Long-telomeropathy is associated with tumor predisposition syndrome.

Telomeres protect chromosomal integrity, and telomere length (TL) is influenced by environmental and genetic factors. While short-telomeres are linked to rare telomeropathies, this study explored the hypothesis that a "long-telomeropathy" is associated with a cancer-predisposing syndrome. Using genomic and health data from 113,861 individuals, a trans-ancestry polygenic risk score for TL (PRS ) was developed.

Familial Renal Glucosuria and Potential Pharmacogenetic Impact on SGLT2 Inhibitors.

Background: Renal glucosuria is a rare inheritable trait caused by loss-of-function variants in the gene that encodes SGLT2 (i.e., SLC5A2).

Phenome-wide association study identifies new clinical phenotypes associated with Staphylococcus aureus infections.

Background: Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered.

Method And Cohorts: We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs.

An evolutionary learning-based method for identifying a circulating miRNA signature for breast cancer diagnosis prediction.

Breast cancer (BC) is one of the most commonly diagnosed cancers worldwide. As key regulatory molecules in several biological processes, microRNAs (miRNAs) are potential biomarkers for cancer. Understanding the miRNA markers that can detect BC may improve survival rates and develop new targeted therapeutic strategies.

Genetic and clinical determinants of telomere length.

Many epidemiologic studies have identified important relationships between leukocyte telomere length (LTL) with genetics and health. Most of these studies have been significantly limited in scope by focusing predominantly on individual diseases or restricted to GWAS analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks linked to genomic and phenomic data from medical records, we investigated the inter-relationship between LTL, genomics, and human health.

Survival estimation in patients with stomach and esophageal carcinoma using miRNA expression profiles.

Identifying a miRNA signature associated with survival will open a new window for developing miRNA-targeted treatment strategies in stomach and esophageal cancers (STEC). Here, using data from The Cancer Genome Atlas on 516 patients with STEC, we developed a Genetic Algorithm-based Survival Estimation method, GASE, to identify a miRNA signature that could estimate survival in patients with STEC. GASE identified 27 miRNAs as a survival miRNA signature and estimated the survival time with a mean squared correlation coefficient of 0.

Casein Kinase 1δ Stabilizes Mature Axons by Inhibiting Transcription Termination of Ankyrin.

After axon outgrowth and synapse formation, the nervous system transitions to a stable architecture. In C. elegans, this transition is marked by the appearance of casein kinase 1δ (CK1δ) in the nucleus.

Analysis of connecdenn 1-3 (DENN1A-C) GEF activity for Rab35.

Rabs (Ras-related proteins in brain) form the largest family of small GTPases and control numerous aspects of membrane trafficking at multiple cellular sites. Rab GTPases toggle between an inactive GDP-bound state and an active GTP-bound state. Activation of Rab GTPases requires guanine nucleotide exchange factors (GEFs) that interact with inactive GDP-bound Rabs and catalyze the removal of GDP, allowing GTP to bind.

Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration.

Cells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to downregulate an Arf6-dependent recycling pathway for β1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors.

The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes.

The DENN domain is an evolutionarily ancient protein module. Mutations in the DENN domain cause developmental defects in plants and human diseases, yet the function of this common module is unknown. We now demonstrate that the connecdenn/DENND1A DENN domain functions as a guanine nucleotide exchange factor (GEF) for Rab35 to regulate endosomal membrane trafficking.

Isolation of clathrin-coated vesicles by differential and density gradient centrifugation.

Clathrin-coated vesicles (CCVs) are an important class of transport organelles that mediate the endocytosis of proteins and lipids at the plasma membrane and the transport of proteins from the trans-Golgi network to the endosomal/lysosomal system. The authors describe a protocol for isolating CCVs from adult rat brain using differential centrifugation, Ficoll and D(2)O-sucrose density gradient centrifugation, and velocity sedimentation in linear sucrose gradients. The application of this basic method to the isolation of CCVs from developing rat brains and to the generation of relatively crude CCVs from cultured cells is also described.

The NECAP PHear domain increases clathrin accessory protein binding potential.

AP-2 is a key regulator of the endocytic protein machinery driving clathrin-coated vesicle (CCV) formation. One critical function, mediated primarily by the AP-2 alpha-ear, is the recruitment of accessory proteins. NECAPs are alpha-ear-binding proteins that enrich on CCVs.

Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis.

Clathrin-coated vesicles (CCVs) are responsible for the endocytosis of multiple cargo, including synaptic vesicle membranes. We now describe a new CCV protein, termed connecdenn, that contains an N-terminal DENN (differentially expressed in neoplastic versus normal cells) domain, a poorly characterized protein module found in multiple proteins of unrelated function and a C-terminal peptide motif domain harboring three distinct motifs for binding the alpha-ear of the clathrin adaptor protein 2 (AP-2). Connecdenn coimmunoprecipitates and partially colocalizes with AP-2, and nuclear magnetic resonance and peptide competition studies reveal that all three alpha-ear-binding motifs contribute to AP-2 interactions.

Non-stoichiometric relationship between clathrin heavy and light chains revealed by quantitative comparative proteomics of clathrin-coated vesicles from brain and liver.

We used tandem mass spectrometry with peptide counts to identify and to determine the relative levels of expression of abundant protein components of highly enriched clathrin-coated vesicles (CCVs) from rat liver. The stoichiometry of stable protein complexes including clathrin heavy chain and clathrin light chain dimers and adaptor protein (AP) heterotetramers was assessed. We detected a deficit of clathrin light chain compared with clathrin heavy chain in non-brain tissues, suggesting a level of regulation of clathrin cage formation specific to brain.

Tandem MS analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling.

Tandem MS has identified 209 proteins of clathrin-coated vesicles (CCVs) isolated from rat brain. An overwhelming abundance of peptides were assigned to the clathrin coat with a 1:1 stoichiometry observed for clathrin heavy and light chains and a 2:1 stoichiometry of clathrin heavy chain with clathrin adaptor protein heterotetramers. Thirty-two proteins representing many of the known components of synaptic vesicles (SVs) were identified, supporting that a main function for brain CCVs is to recapture SVs after exocytosis.