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.

Hybrid Continuous-Flow Total Artificial Heart.

Clinical studies using total artificial hearts (TAHs) have demonstrated that pediatric and adult patients derive quality-of-life benefits from this form of therapy. Two clinically-approved TAHs and other pumps under development, however, have design challenges and limitations, including thromboembolic events, neurologic impairment, infection risk due to large size and percutaneous drivelines, and lack of ambulation, to name a few. To address these limitations, we are developing a hybrid-design, continuous-flow, implantable or extracorporeal, magnetically-levitated TAH for pediatric and adult patients with heart failure.

Total Artificial Hearts-Past, Current, and Future.

We present a review of the evolution of total artificial hearts (TAHs) and new directions in development, including the coupling of VADs as biventricular TAH support.

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.

Method of backflow reduction in ventricular assist devices.

Ventricular assist devices (VADs) have been developed to augment the deteriorating heart function of those suffering from end-stage congestive heart failure. While these devices have the potential to extend the life span and improve the quality of life of their recipients, they are also susceptible to mechanical failure. In the case of many known VADs, pump failure allows blood to flow retrograde through the device leading to a rapid loss of systemic pressure and loss of life.

Lifeflow vad: design and numerical modeling of magnetic bearing system.

The non-contact and lubrication free support of magnetic bearings make them ideal to support rotating machines. One area of application of magnetic bearings is in the design of the mechanical heart pumps. The LifeFlow heart pump developed by the University of Virginia is one such heart pump which uses active and passive magnetic bearings to support the impeller.

Gingival mucosa regeneration in athymic mice using in vitro engineered human oral mucosa.

Our goal was to investigate in vivo tissue formation following the grafting of engineered human oral mucosa to demonstrate its usefulness in replacing mucosal defects in the oral cavity. Human gingival cells were isolated from the oral mucosa and were used in combination with a collagen scaffold to engineer oral mucosa. Structural and ultrastructural analyses revealed that the engineered mucosa had a well-organized stratified epithelium on the surface of the fibroblast-populated lamina propria tissue.

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.

Numerical evaluation of blood damage in a magnetically levitated heart pump - biomed 2009.

The prospect of Ventricular Assist Devices used for long-term support of congestive heart failure patients is directly dependent upon excellent blood compatibility. High fluid stress levels may arise due to high rotational speeds and narrow clearances between the stationary and rotating parts of the pump. Thus, fluid stress may result in damage to red blood cells and activation of platelets, contributing to thrombus formation.

Implantable axialflow blood pump for left ventricular support.

Artificial blood pumps, either ventricular assist devices (VADs) or total artificial hearts, are currently employed for bridge to recovery, bridge to transplant, and destination therapy situations. The clinical effectiveness of VADs has been demonstrated; however, all of the currently available pumps have a limited life because of either the damage they cause to blood or their limited mechanical design life. A magnetically suspended rotary blood pump offers the potential to meet the requirements of both extending design life and causing negligible blood damage due to superior hemodynamics.

Gait synchronized force modulation during the stance period of one limb achieved by an active partial body weight support system.

Our purpose was to demonstrate the ability of an actively controlled partial body weight support (PBWS) system to provide gait synchronized support during the stance period of a single lower extremity while examining the affect of such a support condition on gait asymmetry. Using an instrumented treadmill and a motion capture system, we compared gait parameters of twelve healthy elderly subjects (age 65-80 years) during unsupported walking to those while walking with 20% body weight support provided during only the stance period of the right limb. Specifically, we examined peak three-dimensional ground reaction force (GRF) data and the symmetry of lower extremity sagittal plane joint angles and of time and distance parameters.

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.

Numerical design and experimental hydraulic testing of an axial flow ventricular assist device for infants and children.

Mechanical circulatory support options for infants and children are very limited in the United States. Existing circulatory support systems have proven successful for short-term pediatric assist, but are not completely successful as a bridge-to-transplant or bridge-to-recovery. To address this substantial need for alternative pediatric mechanical assist, we are developing a novel, magnetically levitated, axial flow pediatric ventricular assist device (PVAD) intended for longer-term ventricular support.

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.

Physiological modulation of gait variables by an active partial body weight support system.

Partial body weight support (PBWS) systems used for rehabilitation status post-neurological and musculoskeletal pathologies and injuries are traditionally passive. Our purpose was to demonstrate the ability of an actively controlled PBWS system to provide a clinically relevant modulated support condition while investigating the impact of such a condition on the dynamics of gait. Using an instrumented treadmill and a motion capture system, we compared gait parameters of six healthy young adults (age 24-31 years) during unsupported walking to those under the assistance of two support conditions (a constant 20% body weight support, and a modulated support providing 20% body weight support during the loading response of each leg while allowing for an unsupported terminal stance).

Fluid force predictions and experimental measurements for a magnetically levitated pediatric ventricular assist device.

The latest generation of artificial blood pumps incorporates the use of magnetic bearings to levitate the rotating component of the pump, the impeller. A magnetic suspension prevents the rotating impeller from contacting the internal surfaces of the pump and reduces regions of stagnant and high shear flow that surround fluid or mechanical bearings. Applying this third-generation technology, the Virginia Artificial Heart Institute has developed a ventricular assist device (VAD) to support infants and children.