Metagenomic Analysis of the Buccal Microbiome by Nanopore Sequencing Reveals Structural Differences in the Microbiome of a Patient with Molar Incisor Hypomineralization (MIH) Compared to a Healthy Child-Case Study.

Molar incisor hypomineralization (MIH) is a qualitative developmental defect that affects the enamel tissue of permanent molars and can also occur in permanent incisors. Enamel affected by MIH has reduced hardness, increased porosity, and a higher organic content than unaffected enamel. These characteristics predispose the enamel to accumulation of bacteria and a higher prevalence of caries lesions.

Sequencing Analysis of and Gene Fragments in Patients with Oropharyngeal Squamous Cell Carcinoma Reveals Novel Mutations: A Preliminary Study.

The growing incidence of oropharyngeal squamous cell carcinoma (OPSCC) calls for better understanding of the mutational landscape of such cases. Mucins (MUCs) are multifunctional glycoproteins expressed by the epithelial cells and may be associated with the epithelial tumour invasion and progression. The present study aimed at the analysis of the sequence of selected and gene fragments in the tumour, as well as the margin, samples obtained from 18 OPSCC patients.

Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain.

Hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) mediate glucocorticoid hormone (GC) action in the hippocampus. These receptors bind to glucocorticoid responsive elements (GREs) within target genes, eliciting transcriptional effects in response to stress and circadian variation. Until recently, little was known about the genome-wide targets of hippocampal MRs and GRs under physiological conditions.

Novel canonical and non-canonical viral antigens extend current targets for immunotherapy of HPV-driven cervical cancer.

Current immunotherapeutic approaches for human papillomavirus (HPV)-driven cervical cancer target the viral oncogenes E6 and E7. We report viral canonical and alternative reading frame (ARF)-derived sequences presented on cervical tumor cells, including antigens encoded by the conserved viral gene E1. We confirm immunogenicity of the identified viral peptides in HPV-positive women, and women with cervical intraepithelial neoplasia.

Ionizing Radiation Drives Key Regulators of Antigen Presentation and a Global Expansion of the Immunopeptidome.

Little is known about the pathways regulating MHC antigen presentation and the identity of treatment-specific T cell antigens induced by ionizing radiation. For this reason, we investigated the radiation-specific changes in the colorectal tumor cell proteome. We found an increase in DDX58 and ZBP1 protein expression, two nucleic acid sensing molecules likely involved in induction of the dominant interferon response signature observed after genotoxic insult.

New Variants of the Cytochrome P450 2R1 () Gene in Individuals with Severe Vitamin D-Activating Enzyme 25(OH)D Deficiency.

Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D).

Methods: We collected 89 (100%) subjects, 46 of which (51.

Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.

Glucocorticoid hormones (GCs) - acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) - are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes.

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders.

Purpose: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients.

Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy.

Background: Although rare missense variants in Mendelian disease genes often cluster in specific regions of proteins, it is unclear how to consider this when evaluating the pathogenicity of a gene or variant. Here we introduce methods for gene association and variant interpretation that use this powerful signal.

Methods: We present statistical methods to detect missense variant clustering () combined with burden information ().

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes.

Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation.

Reevaluation of the South Asian Intronic Deletion in Hypertrophic Cardiomyopathy.

Background: The common intronic deletion, , detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of to hypertrophic cardiomyopathy (HCM) in a large patient cohort.

Methods: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine frequency and co-occurrence of pathogenic variants in HCM genes.

Targeting Mutated Plus Germline Epitopes Confers Pre-clinical Efficacy of an Instantly Formulated Cancer Nano-Vaccine.

Personalized cancer vaccines hold promises for future cancer therapy. Targeting neoantigens is perceived as more beneficial compared to germline, non-mutated antigens. However, it is a practical challenge to identify and vaccinate patients with neoantigens.

Crunch: integrated processing and modeling of ChIP-seq data in terms of regulatory motifs.

Although ChIP-seq has become a routine experimental approach for quantitatively characterizing the genome-wide binding of transcription factors (TFs), computational analysis procedures remain far from standardized, making it difficult to compare ChIP-seq results across experiments. In addition, although genome-wide binding patterns must ultimately be determined by local constellations of DNA-binding sites, current analysis is typically limited to identifying enriched motifs in ChIP-seq peaks. Here we present Crunch, a completely automated computational method that performs all ChIP-seq analysis from quality control through read mapping and peak detecting and that integrates comprehensive modeling of the ChIP signal in terms of known and novel binding motifs, quantifying the contribution of each motif and annotating which combinations of motifs explain each binding peak.

Sequencing of human genomes with nanopore technology.

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels.

Repo-Man/PP1 regulates heterochromatin formation in interphase.

Repo-Man is a protein phosphatase 1 (PP1) targeting subunit that regulates mitotic progression and chromatin remodelling. After mitosis, Repo-Man/PP1 remains associated with chromatin but its function in interphase is not known. Here we show that Repo-Man, via Nup153, is enriched on condensed chromatin at the nuclear periphery and at the edge of the nucleopore basket.

The role of natural galactagogues during breast feeding: focus on a Galega officinalis based food supplement.

Maternal milk is the optimal food for newborns. To this end, a number of interventions are used to enhance milk production. However, pharmacological interventions may be associated with a perceived risk of adverse effects and therefore many mothers prefer to rely on natural herbal remedies.

Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.

Background: High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging.

Methods And Results: Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes.

BrowseVCF: a web-based application and workflow to quickly prioritize disease-causative variants in VCF files.

Following variant calling and annotation, accurate variant filtering is a crucial step to extract meaningful information from sequencing data and to investigate disease aetiology. However, the variant call format (VCF) used to store this information is not easy to handle for non-bioinformaticians. We present BrowseVCF, a flexible and intuitive software to enable researchers to browse and filter millions of variants in a few seconds.

The Genomic Context and Corecruitment of SP1 Affect ERRα Coactivation by PGC-1α in Muscle Cells.

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, eg, by coactivating the estrogen-related receptor-α (ERRα) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these 2 proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERRα to DNA in a skeletal muscle cell line with elevated PGC-1α and linked the DNA recruitment to global PGC-1α target gene regulation.

Integrative management of pediatric tonsillopharyngitis: An international survey.

This survey investigated the management of pediatric tonsillopharyngitis, with a focus on natural remedies. 138 pediatricians, general practitioners and ear-nose-throat (ENT) specialists in 7 countries were surveyed by a dedicated questionnaire. A rapid strept test (RST) to diagnose acute tonsillopharyngitis was routinely used by 56/138 participants (41%).

Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice.

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic.

Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program.

Skeletal muscle tissue shows an extraordinary cellular plasticity, but the underlying molecular mechanisms are still poorly understood. Here, we use a combination of experimental and computational approaches to unravel the complex transcriptional network of muscle cell plasticity centered on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a regulatory nexus in endurance training adaptation. By integrating data on genome-wide binding of PGC-1α and gene expression upon PGC-1α overexpression with comprehensive computational prediction of transcription factor binding sites (TFBSs), we uncover a hitherto-underestimated number of transcription factor partners involved in mediating PGC-1α action.

The peroxisome proliferator-activated receptor γ coactivator 1α/β (PGC-1) coactivators repress the transcriptional activity of NF-κB in skeletal muscle cells.

A persistent, low-grade inflammation accompanies many chronic diseases that are promoted by physical inactivity and improved by exercise. The beneficial effects of exercise are mediated in large part by peroxisome proliferator-activated receptor γ coactivator (PGC) 1α, whereas its loss correlates with propagation of local and systemic inflammatory markers. We examined the influence of PGC-1α and the related PGC-1β on inflammatory cytokines upon stimulation of muscle cells with TNFα, Toll-like receptor agonists, and free fatty acids.