Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci.

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B-trafficking proteins ABCD4 and LMBD1.

Vitamin B (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes and result in the cobalamin metabolism disorders cblF and cblJ.

Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.

Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits.

Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.

Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT.

Sunitinib specifically augments glucose-induced insulin secretion.

The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells.

A new immunochemistry platform for a guideline-compliant cardiac troponin T assay at the point of care: proof of principle.

Background: A multitude of troponin assays for the point-of-care (POC) have been developed showing a lack of analytical sensitivity and precision. We present a new platform solution for the high-sensitivity detection of cardiac troponin T (cTnT) in a 30 μL whole blood sample with a turnaround time of 11 min.

Methods: The immunoassay was completely run in a ready-to-use plastic disposable, a centrifugal microfluidic disc with fully integrated reagents.

Biological phosphorylation of an Unnatural Base Pair (UBP) using a Drosophila melanogaster deoxynucleoside kinase (DmdNK) mutant.

One research goal for unnatural base pair (UBP) is to replicate, transcribe and translate them in vivo. Accordingly, the corresponding unnatural nucleoside triphosphates must be available at sufficient concentrations within the cell. To achieve this goal, the unnatural nucleoside analogues must be phosphorylated to the corresponding nucleoside triphosphates by a cascade of three kinases.

Genetic correlation between smoking behaviors and schizophrenia.

Nicotine dependence is highly comorbid with schizophrenia, and the etiology of the comorbidity is unknown. To determine whether there is a genetic correlation of smoking behavior with schizophrenia, genome-wide association study (GWAS) meta-analysis results from five smoking phenotypes (ever/never smoker (N=74,035), age of onset of smoking (N=28,647), cigarettes smoked per day (CPD, N=38,860), nicotine dependence (N=10,666), and current/former smoker (N=40,562)) were compared to GWAS meta-analysis results from schizophrenia (N=79,845) using linkage disequilibrium (LD) score regression. First, the SNP heritability (h) of each of the smoking phenotypes was computed using LD score regression (ever/never smoker h=0.

Efficacy of single fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review and meta-analysis.

Background: Single fraction radiotherapy (SFRT) and multiple fraction radiotherapy (MFRT) are effective for painful uncomplicated bone metastases and have been shown to be of similar efficacy. The optimal conventional external beam SFRT dose for maximum pain relief remains uncertain. The aim of this systematic review was to comprehensively review and synthesize overall pain response rates by dose.

Palliative care and palliative radiation therapy education in radiation oncology: A survey of US radiation oncology program directors.

Purpose: The purpose of this study was to assess the state of palliative and supportive care (PSC) and palliative radiation therapy (RT) educational curricula in radiation oncology residency programs in the United States.

Methods And Materials: We surveyed 87 program directors of radiation oncology residency programs in the United States between September 2015 and November 2015. An electronic survey on PSC and palliative RT education during residency was sent to all program directors.

Hypoxia-stimulated membrane trafficking requires T-plastin.

Aim: Traffic between the plasma membrane and the endomembrane compartments is an essential feature of eukaryotic cells. The secretory pathway sends cargoes from biosynthetic compartments to the plasma membrane. This is counterbalanced by a retrograde endocytic route and is essential for cell homoeostasis.

The First Biocatalytic Carbon-Silicon Bond Formation.

Linking two worlds: As a further expansion of the biocatalytic repertoire, carbene insertion into Si-H bonds catalyzed by the heme protein cytochrome c was recently reported. This new biocatalyst holds great promise because it enables the highly selective incorporation of silicon into molecules without prior protection of existing functional groups.

Gene-based segregation method for identifying rare variants in family-based sequencing studies.

Whole-exome sequencing using family data has identified rare coding variants in Mendelian diseases or complex diseases with Mendelian subtypes, using filters based on variant novelty, functionality, and segregation with the phenotype within families. However, formal statistical approaches are limited. We propose a gene-based segregation test (GESE) that quantifies the uncertainty of the filtering approach.

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis.

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear.

Two-state reactivity in C-H activation by a four-coordinate iron(0) complex.

The ground state structure of [PhB(BuIm)Fe(CO)] is trigonal pyramidal (S = 1), with a thermally accessible square planar (S = 0) geometry. Experimentally calibrated electronic structure calculations provide evidence for two-state reactivity, with C-H oxidative addition on the singlet surface providing an iron(ii) product (S = 0).

Paralog-Specific Functions of and Mediated by Ribosomal Protein or snoRNA Dosage in .

Most ribosomal proteins in are encoded by two paralogs that additively produce the optimal protein level for cell growth. Nonetheless, deleting one paralog of most ribosomal protein gene pairs results in a variety of phenotypes not observed when the other paralog is deleted. To determine whether paralog-specific phenotypes associated with deleting or stem from distinct functions or different levels of the encoded isoforms, the coding region and introns of one paralog, including an intron-embedded snoRNA (small nucleolar RNA) gene, were exchanged with that of the other paralog.

Arrested α-hydride migration activates a phosphido ligand for C-H insertion.

Bulky tris(carbene)borate ligands provide access to high spin iron(ii) phosphido complexes. The complex PhB(MesIm)FeP(H)Ph is thermally unstable, and [PPh] group insertion into a C-H bond of the supporting ligand is observed. An arrested α-hydride migration mechanism suggests increased nucleophilicity of the phosphorus atom facilitates [PPh] group transfer reactivity.

A Single Deoxynucleoside Kinase Variant from Drosophila melanogaster Synthesizes Monophosphates of Nucleosides That Are Components of an Expanded Genetic System.

Deoxynucleoside kinase from D. melanogaster (DmdNK) has broad specificity; although it catalyzes the phosphorylation of natural pyrimidine more efficiently than natural purine nucleosides, it accepts all four 2'-deoxynucleosides and many analogues, using ATP as a phosphate donor to give the corresponding deoxynucleoside monophosphates. Here, we show that replacing a single amino acid (glutamine 81 by glutamate) in DmdNK creates a variant that also catalyzes the phosphorylation of nucleosides that form part of an artificially expanded genetic information system (AEGIS).

Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure.

Background: Chronic heart failure (HF) is associated with altered signal transduction via β-adrenoceptors and G proteins and with reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of patients with end-stage HF, but the functional consequences of this are largely unknown, particularly for NDPK-C. Here, we investigated the potential role of NDPK-C in cardiac cAMP formation and contractility.

Active Music Therapy and Physical Improvements From Rehabilitation for Neurological Conditions.

Context • A variety of rehabilitation-based interventions are currently available for individuals with physical impairments resulting from neurological conditions, including physiotherapy, occupational therapy, and speech language pathology. Many individuals find participation in those therapies to be challenging. Alternative therapies have emerged as beneficial adjunctive treatments for individuals undergoing neurological rehabilitation, including music therapy (MT).

Asymmetric Ketone Reduction by Imine Reductases.

The rapidly growing area of asymmetric imine reduction by imine reductases (IREDs) has provided alternative routes to chiral amines. Here we report the expansion of the reaction scope of IREDs by showing the stereoselective reduction of 2,2,2-trifluoroacetophenone. Assisted by an in silico analysis of energy barriers, we evaluated asymmetric hydrogenations of carbonyls and imines while considering the influence of substrate reactivity on the chemoselectivity of this novel class of reductases.

A general approach to testing for pleiotropy with rare and common variants.

Through genome-wide association studies, numerous genes have been shown to be associated with multiple phenotypes. To determine the overlap of genetic susceptibility of correlated phenotypes, one can apply multivariate regression or dimension reduction techniques, such as principal components analysis, and test for the association with the principal components of the phenotypes rather than the individual phenotypes. However, as these approaches test whether there is a genetic effect for at least one of the phenotypes, a significant test result does not necessarily imply pleiotropy.

Pulmonary Predictors of Incident Diabetes in Smokers.

Background: Diabetes mellitus and its complications are a large and increasing burden for health care worldwide. Reduced pulmonary function has been observed in diabetes (both type 1 and type 2), and this reduction is thought to occur prior to diagnosis. Other measures of pulmonary health are associated with diabetes, including lower exercise tolerance, greater dyspnea, lower quality of life (as measured by the St.