Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups.

Type 1 Conventional CD103 Dendritic Cells Control Effector CD8 T Cell Migration, Survival, and Memory Responses During Influenza Infection.

Type 1 conventional CD103 dendritic cells (cDC1) contribute significantly to the cytotoxic T lymphocyte (CTL) response during influenza virus infection; however, the mechanisms by which cDC1s promote CTL recruitment and viral clearance are unclear. We demonstrate that cDC1 ablation leads to a deficient influenza-specific primary CD8 T cell response alongside severe pulmonary inflammation, intensifying susceptibility to infection. The diminished pulmonary CTL population is not only a consequence of reduced priming in the lymph node (LN), but also of dysregulated CD8 T cell egression from the LN and reduced CD8 T cell viability in the lungs.

Cell-free DNA as a biomarker of aging.

Cell-free DNA (cfDNA) is present in the circulating plasma and other body fluids and is known to originate mainly from apoptotic cells. Here, we provide the first in vivo evidence of global and local chromatin changes in human aging by analyzing cfDNA from the blood of individuals of different age groups. Our results show that nucleosome signals inferred from cfDNA are consistent with the redistribution of heterochromatin observed in cellular senescence and aging in other model systems.

Three Level Thoracolumbar Spondylectomy for Recurrent Giant Cell Tumour of the Spine: A Case Report.

Giant cell tumour (GCT) is a benign tumour but can be locally aggressive and with the potential to metastasise especially to the lungs. Successful treatments have been reported for long bone lesions; however, optimal surgical and medical treatment for spinal and sacral lesions are not well established. In treating spinal GCTs, the aim is to achieve complete tumour excision, restore spinal stability and decompress the neural tissues.

Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans.

Leaves of the plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial.

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model.

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

Background: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.

Methods: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents.

Mutant MRPS5 affects mitoribosomal accuracy and confers stress-related behavioral alterations.

The 1555 A to G substitution in mitochondrial 12S A-site rRNA is associated with maternally transmitted deafness of variable penetrance in the absence of otherwise overt disease. Here, we recapitulate the suggested A1555G-mediated pathomechanism in an experimental model of mitoribosomal mistranslation by directed mutagenesis of mitoribosomal protein MRPS5. We first establish that the ratio of cysteine/methionine incorporation and read-through of mtDNA-encoded MT-CO1 protein constitute reliable measures of mitoribosomal misreading.

A novel molecular rotor facilitates detection of p53-DNA interactions using the Fluorescent Intercalator Displacement Assay.

We have investigated the use of fluorescent molecular rotors as probes for detection of p53 binding to DNA. These are a class of fluorophores that undergo twisted intramolecular charge transfer (TICT). They are non-fluorescent in a freely rotating conformation and experience a fluorescence increase when restricted in the planar conformation.

Non-oxidative hair dye products on the European market: What do they contain?

Background: Hair dyeing is very common and may cause allergic contact dermatitis. Oxidative (often termed permanent or semi-permanent) hair dye products have constituted the focus of market surveys and toxicological risk assessments, while non-oxidative (semi-permanent, temporary or direct) products have not been assessed.

Objectives: To identify the hair dye substances presently used in non-oxidative hair dye products in Europe.

CHARACTERIZATION OF THE CHOROIDAL VASCULATURE IN MYOPIC MACULOPATHY WITH OPTICAL COHERENCE TOMOGRAPHIC ANGIOGRAPHY.

Purpose: To characterize the choriocapillaris (CC) in highly myopic eyes with myopic maculopathy, using optical coherence tomographic angiography.

Methods: Prospective, clinic-based study of 42 eyes of 38 patients with high myopia (≤-6 diopters and axial length ≥26.5 mm).

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions.

Update: Efficacy of Military Fluid Intake Guidance.

Background: Fluid intake during military training is prescribed based on the interactions among work rates, environmental conditions, and uniform configurations. The efficacy of this guidance has not been empirically assessed in over a decade. To determine the acceptability of the fluid intake guidance, sweat losses were measured in a variety of conditions with modern uniform/body armor configurations and were then compared to prescribed fluid intakes for each condition (workload, environment, clothing).

Comparing Outcomes of Tumor Prosthesis Revision and Locking Plate Fixation in Supracondylar Femoral Periprosthetic Fractures.

Background: Periprosthetic fractures around a total knee replacement (TKR) can be complex and difficult to manage, requiring the surgical expertise of the trauma and arthroplasty surgeon. There are a number of treatment modalities available, each with their own merits and limitations. As data on tumor prosthesis revision in periprosthetic fractures is sparse, this study aims to evaluate the results of revision using a tumor prosthesis and compare them with those of fixation using a locking plate in periprosthetic fractures after TKR.

Rheological behavior of biodegradable N-succinyl chitosan-g-poly (acrylic acid) hydrogels and their applications as drug carrier and in vitro theophylline release.

Novel pH sensitive N-succinyl chitosan-g-poly (acrylic acid) hydrogels were synthesized through free radical mechanism. Rheometer was used to observe the mechanical strength of the hydrogels. In vitro degradation was conducted in SIF (pH 7.

Frequent transmission of the Mycobacterium tuberculosis Beijing lineage and positive selection for the EsxW Beijing variant in Vietnam.

To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb.

Synthesis of Cyclobutadienoid-Fused Phenazines with Strongly Modulated Degrees of Antiaromaticity.

The streamlined synthesis of a series of regioisomeric azaacene analogues containing fused phenazine and antiaromatic cyclobutadienoids (CBDs), using a catalytic arene-oxanorbornene annulation, followed by aromatization is reported. Controlling the fusion patterns allowed strong modulation of local antiaromaticity. Enhancing antiaromaticity in these regioisomeric azaacenes led to stabilized LUMO, reduced band gap, and quenched fluorescence.

Similar radiological results with accelerometer-based navigation versus conventional technique in total knee arthroplasty.

Background: The Zimmer iASSIST system is an accelerometer-based, portable navigation device for total knee arthroplasty (TKA) that does not require the use of a large console for alignment feedback as required in computer-assisted surgery. The purpose of this study was to determine the accuracy of the accelerometer-based system in component positioning and overall mechanical alignment.

Methods: Two groups of 30 patients each with primary osteoarthritis underwent TKA using either conventional method or Zimmer iASSIST navigation in 2013 was retrospectively studied.

Interplay of cell death signaling pathways mediated by alternating magnetic field gradient.

The ability to control or manipulate the pathways leading to cell death plays a pivotal role in cancer treatment. We demonstrate magneto-actuation of magnetic nanoparticles (MNPs) to induce different cell death signaling pathways, exemplifying the intricate interplay between apoptosis and necrosis. In vitro cell experiments show the cell viabilities decreases with increasing field strength and is lower in cells treated with low aspect ratio MNPs.

Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

This corrects the article DOI: 10.1038/ncomms5999.

Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways.

Polycomb group (PcG) factors maintain facultative heterochromatin and mediate many important developmental and differentiation processes. EZH2, a PcG histone H3 lysine-27 methyltransferase, is repressed in senescent cells. We show here that downregulation of EZH2 promotes senescence through two distinct mechanisms.

Comparative whole-genome sequence analysis of Mycobacterium tuberculosis isolated from tuberculous meningitis and pulmonary tuberculosis patients.

Tuberculous meningitis (TBM) is a severe form of tuberculosis with a high mortality rate. The factors associated with TBM pathogenesis are still unclear. Using comparative whole-genome sequence analysis we compared Mycobacterium tuberculosis (Mtb) isolates from cerebrospinal fluid of TBM cases (n = 73) with those from sputum of pulmonary tuberculosis (PulTB) patients (n = 220) from Thailand.

Genetic relatedness of indigenous ethnic groups in northern Borneo to neighboring populations from Southeast Asia, as inferred from genome-wide SNP data.

The region of northern Borneo is home to the current state of Sabah, Malaysia. It is located closest to the southern Philippine islands and may have served as a viaduct for ancient human migration onto or off of Borneo Island. In this study, five indigenous ethnic groups from Sabah were subjected to genome-wide SNP genotyping.