disentangled. Conceptually, the problem comes from the fact that phylogenetic codon models cannot correctly capture the fixation bias acting against the mutational pressure at the mutation-selection equilibrium. To address this problem, we present an improved codon modeling approach where the fixation rate is not seen as a scalar anymore, but as a tensor unfolding along multiple directions, which gives an accurate representation of how mutation and selection oppose each other at equilibrium. Thanks to this, this modelling approach yields a reliable estimate of the mutational process, while disentangling fixation probabilities in different directions.
Epigenetic mediation of AKT1 rs1130233’s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing
Authors: Blest-Hopley Grace , Colizzi Marco , Prata Diana , Giampietro Vincent , Brammer Michael , McGuire Philip , Bhattacharyya Sagnik 
Published: July 2021

AbstractHigh doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Also, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signaling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data was available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG11-12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/ hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.
Development of epigenetic clocks for New Zealand livestock
Authors: Caulton Alex , Dodds Ken G. , McRae Kathryn M. , Couldrey Christine , Horvath Steve , Clarke Shannon M. 
Published: July 2021

ABSTRACTRobust biological biomarkers of chronological age have been developed in humans and model mammalian species such as rats and mice using DNA methylation data. The concept of these so-called “epigenetic clocks” has emerged from a large body of literature describing the correlation between genome-wide methylation levels and age. Epigenetic clocks exploit this phenomenon and use small panels of differentially methylated cytosine (CpG) sites to make robust predictions of chronological age, independent of tissue type.Here we present highly accurate livestock epigenetic clocks whereby we have used the custom mammalian methylation array “HorvathMammalMethyl40”1 to construct the first epigenetic clock for domesticated goat (Capra hircus), cattle (Bos taurus), Red (Cervus elaphus) and Wapiti deer (Cervus canadensis) and composite-breed sheep (Ovis aries). Additionally, we have constructed a New Zealand livestock ‘farm animal clock’ for all animals included in the study, which will enable robust predictions to be extended to various breeds. The farm animal clock shows similarly high accuracies to the individual species’ clocks (r>0.97), utilising only 217 CpG sites to estimate age (relative to the maximum lifespan of the species) with a single mathematical model.We envision that the applications of this livestock clock could extend well beyond the scope of chronological age estimates. Many independent studies have demonstrated that a deviation between true age and clock derived molecular age is indicative of past and/or present health (including stress) status. There is, therefore, untapped potential to utilise livestock clocks in breeding programmes as a predictor for age-related, production traits.
Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model
Authors: Ribeiro Mayara C. , MacDonald Jessica L. 
Published: July 2021

AbstractRett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-κB pathway. Genetically attenuating the NF-κB pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-κB pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-κB signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-κB activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/- cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, motor and anxiety-like behavioral phenotypes in Mecp2+/- mice correlate with circulating vitamin D levels, and there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/- mice. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.
Reducing Movement Synchronization to Increase Interest Improves Interpersonal Liking
Authors: Ravreby Inbal , Shilat Yoel , Yeshurun Yaara 
Published: July 2021

AbstractSynchronization has been identified as a key aspect of achieving mutual goals and enhancing social bonding. While synchronization could be maximized by increasing the predictability of an interaction, such predictability is in tension with individuals’ level of interest, which is tied to the interaction’s complexity and novelty. In this study, we tested the interplay between synchronization and interest. We asked 104 female dyads to play the Mirror Game, in which they were instructed to move their hands as coordinately as possible, and then report how much they liked each other. Utilizing information theory and video processing tools, we found that a combination of movement synchronization and complexity explained liking almost two times better than movement synchronization alone. Moreover, we found that people initiated novel and challenging interactions, even though they paid a price – being less synchronized. Examining the interactions’ dynamics, we found that people who liked each other moved in a more synchronized, complex, and novel manner during most of the interaction. This suggests that in addition to synchronization, maintaining interest may be critical for positive social bonding. Thus, we propose a new framework in which balancing synchronization and interest, rather than merely maximizing synchronization, optimizes the interaction quality.
Reduced Lytic Activity of Bacteriophages in Presence of Antibiotics Targeting Bacterial Protein Synthesis
Authors: Vashisth Medhavi , Yashveer Shikha , Virmani Nitin , Bera Bidhan Chandra , Vaid Rajesh Kumar , Anand Taruna 
Published: July 2021

AbstractCombination therapy of bacteriophage and antibiotics offers promise to treat multiple drug resistant bacterial infections through phage antibiotic synergy. However, its usage requires careful assessment as most antibiotics with mechanisms dependent upon inhibiting cell growth through interfering bacterial protein synthesis machinery were found to have an antagonistic effect on phage activity.
Functional Characterization of Lipid Regulatory Effects of Three Genes Using Knockout Mouse Models
Authors: Yao Chen , Savage Holly , Hao Tong , Lee Gha Young , Takemon Yuka , Bian Wenting , Hill David E , Vidal Marc , Korstanje Ron , Levy Daniel 
Published: July 2021

AbstractIntegrative analysis that combines genome-wide association data with expression quantitative trait analysis and network representation may illuminate causal relationships between genes and diseases. To identify causal lipid genes, we utilized genotype, gene expression, protein-protein interaction networks, and phenotype data from 5,257 Framingham Heart Study participants and performed Mendelian randomization to investigate possible mechanistic explanations for observed associations. We selected three putatively causal candidate genes (ABCA6, ALDH2, and SIDT2) for lipid traits (LDL cholesterol, HDL cholesterol and triglycerides) in humans and conducted mouse knockout studies for each gene to confirm its causal effect on the corresponding lipid trait. We conducted the RNA-seq from mouse livers to explore transcriptome-wide alterations after knocking out the target genes. Our work builds upon a lipid-related gene network and expands upon it by including protein-protein interactions. These resources, along with the innovative combination of emerging analytical techniques, provide a groundwork upon which future studies can be designed to more fully understand genetic contributions to cardiovascular diseases.
Low mitochondrial copy number drives atherogenic cardiovascular disease: evidence from prospective cohort analyses in the UK Biobank combined with Mendelian Randomization
Authors: Luo Jiao , Noordam Raymond , Jukema J Wouter , van Dijk Ko Willems , Hägg Sara , Grassmann Felix , Cessie Saskia le , van Heemst Diana 
Published: July 2021

AbstractBackgroundMitochondrial DNA (mtDNA) content might be involved in the risk of cardiovascular disease. We aimed to investigate the association of mtDNA copy number (mtDNA-CN), as a proxy of mtDNA content, and coronary artery disease (CAD) and heart failure (HF) using multivariable adjusted and Mendelian Randomizations (MR) analyses.MethodsMultivariable-adjusted analyses were conducted using Cox-proportional hazard models in 273,619 unrelated European descendants from UK Biobank (UKB). MtDNA-CN in peripheral blood cells was computed based on the weighted intensities of the mitochondrial genome probes. For the two-sample MR analyses, single nucleotide polymorphisms (SNPs) associated with mtDNA-CN were retrieved from genome-wide association studies in UKB. SNP-outcome associations were obtained for CAD from CARDIoGRAMplusC4D, UKB and FinnGen, comprising 902,538 participants (134,759 cases), and for HF from the HERMES consortium and FinnGen, collectively having data on 1,195,531 participants (70,706 cases). MR analyses were performed per database and results were subsequently meta analyzed using fixed-effects models per study.ResultsDuring a median follow-up of 11.8 years, participants in the lowest quintile of mtDNA-CN had higher risk for CAD (hazard ratio [95% CI]: 1.08 [1.03, 1.14]) and HF (hazard ratio [95% CI]: 1.15 [1.05, 1.24]) compared to those in the highest quintile. In MR analyses, the pooled odds ratios of genetically predicted per one-SD decrease in mtDNA were 1.16 (95% CI: 1.05, 1.27) for CAD and 1.00 (95% CI: 0.90, 1.10) for HF, respectively.ConclusionOur findings support a possible causal role of lower mtDNA-CN in higher CAD risk, but not in higher HF risk.
GABAAα Subunit Control of Hyperactive Behavior in Developing Zebrafish
Authors: Barnaby Wayne , Barclay Hanna E. Dorman , Nagarkar Akanksha , Perkins Matthew , Teicher Gregory , Trapani Josef G. , Downes Gerald B. 
Published: July 2021

ABSTRACTGABAAreceptors mediate rapid responses to the neurotransmitter GABA and are robust regulators of the brain and spinal cord neural networks that control locomotor behaviors, such as walking and swimming. In developing zebrafish, gross pharmacological blockade of these receptors causes hyperactive swimming, which has been embraced as an epilepsy model. Although GABAAreceptors are important to control locomotor behavior, the large number of subunits and homeostatic compensatory mechanisms have challenged efforts to determine subunit-selective roles. To address this issue, we mutated each of the eight zebrafish GABAAα subunit genes individually and in pairs using a CRISPR-Cas9 somatic inactivation approach, then we examined the swimming behavior of the mutants at two developmental stages. We found that disrupting the expression of specific pairs of subunits resulted in different abnormalities in swimming behavior at the first development stage. Mutation of α4 and α5 selectively resulted in longer duration swimming episodes, mutations in α3 and α4 selectively caused excess, large-amplitude body flexions (C-bends), and mutation of α3 and α5 resulted in increases in both of these measures of hyperactivity. At the later stage of development, hyperactive phenotypes were nearly absent, suggesting that homeostatic compensation was able to overcome the disruption of even multiple subunits. Taken together, our results identify subunit-selective roles for GABAAα3, α4, and α5 in regulating locomotion. Given that these subunits exhibit spatially restricted expression patterns, these results provide a foundation to identify neurons and GABAergic networks that control discrete aspects of locomotor behavior.
Network analysis after epigenome wide methylation study revealed JUP as a regulator of co-methylated risk-module for T2DM
Authors: Giri Anil K , Prasad Gauri , Parekkat Vaisak , Rajashekar Donaka , Tandon Nikhil , Bharadwaj Dwaipayan 
Published: July 2021

AbstractControlling the global Type 2 diabetes mellitus (T2DM) pandemic requires a better understanding of its risk factors across different populations, and needs markers that can precisely predict the individual risk to the disease. DNA methylation due to environmental factors is a known mechanism for conferring risk to T2DM. To identify such methylation signatures and associated risk to the disease, we performed an epigenome-wide-association study (EWAS) in 844 individuals of Indo-European origin. Within the Indian population, we identified and validated 6 novel differentially methylated CpG sites in PDCD6IP, MIR1287, 5S_rRNA, HDAC9, KCNK16, and RTN1 genes associated with T2DM risk at the epigenome-wide-significance-level (p<1.2×10-7). Further, we also replicated the association of 3 known CpG sites in TXNIP, SREBF1 and CPT1A in the Indian population. Using methylation-based-network analysis, we identified 4 co-methylated modules, which we named as turquoise, yellow, brown, and blue, among differentially methylated CpG sites in discovery phase samples. We observed that methylation of the brown module with 28 CpG sites, associated with T2DM risk factors (e.g., BMI, insulin, C-peptide). Upon further analysis, we noted that these methylation signatures at 14 of the brown module’s CpG can be used as marker to segregate T2DM patients with good glycemic control (e.g., low HbA1c) but poor lipid profile (low HDL and high TG) from the other patients. Additionally, we discovered that rs6503650 in the JUP gene regulates methylation at all the 14 hub CpG sites of the brown modules as methQTL. Our network-assisted epigenome-wide association study is the first to systematically explore DNA methylations conferring risks to T2DM. In addition, the study shows the potential use of identified risk CpG sites for patient segregation with different clinical outcomes. These findings can be useful for better stratification of patient in order to improve the clinical management and treatment outcomes.
Parallel genetic changes underlie integrated craniofacial traits in an adaptive radiation of trophic specialist pupfishes
Authors: St. John Michelle E. , Dunker Julia C. , Richards Emilie J. , Romero Stephanie , Martin Christopher H. 
Published: July 2021

AbstractMany factors such as divergence time, shared standing genetic variation, frequency of introgression, and mutation rates can influence the likelihood of whether populations adapt to similar environments via parallel or non-parallel genetic changes. However, the frequency of parallel vs non-parallel genetic changes resulting in parallel phenotypic evolution is still unknown. In this study, we used a QTL mapping approach to investigate the genetic basis of highly divergent craniofacial traits between scale- and snail-eating trophic specialist species across similar hypersaline lake environments in an adaptive radiation of pupfishes endemic to San Salvador Island, Bahamas. We raised F2 intercrosses of scale- and snail-eaters from two different lake populations of sympatric specialists, estimated linkage maps, scanned for significant QTL for 30 skeletal and craniofacial traits, and compared the location of QTL between lakes to quantify parallel and non-parallel genetic changes. We found strong support for parallel genetic changes in both lakes for five traits in which we detected a significant QTL in at least one lake. However, many of these shared QTL affected different, but highly correlated craniofacial traits in each lake, suggesting that pleiotropy and trait integration should not be neglected when estimating rates of parallel evolution. We further observed a 23-52% increase in adaptive introgression within shared QTL, suggesting that introgression may be important for parallel evolution. Overall, our results suggest that the same genomic regions contribute to parallel integrated craniofacial phenotypes across lakes. We also highlight the need for more expansive searches for shared QTL when testing for parallel evolution.