Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes.

Background: Few studies have explored the association between DNA methylation and physical activity. The aim of this study was to evaluate the association of objectively measured hours of sedentary behavior (SB) and moderate physical activity (MPA) with DNA methylation. We further aimed to explore the association between SB or MPA related CpG sites and cardiometabolic traits, gene expression, and genetic variation.

Integrated Network Pharmacology, Machine Learning and Experimental Validation to Identify the Key Targets and Compounds of for the Treatment of Breast Cancer.

Background: TiaoShenGongJian (TSGJ) decoction, a traditional Chinese medicine for breast cancer, has unknown active compounds, targets, and mechanisms. This study identifies TSGJ's key targets and compounds for breast cancer treatment through network pharmacology, machine learning, and experimental validation.

Methods: Bioactive components and targets of TSGJ were identified from the TCMSP database, and breast cancer-related targets from GeneCards, PharmGkb, and RNA-seq datasets.

Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations.

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was formed, presenting here the largest sequencing study of ASD in Latin American individuals (n>15,000).

The associations of long-term physical activity in adulthood with later biological ageing and all-cause mortality - a prospective twin study.

Objectives: The association between leisure-time physical activity (LTPA) and a lower risk of mortality is susceptible to bias from multiple sources. We investigated the potential of biological ageing to mediate the association between long-term LTPA and mortality and whether the methods used to account for reverse causality affect the interpretation of this association.

Methods: Study participants were twins from the older Finnish Twin Cohort (n = 22,750; 18-50 years at baseline).

Tattoo ink exposure is associated with lymphoma and skin cancers - a Danish study of twins.

Background: We aim to study the potential association between tattoo ink exposure and development of certain types of cancers in the recently established Danish Twin Tattoo Cohort. Tattoo ink is known to transfer from skin to blood and accumulate in regional lymph nodes. We are concerned that tattoo ink induces inflammation at the deposit site, leading to chronic inflammation and increasing risk of abnormal cell proliferation, especially skin cancer and lymphoma.

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia.

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells.

Refining fine-mapping: Effect sizes and regional heritability.

Recent statistical approaches have shown that the set of all available genetic variants explains considerably more phenotypic variance of complex traits and diseases than the individual variants that are robustly associated with these phenotypes. However, rapidly increasing sample sizes constantly improve detection and prioritization of individual variants driving the associations between genomic regions and phenotypes. Therefore, it is useful to routinely estimate how much phenotypic variance the detected variants explain for each region by taking into account the correlation structure of variants and the uncertainty in their causal status.

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Suboptimal dietary patterns are associated with accelerated biological aging in young adulthood: A study with twins.

Background & Aims: Suboptimal diets increase morbidity and mortality risk. Epigenetic clocks are algorithms that can assess health and lifespan, even at a young age, before clinical manifestations of diseases. We investigated the association between dietary patterns and biological aging in young adult twins.

Genetic vulnerability and adverse mental health outcomes following mild traumatic brain injury: a meta-analysis of CENTER-TBI and TRACK-TBI cohorts.

Background: Post-traumatic stress disorder (PTSD) and depression are common after mild traumatic brain injury (mTBI), but their biological drivers are uncertain. We therefore explored whether polygenic risk scores (PRS) derived for PTSD and major depressive disorder (MDD) are associated with the development of cognate TBI-related phenotypes.

Methods: Meta-analyses were conducted using data from two multicenter, prospective observational cohort studies of patients with mTBI: the CENTER-TBI study (ClinicalTrials.

Cross-sectional relationships of circadian misalignment and rest-activity rhythms with occupational attainment in UK Biobank participants.

Circadian misalignment and disrupted rest-activity rhythms have been linked to adverse health and educational outcomes, yet few studies have considered their relationships with economic outcomes. We investigate associations between multiple accelerometer-measured circadian misalignment traits (Composite Phase Deviation and the Sleep Regularity Index) and rest-activity rhythm traits (Inter-daily Stability, Intra-daily variability and relative amplitude), with occupational attainment, measured using the average wage paid to an individual's occupation. We use data from 20 356 UK Biobank participants who wore an accelerometer (2013-16), provided employment data for the year they wore the accelerometer, and supplied covariate data at recruitment (2006-10).

Exploiting NRF2-ARE pathway activation in papillary renal cell carcinoma.

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cancer subtype but has no indicated targeted treatments. MET inhibition may be a treatment for MET-driven pRCC, but there is a large group of non-MET-driven pRCC without targeted therapy. Activation of NRF2-ARE pathway has been suggested to be involved in pRCC.

Etiology and correlates of alcohol misuse in early midlife.

Background: Early midlife individuals (ages 30-40) experience demographic shifts that may influence the remainder of adult life. Although new or persistent alcohol misuse is common during this period, early midlife is understudied in alcohol use literature. We examined the heritability of alcohol misuse; the associations between alcohol misuse and sociodemographic factors, physical health, and well-being; and whether these associations were robust in cotwin comparisons.

Differential somatic coding variant landscapes between laser microdissected luminal epithelial cells from canine mammary invasive ductal solid carcinoma and comedocarcinoma.

Background: Breast cancer (BC) is the most common cancer in women. Likewise, canine mammary tumors (CMT) represent the most common cancer in intact female dogs and develop in the majority spontaneously. Similarities exist in clinical presentation, histopathology, biomarkers, and treatment.

Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins.

Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins.

Characterization of tumor microenvironment and cell interaction patterns in testicular and diffuse large B-cell lymphomas.

The tumor microenvironments (TME) of diffuse large B-cell lymphoma (DLBCL) subgroups have remained poorly characterized. Here, we dissected the composition and spatial organization of the TME in germinal center B-cell (GCB), activated B-cell (ABC), and testicular DLBCLs (T-DLBCL) using gene expression profiling and multiplex immunohistochemistry. We found that high proportions of M2-like tumor-associated macrophages (TAMs) and cytotoxic tumor-infiltrating T cells (TILs) were characteristic of ABC DLBCL TME.

Artificial intelligence aided serum protein electrophoresis analysis of Finnish patient samples: Retrospective validation.

Background And Aims: Serum protein electrophoresis interpretation requires a substantial amount of manual work. In 2020, Chabrun et al. created a machine learning method called SPECTR for the task.

Associations of body size and morphology with cardiometabolic health in children: the contribution of genetic factors.

Objective: We analyzed how anthropometric measures predict cardiometabolic health and how genetic and environmental factors contribute to these associations.

Methods: Data on 8 indicators of cardiometabolic health, 21 anthropometric measures, and 11 anthropometric indices were available for 216 twin pairs of individuals age 3 to 18 years living in the Autonomous Region of Madeira, Portugal (51% girls). Genetic twin modeling was used to estimate genetic and environmental correlations between the cardiometabolic and anthropometric indicators.

Molecular and functional profiling of primary normal ovarian cells defines insights into cancer development and drug responses.

Patients with ovarian cancer, especially the high-grade serous ovarian cancer (HGSOC) subtype, face poor prognosis due to late diagnosis and treatment resistance. Owing to the high heterogeneity of HGSOC, identifying the origin of the disease and optimal treatments is difficult. Here, we characterized two primary immortalized human ovarian cell lines, human ovarian surface epithelium (HOSE)1C and HOSE2C, comparing their molecular profiling with representative HGSOC cells.

Branched-chain amino acid supplementation and voluntary running have distinct effects on the serum metabolome of rats with high or low intrinsic aerobic capacity.

Introduction: A growing body of literature associates branched-chain amino acid (BCAA) catabolism to increased fatty acid oxidation and better metabolic health. Hence, BCAA-rich diets may improve body composition and muscle protein synthesis. However, the role of individual characteristics such as a low aerobic fitness, a well-established risk factor for cardio-metabolic diseases, has not been studied.

Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.

Background: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.

Methods: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.

Results: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D.