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.

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation.

Validation guidelines for drug-target prediction methods.

Introduction: Mapping the interactions between pharmaceutical compounds and their molecular targets is a fundamental aspect of drug discovery and repurposing. Drug-target interactions are important for elucidating mechanisms of action and optimizing drug efficacy and safety profiles. Several computational methods have been developed to systematically predict drug-target interactions.

Inherited infertility: Mapping loci associated with impaired female reproduction.

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%-30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder.

PGxDB: an interactive web-platform for pharmacogenomics research.

Pharmacogenomics, the study of how an individual's genetic makeup influences their response to medications, is a rapidly evolving field with significant implications for personalized medicine. As researchers and healthcare professionals face challenges in exploring the intricate relationships between genetic profiles and therapeutic outcomes, the demand for effective and user-friendly tools to access and analyze genetic data related to drug responses continues to grow. To address these challenges, we have developed PGxDB, an interactive, web-based platform specifically designed for comprehensive pharmacogenomics research.

Tear fluid reflects the altered protein expressions of Alzheimer's disease patients in proteins involved in protein repair and clearance system or the regulation of cytoskeleton.

Background: New biomarkers that improve diagnosis of Alzheimer's disease (AD) are warranted. Tear fluid (TF) containing variety of proteins that reflect pathophysiological changes of systemic diseases makes TF proteins potential biomarker candidates for AD.

Objective: We investigated the expression levels of TF proteins in persons with mild AD and cognitively healthy controls (CO) to find out if altered proteins may link to the AD pathophysiology.

Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk factors.

Background: Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health-related behavior, or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity.

Probe set selection for targeted spatial transcriptomics.

Targeted spatial transcriptomic methods capture the topology of cell types and states in tissues at single-cell and subcellular resolution by measuring the expression of a predefined set of genes. The selection of an optimal set of probed genes is crucial for capturing the spatial signals present in a tissue. This requires selecting the most informative, yet minimal, set of genes to profile (gene set selection) for which it is possible to build probes (probe design).

Disease associations of natural killer (NK) cell KIR gene content variation in 352,783 Finns.

Allelic, gene presence/absence, and gene-copy number variations in the KIR genes encoding Natural Killer (NK) cell surface receptors have been reported to be associated in case-control studies with infectious and autoimmune diseases, and relapse after stem cell transplantation. To understand more comprehensively the role of KIR gene presence/absence variation and HLA-KIR interactions in disease susceptibility, we imputed from genome SNP data the presence and absence of 10 KIR genes in the FinnGen cohort. The cohort consists of 352,783 Finns with extensive phenotypes from the national health registries.

Genome-wide meta-analysis conducted in three large biobanks expands the genetic landscape of lumbar disc herniations.

Given that lumbar disc herniation (LDH) is a prevalent spinal condition that causes significant individual suffering and societal costs, the genetic basis of LDH has received relatively little research. Our aim is to increase understanding of the genetic factors influencing LDH. We perform a genome-wide association analysis (GWAS) of LDH in the FinnGen project and in Estonian and UK biobanks, followed by a genome-wide meta-analysis to combine the results.

Traumatic life events as predictors for depression in middle-aged men and women: A Finnish twin study.

Background: We examined exposure to adulthood traumatic life events (TLEs) and their associations with depression in women and men. Then we examined whether those associations are independent of exposure loading and vulnerability including familial confounding.

Methods: The fourth survey in 2011 of the population-based Finnish Twin Cohort had 8410 participants (45 % men, mean age 60 years).

Development and evaluation of a web-based diet quality screener for vegans (VEGANScreener): a cross-sectional, observational, multicenter, clinical study.

Consumption of plant-based diets, including vegan diets, necessitates attention to the quality of the diet for the prevention and early detection of nutritional deficiencies. Within the VEGANScreener project, a unique brief screening tool for the assessment and monitoring of diet quality among vegans in Europe was developed. To provide a standardized tool for public use, a clinical study will be conducted to evaluate the VEGANScreener against a reference dietary assessment method and nutritional biomarkers.

Cancer incidence following non-neoplastic medical conditions: a prospective population-based cohort study.

Background And Purpose: Many non-neoplastic diseases have been established to be tumorigenic, and cancers are sometimes misdiagnosed as non-neoplastic diseases. We conducted a comprehensive registry-based study of site-specific cancer diagnosis risk following the diagnosis of any preceding medical condition (PMC) encoded by the International Classification of Diseases (ICD)-10 classification.

Material And Methods: We analyzed healthcare data and cancer data for a random population-based sample of 2.

A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery.

The gene-regulatory dynamics governing drug responses in cancer are yet to be fully understood. Here, we report a pipeline capable of producing high-throughput pharmacotranscriptomic profiling through live-cell barcoding using antibody-oligonucleotide conjugates. This pipeline combines drug screening with 96-plex single-cell RNA sequencing.

Y chromosome sequencing data suggest dual paths of haplogroup N1a1 into Finland.

The paternally inherited Y chromosome is highly informative of genetic ancestry, therefore making it useful in studies of population history. In Finland, two Y-chromosomal haplogroups reveal the major substructure of the population: N1a1 enriched in the northeast and I1a in the southwest, suggested to reflect eastern and western ancestry contributions to the population. Yet, beyond these major Y-chromosomal lineages, the distribution of finer-scale Y-chromosomal variation has not been assessed in Finland.

Distinct molecular profiles and shared drug vulnerabilities in pancreatic metastases of renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is the most common origin of pancreatic metastases (PM). Distinct genomic aberrations, favorable prognosis, and clinical observations on high angiogenesis, and succeeding tyrosine kinase inhibitor (TKI) sensitivity have been reported in PM-ccRCC. However, no functional or single-cell studies have been conducted thus far.

Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment.

Association Between Accelerometer-Measured Physical Activity and Mobility Limitations in Twins.

Background: The associations between mobility limitations and device-measured physical activity are sparsely studied. In this study, these associations are studied among community-dwelling older twins.

Methods: This cross-sectional study utilized data gathered in 2014-2016 for the MOBILETWIN study.

Fine-mapping a genome-wide meta-analysis of 98,374 migraine cases identifies 181 sets of candidate causal variants.

Migraine is a highly prevalent neurovascular disorder for which genome-wide association studies (GWAS) have identified over one hundred risk loci, yet the causal variants and genes remain mostly unknown. Here, we meta-analyzed three migraine GWAS including 98,374 cases and 869,160 controls and identified 122 independent risk loci of which 35 were new. Fine-mapping of a meta-analysis is challenging because some variants may be missing from some participating studies and accurate linkage disequilibrium (LD) information of the variants is often not available.