3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts.

Discovery of novel 'sugarcane totivirus 1' from Saccharum officinarum by high-throughput sequencing.

Background: Sugarcane is cultivated globally and affected by more than 125 pathogens, which lead to various plant diseases. In recent years, high-throughput sequencing (HTS)-based genome analyses have been broadly adopted for the discovery of both characterized and un-characterized viruses from plant samples. In this study, the HTS data of sugarcane pooled sample retrieved from sequence read archive (SRA) were de novo re-assembled using CLC Genomic Workbench.

Targeting InhA in drug-resistant Mycobacterium tuberculosis: potent antimycobacterial activity of diaryl ether dehydrozingerone derivatives.

Tuberculosis (TB) remains a major global threat, with 10 million new cases and 1.5 million deaths each year. In multidrug-resistant tuberculosis (MDR-TB), resistance is most commonly observed against isoniazid (INH) and rifampicin (RIF), the two frontline drugs.

Soma and neurite density abnormalities of paramagnetic rim lesions and core-sign lesions in multiple sclerosis.

Background: In multiple sclerosis (MS), susceptibility-weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim ("paramagnetic rim lesions" [PRLs]) or diffuse hypointensity ("core-sign lesions"), reflecting different stages of WML evolution.

Objective: Using the soma and neurite density imaging (SANDI) model on diffusion-weighted magnetic resonance imaging (MRI), we characterized microstructural abnormalities of MS PRLs and core-sign lesions and their clinical relevance.

Methods: Forty MS patients and 20 healthy controls (HC) underwent a 3 T brain MRI.

Endocytic recycling is central to circadian collagen fibrillogenesis and disrupted in fibrosis.

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis.

Genetically Predicted Gene Expression Effects on Changes in Red Blood Cell and Plasma Polyunsaturated Fatty Acids.

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. In vivo conversion of omega-3 and omega-6 PUFAs from short- to long-chain counterparts occurs via a shared metabolic pathway involving fatty acid desaturases and elongase. This analysis leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs, along with expression quantitative trait loci (eQTL) to estimate tissue-specific genetically predicted gene expression effects for delta-5 desaturase (FADS1), delta-6 desaturase (FADS2), and elongase (ELOVL2) on changes in RBC and plasma biomarkers.

General Kernel Machine Methods for Multi-Omics Integration and Genome-Wide Association Testing With Related Individuals.

Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.

Naturally Acquired Genotype-Specific HPV Seroreactivity and Subsequent HPV Detection Among Heterosexual Partners.

The protective effect of naturally acquired humoral immunity against human papillomavirus (HPV) infection remains unclear. To investigate the role of infection-induced antibodies on HPV detection in heterosexual partners, we used data from 392 unvaccinated couples (females aged 18-25 years attended up to six visits over 2 years; males aged 17-37 years attended up to two visits 4 months apart) enrolled (2005-2011) in Montreal. Genital and blood samples were HPV DNA genotyped and tested for L1 antibody titers of 14 HPV genotypes.

Conventional and regionally distinctive risk factors for first-onset myocardial infarction: the Bangladesh Risk of Acute Vascular Events (BRAVE) case-control study.

Background: South Asians may be particularly susceptible to premature myocardial infarction (MI) owing both to conventional cardiovascular risk factors and practices distinctive to South Asia. Identifying modifiable risk factors for MI in these populations could inform prevention strategies. We have, therefore, studied conventional risk factors and other characteristics in relation to occurrence of first MI in Bangladesh.

Effective Newborn Screening for Type 1 and 3 Primary Hyperoxaluria.

Introduction: Newborn screening (NBS) programs for a defined set of eligible diseases have been enormously successful, but genomic NBS allowing for detection of additional treatable disorders has not been broadly implemented. All 3 types of primary hyperoxaluria (PH1-3) are rare autosomal recessive diseases caused by distinct defects of glyoxylate metabolism that are diagnosed genetically with certainty. Early diagnosis and treatment are mandatory to avoid renal failure or sequalae associated with persistent hyperoxaluria.

Mixed nontuberculous mycobacteria in an immunocompromised patient with probable progressive multifocal leukoencephalopathy.

Objectives: Nontuberculous mycobacteria (NTM) are increasingly recognized opportunistic pathogens found ubiquitously in the environment. The presence of multiple NTM species at the site of disease complicates diagnosis and treatment.

Case And Management: A 40-year-old patient who tested positive for HIV, with an absolute clusters of differentiation 4+ T-cell count of 3 cells/µl and cryptococcaemia, presented with hemoptysis, productive cough, and weight loss.

Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy.

Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.

Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice.

Metabolically activated and highly polyfunctional intratumoral VISTA regulatory B cells are associated with tumor recurrence in early-stage NSCLC.

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC.

Development of a TSR-based method for understanding structural relationships of cofactors and local environments in photosystem I.

Background: All chemical forms of energy and oxygen on Earth are generated via photosynthesis where light energy is converted into redox energy by two photosystems (PS I and PS II). There is an increasing number of PS I 3D structures deposited in the Protein Data Bank (PDB). The Triangular Spatial Relationship (TSR)-based algorithm converts 3D structures into integers (TSR keys).

Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants.

Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications.

Early life microbial succession in the gut follows common patterns in humans across the globe.

Characterizing the dynamics of microbial community succession in the infant gut microbiome is crucial for understanding child health and development, but no normative model currently exists. Here, we estimate child age using gut microbial taxonomic relative abundances from metagenomes, with high temporal resolution (±3 months) for the first 1.5 years of life.

Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival.

Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.

Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa.

Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood.

Successful Pregnancies During Crizotinib Therapy for Anaplastic Lymphoma Kinase Positive Lymphoma.

Anaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma (ALCL) typically affects young individuals and, despite high responsiveness to cytotoxic drugs, relapses occur in over 50% of patients. Crizotinib has improved outcomes, but its management in patients desiring parenthood remains an issue. This study presents the first description of four successful pregnancies during crizotinib treatment for ALK+ALCL: a female patient achieving two pregnancies through assisted reproductive technologies (ART), temporarily discontinuing crizotinib and maintaining a complete remission (CR), and a male patient conceiving naturally while on continuous therapy.

Human chorionic gonadotropin-secreting osteosarcoma.

Secretion of beta human chorionic gonadotropin (β-hCG) is a rare, recently recognised paraneoplastic syndrome. Herein, we present a case of a woman in her 30s with right femur conventional high-grade osteosarcoma and a positive screening urine pregnancy test. Subsequent workup failed to reveal an intrauterine or extrauterine pregnancy.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.

Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents.

The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential.