Nano-Sim: A Step Wise Equivalent Conductance based Statistical Simulator for Nanotechnology Circuit Design

New nanotechnology based devices are replacing CMOS devices to overcome CMOS technology's scaling limitations. However, many such devices exhibit non-monotonic I-V characteristics and uncertain properties which lead to the negative differential resistance (NDR) problem and the chaotic performance. This paper proposes a new circuit simulation approach that can effectively simulate nanotechnology devices with uncertain input sources and negative differential resistance (NDR) problem. The experimental results show a 20-30 times speedup comparing with existing simulators.Comment: Submitted on behalf of EDAA (http://www.edaa.com/

Structural basis of mitochondrial receptor binding and constriction by DRP1.

Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery

Removal of High-Molecular-Weight DNA by Carboxylated Magnetic Beads Enhances the Detection of Mutated K-ras DNA in Urine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75249/1/annals.1448.019.pd

An electronic family health history tool to identify and manage patients at increased risk for colorectal cancer: protocol for a randomized controlled trial.

BackgroundColorectal cancer is the fourth most commonly diagnosed cancer in the United States. Approximately 3-10% of the population has an increased risk for colorectal cancer due to family history and warrants more frequent or intensive screening. Yet, < 50% of that high-risk population receives guideline-concordant care. Systematic collection of family health history and decision support may improve guideline-concordant screening for patients at increased risk of colorectal cancer. We seek to test the effectiveness of a web-based, systematic family health history collection tool and decision support platform (MeTree) to improve risk assessment and appropriate management of colorectal cancer risk among patients in the Department of Veterans Affairs primary care practices.MethodsIn this ongoing randomized controlled trial, primary care providers at the Durham Veterans Affairs Health Care System and the Madison VA Medical Center are randomized to immediate intervention or wait-list control. Veterans are eligible if assigned to enrolled providers, have an upcoming primary care appointment, and have no conditions that would place them at increased risk for colorectal cancer (such as personal history, adenomatous polyps, or inflammatory bowel disease). Those with a recent lower endoscopy (e.g. colonoscopy, sigmoidoscopy) are excluded. Immediate intervention patients put their family health history information into a web-based platform, MeTree, which provides both patient- and provider-facing decision support reports. Wait-list control patients access MeTree 12 months post-consent. The primary outcome is the risk-concordant colorectal cancer screening referral rate obtained via chart review. Secondary outcomes include patient completion of risk management recommendations (e.g. colonoscopy) and referral for genetic consultation. We will also conduct an economic analysis and an assessment of providers' experience with MeTree clinical decision support recommendations to inform future implementation efforts if the intervention is found to be effective.DiscussionThis trial will assess the feasibility and effectiveness of patient-collected family health history linked to decision support to promote risk-appropriate screening in a large healthcare system such as the Department of Veterans Affairs.Trial registrationClinicalTrials.gov, NCT02247336 . Registered on 25 September 2014

Serum Levels of Alpha-1 Antitrypsin following Vascular Limb or Intra-Muscular Delivery of AAV1 or AAV8 Gene Therapy Vectors in Rhesus Macaques

Alpha-one antitrypsin (AAT) deficiency is a genetic disease that results in both lung disease and potentially liver failure in affected patients. In un-affected people AAT is produced in the liver and secreted to act as an anti-protease (primarily counteracting the effects of neutrophil elastase) in the lung. On-going human clinical trials have focused on intra-muscular delivery of adeno-associated virus (AAV1) to patients. The goal of delivery to the muscle is to have the myocytes serve as bio-factories to produce normal AAT protein and secrete it into the blood where it can exert its normal function in the lung. In the last Phase II trial patients in the highest dose cohort were given 100 intra-muscular (IM) injections with serum AAT levels still below therapeutic thresholds. Previous work has shown that delivering AAV vector to the musculature of the limb via the vasculature, while blood flow is obstructed using a tourniquet, leads to wide-spread gene expression in myocytes. We hypothesize that local delivery via IM injection results in saturated AAT expression within the myocytes surrounding the injection sight and that a more widespread delivery would result in an overall increase in serum AAT levels with the same dose of AAV gene therapy vector due to production by a larger overall number of myocytes. We have been able to show that we can attain similar or slightly higher (573.0 ng/ml versus 562.5 ng/nl) serum AAT levels using a vascular delivery method in rhesus macaques when compared to IM delivery. These results have been obtained using AAV1. Animals receiving either AAV1 or AAV8 show a decrease in muscle immune cell infiltrates following intra-vascular delivery versus IM delivery, which may improve long-term expression. Serum AAT data from animals dosed using AAV8, a serotype shown to better target muscle following vascular delivery, are currently being processed

Evolution of the Alpha-1 Antitrypsin Muscle Gene Therapy: Translation from Clinical Trial to Benchtop and Back Again

Alpha-one antitrypsin (AAT) deficiency is a genetic disease affecting the lungs due to inadequate anti-protease activity in the pulmonary interstitium. On-going human trials use intra-muscular delivery of adeno-associated virus (rAAV1), allowing expressing myofibers to secrete normal (M)AAT protein. In the Phase IIa trial, patients in the highest dose cohort (6x1012vg/kg) were given 100 intra-muscular (IM) injections of undiluted vector, with serum AAT levels still substantially below target levels. Previous work has shown that delivering rAAV vector to the musculature via limb perfusion leads to widespread gene expression in myofibers. We hypothesize that widespread delivery would result in an overall increase in serum AAT levels with the same dose of AAV gene therapy vector and allow for increased volume and thereby dose of vector. In macaques, similar serum myc-tagged rhAAT was produced using regional venous infusion when compared to direct IM delivery at the same total vg dose with either rAAV1 or rAAV8, while not being limited to a small volume as with IM injection. These data prove the concept that a 30-fold expanded volume of rAAV-AAT could be delivered to myofibers using limb perfusion without loss of potency on a per vg basis, thereby enabling potential achievement of therapeutic AAT levels in patients. This will allow us to proceed to a phase IIb clinical trial in AAT patients employing venous limb perfusion

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection