Lysosomal pH Plays a Key Role in Regulation of mTOR Activity in Osteoclasts.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth. It has been shown to play an important role in osteoclast differentiation, particularly at the earlier stages of osteoclastogenesis. mTOR activation and function, as part of mTORC1 complex, is dependent on lysosomal localization and the vacuolar H(+) -ATPase (V-ATPase) activity; however, the precise mechanism is still not well understood.

Improving customized fetal biometry by longitudinal modelling.

Objective: To develop customized biometric charts to better define abnormal fetal growth.

Methods: A total of 1056 singleton fetuses from the Raine Study underwent serial ultrasound biometry (abdominal circumference [AC], head circumference, and femur length) at 18, 24, 28, 34, and 38 weeks' gestation. Customized biometry trajectories were developed adjusting for epidemiological influences upon fetal biometry using covariates available at 18 weeks gestation.

Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls.

T cell activation is reduced by the catalytically inactive form of protein tyrosine phosphatase SHP-2.

Src-homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) is a ubiquitously expressed cytosolic tyrosine phosphatase implicated in many different signaling pathways involving cytokine receptors and T and B cell receptors; however, the precise functional role of SHP-2 in T cell signaling is not entirely clear. In this study, we overexpressed a catalytically inactive form of SHP-2 with a classic cysteine 459-to-serine mutation (dnSHP-2) to elucidate the in vivo effects of SHP-2 on T cells. We found that mice overexpressing dnSHP-2 showed reduced T cell activation, presumably due to increased tyrosine phosphorylation of Grb2-binding protein (Gab2) and inhibition of mitogen-activated protein kinase (MAPK) activity.

A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis.

During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4.

Atypical Cadherin Fat1 Is Required for Lens Epithelial Cell Polarity and Proliferation but Not for Fiber Differentiation.

Purpose: The Fat family of atypical cadherins, originally identified in Drosophila, play diverse roles during embryogenesis and adult tissue maintenance. Among four mammalian members, Fat1 is essential for kidney and muscle organization, and is also essential for eye development; Fat1 knockout causes partial penetrant microphthalmia or anophthalmia. To account for the partial penetrance of the Fat1 phenotype, involvement of Fat4 in eye development was assessed.

Risk of cardiovascular events and mortality among a population-based cohort of immigrants and long-term residents with diabetes: Are all immigrants healthier and if so, for how long?

Background: Cardiovascular events are responsible for half of all deaths among individuals with diabetes. Immigrants to Western countries may experience an acceleration of cardiovascular risk in the first 10 years of arrival because of a sedentary lifestyle, poor diet, or barriers to accessing care, leading to higher levels of obesity and diabetes.

Objectives: To compare the risk of cardiovascular events and mortality between immigrants to Canada and long-term residents with diabetes and to assess whether immigrants experience acceleration in risk after arrival.

Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death.

Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells.

A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project.

Accuracy of testosterone concentrations in compounded testosterone products.

Objective: This study aims to evaluate the accuracy of the testosterone concentrations within testosterone gels and creams manufactured by compounding pharmacies.

Methods: Ten compounding pharmacies within Toronto area were included. Pharmacies were blinded as to the nature of the study.

Associations of circulating 25(OH)D with cardiometabolic disorders underlying type 2 diabetes mellitus in an Aboriginal Canadian community.

Aims: To investigate the associations of 25-hydroxyvitamin D (25(OH)D) with insulin resistance (IR), beta-cell function and metabolic syndrome (MetS) in a First Nations population.

Methods: We conducted a cross-sectional analysis using data from the Sandy Lake Health and Diabetes Project (2003-2005). A total of 390 participants (>12 y) were assessed for 25(OH)D, fasting glucose, insulin, lipids, blood pressure, inflammatory markers, anthropometric and lifestyle variables and a 75-g oral glucose tolerance test was administered.

A microfluidic technique for quantification of steroids in core needle biopsies.

Core needle biopsy (CNB) sampling is known to be inexpensive and minimally invasive relative to traditional tissue resectioning. But CNBs are often not used in analytical settings because of the tiny amount of sample and analyte. To address this challenge, we introduce an analytical method capable of multiplexed steroid quantification in CNB samples-those studied here ranged in mass from 2 to 8 mg.

Proteomic analysis of the palmitoyl protein thioesterase 1 interactome in SH-SY5Y human neuroblastoma cells.

Unlabelled: Neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive childhood disorders, characterized by early accumulation of autofluorescent storage material in lysosomes of neurons or other cells. Clinical symptoms of NCL include: progressive loss of vision, mental and motor deterioration, epileptic seizures and premature death. CLN1 disease (MIM#256730) is caused by mutations in the CLN1 gene, which encodes palmitoyl protein thioesterase 1 (PPT1).

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach.

RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins.

Vitamin D metabolic pathway genes and pancreatic cancer risk.

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma.

Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci.

The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.

Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication.

The distinct genetic pattern of ALS in Turkey and novel mutations.

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.

Non-synchronized endometrium and its correction in non-ovulatory cryopreserved embryo transfer cycles.

The aim of this case series study was to investigate the effect of adjusting the length of progesterone exposure on clinical pregnancy rates in cryopreserved embryo transfer cycles of patients with out-of-phase classic endometrial dating. Eighty infertile women with previous implantation failure and good-quality embryos underwent endometrial biopsy before cryopreserved embryo transfer and were included in this study. The main outcome measures were clinical pregnancy rate and histologic endometrial dating.

Septal Glucagon-Like Peptide 1 Receptor Expression Determines Suppression of Cocaine-Induced Behavior.

Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction.

Integrative genomics and transcriptomics analysis of human embryonic and induced pluripotent stem cells.

Background: Human genomic variations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), are associated with several phenotypic traits varying from mild features to hereditary diseases. Several genome-wide studies have reported genomic variants that correlate with gene expression levels in various tissue and cell types.

Results: We studied human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) measuring the SNPs and CNVs with Affymetrix SNP 6 microarrays and expression values with Affymetrix Exon microarrays.

AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress.

Mitochondrial respiration is a crucial component of cellular metabolism that can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress.

Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease.

Polycystic kidney diseases (PKDs) are inherited disorders characterized by the formation of fluid filled renal cysts. Elevated cAMP levels in PKDs stimulate progressive cyst enlargement involving cell proliferation and transepithelial fluid secretion often leading to end-stage renal disease. The glycogen synthase kinase-3 (GSK3) family of protein kinases consists of GSK3α and GSK3β isoforms and has a crucial role in multiple cellular signaling pathways.

Abdominal adiposity and insulin resistance in early pregnancy.

Background: High pre-pregnancy body mass index is a known risk factor for gestational diabetes mellitus, but the contribution of abdominal adiposity to insulin resistance (IR) in pregnancy is not well understood. We assessed the association between abdominal adiposity in early pregnancy and IR.

Methods: We completed a prospective cohort study of 79 pregnant women.