Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type 1 diabetic hearts: A novel mechanism contributing to diabetic cardiomyopathy

Calpain plays a critical role in cardiomyopathic changes in type 1 diabetes (T1D). This study investigated how calpain regulates mitochondrial reactive oxygen species (ROS) generation in the development of diabetic cardiomyopathy. T1D was induced in transgenic mice overexpressing calpastatin, in mice with cardiomyocyte-specific capn4 deletion, or in their wild-type littermates by injection of streptozotocin. Calpain-1 protein and activity in mitochondria were elevated in diabetic mouse hearts. The increased mitochondrial calpain-1 was associated with an increase in mitochondrial ROS generation and oxidative damage and a reduction in ATP synthase-α (ATP5A1) protein and ATP synthase activity. Genetic inhibition of calpain or upregulation of ATP5A1 increased ATP5A1 and ATP synthase activity, preventedmitochondrial ROS generation and oxidative damage, and reduced cardiomyopathic changes in diabetic mice. High glucose concentration induced ATP synthase disruption, mitochondrial superoxide generation, and cell death in cardiomyocytes, all of which were prevented by overexpression of mitochondria-targeted calpastatin or ATP5A1. Moreover, upregulation of calpain-1 specifically in mitochondria induced the cleavage of ATP5A1, superoxide generation, and apoptosis in cardiomyocytes. In summary, calpain-1 accumulation in mitochondria disrupts ATP synthase and induces ROS generation, which promotes diabetic cardiomyopathy. These findings suggest a novel mechanism for and may have significant implications in diabetic cardiac complications

Beyond Gross-Pitaevskii Mean Field Theory

A large number of effects related to the phenomenon of Bose-Einstein Condensation (BEC) can be understood in terms of lowest order mean field theory, whereby the entire system is assumed to be condensed, with thermal and quantum fluctuations completely ignored. Such a treatment leads to the Gross-Pitaevskii Equation (GPE) used extensively throughout this book. Although this theory works remarkably well for a broad range of experimental parameters, a more complete treatment is required for understanding various experiments, including experiments with solitons and vortices. Such treatments should include the dynamical coupling of the condensate to the thermal cloud, the effect of dimensionality, the role of quantum fluctuations, and should also describe the critical regime, including the process of condensate formation. The aim of this Chapter is to give a brief but insightful overview of various recent theories, which extend beyond the GPE. To keep the discussion brief, only the main notions and conclusions will be presented. This Chapter generalizes the presentation of Chapter 1, by explicitly maintaining fluctuations around the condensate order parameter. While the theoretical arguments outlined here are generic, the emphasis is on approaches suitable for describing single weakly-interacting atomic Bose gases in harmonic traps. Interesting effects arising when condensates are trapped in double-well potentials and optical lattices, as well as the cases of spinor condensates, and atomic-molecular coupling, along with the modified or alternative theories needed to describe them, will not be covered here.Comment: Review Article (19 Pages) - To appear in 'Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment', Edited by P.G. Kevrekidis, D.J. Frantzeskakis and R. Carretero-Gonzalez (Springer Verlag

Relationship between knee pain and the presence, location, size and phenotype of femorotibial denuded areas of subchondral bone as visualized by MRI

Objective: Conflicting associations between imaging biomarkers and pain in knee osteoarthritis (OA) have been reported. A relation between pain and denuded areas of subchondral bone (dABs) has been suggested and this study explores this relationship further by relating the presence, phenotype, location and size of dABs to different measures of knee pain. Methods: 633 right knees from the Osteoarthritis Initiative (OAI) (250 men, age 61.7 +/- 9.6 yrs, BMI 29.4 +/- 4.7 kg/m(2)) were included. Manual segmentation of the femorotibial cartilage plates was performed on 3 T coronal fast low angle shot with water excitation (FLASHwe) images. dABs were defined as areas where the subchondral bone was uncovered by cartilage. The following measures of pain were used: weightbearing-, non-weightbearing-, moderate-to-severe-, infrequent- and frequent knee pain. Results: Using pain measures from subjects without dABs as a reference, those with at least one dAB had a 1.64-fold higher prevalence ratio [PR, 95% confidence interval (CI) 1.24-2.18] to have frequent and 1.45-fold higher for moderate-to-severe knee pain (95% CI 1.13-1.85). Subjects with dABs in central subregions had a 1.53-fold increased prevalence of having weightbearing pain (95% Cl 1.20-1.97), especially when the central subregion was moderately (>10%) denuded (PR 1.81, 95% CI 135-2.42). Individuals with cartilage-loss-type dABs had a slightly higher prevalence (PR 1.13, 95% CI 1.00-1.27) of having frequent knee pain compared to individuals with intra-chondral-osteophyte-type dABs. Conclusion: This study supports a positive relation between femorotibial dABs and knee pain, especially when the dABs are located centrally (i.e., in weightbearing regions) or when the respective central subregion is moderately denuded. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved

Raccoon rabies control and elimination in the northeastern USA and southern Québec, Canada

Rabies virus (RABV) is a deadly zoonosis that circulates in wild carnivore populations in North America. Intensive management within the USA and Canada has been conducted to control the spread of the raccoon (Procyon lotor) variant of RABV and work towards elimination. We examined RABV occurrence across the northeastern USA and southeastern Québec, Canada during 2008–2018 using a multi-method, dynamic occupancy model. Using a 10 km× 10 km grid overlaid on the landscape, we examined the probability that a grid cell was occupied with RABV and relationships with management activities (oral rabies vaccination (ORV) and trap-vaccinate-release efforts), habitat, neighbour effects and temporal trends. We compared raccoon RABV detection probabilities between different surveillance samples (e.g. animals that are strange acting, road-kill, public health samples). The management of RABV through ORV was found to be the greatest driver in reducing the occurrence of rabies on the landscape. Additionally, RABV occupancy declined further with increasing duration of ORV baiting programmes. Grid cells north of ORV management were at or near elimination (ψnorth = 0.00, S.E. = 0.15), managed areas had low RABV occupancy (ψmanaged = 0.20, S.E. = 0.29) and enzootic areas had the highest level of RABV occupancy (ψsouth = 0.83, S.E. = 0.06). These results provide evidence that past management actions have been being successful at the goals of reducing and controlling the raccoon variant of RABV. At a finer scale we also found that vaccine bait type and bait density impacted RABV occupancy. Detection probabilities varied; samples from strange acting animals and public health had the highest detection rates. Our results support the movement of the ORV zone south within the USA due to high elimination probabilities along the US border with Québec. Additional enhanced rabies surveillance is still needed to ensure elimination is maintained

Probing quantum and thermal noise in an interacting many-body system

The probabilistic character of the measurement process is one of the most puzzling and fascinating aspects of quantum mechanics. In many-body systems quantum mechanical noise reveals non-local correlations of the underlying many-body states. Here, we provide a complete experimental analysis of the shot-to-shot variations of interference fringe contrast for pairs of independently created one-dimensional Bose condensates. Analyzing different system sizes we observe the crossover from thermal to quantum noise, reflected in a characteristic change in the distribution functions from Poissonian to Gumbel-type, in excellent agreement with theoretical predictions based on the Luttinger liquid formalism. We present the first experimental observation of quasi long-range order in one-dimensional atomic condensates, which is a hallmark of quantum fluctuations in one-dimensional systems. Furthermore, our experiments constitute the first analysis of the full distribution of quantum noise in an interacting many-body system

Intelligent OS X malware threat detection with code inspection

With the increasing market share of Mac OS X operating system, there is a corresponding increase in the number of malicious programs (malware) designed to exploit vulnerabilities on Mac OS X platforms. However, existing manual and heuristic OS X malware detection techniques are not capable of coping with such a high rate of malware. While machine learning techniques offer promising results in automated detection of Windows and Android malware, there have been limited efforts in extending them to OS X malware detection. In this paper, we propose a supervised machine learning model. The model applies kernel base Support Vector Machine (SVM) and a novel weighting measure based on application library calls to detect OS X malware. For training and evaluating the model, a dataset with a combination of 152 malware and 450 benign were is created. Using common supervised Machine Learning algorithm on the dataset, we obtain over 91% detection accuracy with 3.9% false alarm rate. We also utilize Synthetic Minority Over-sampling Technique (SMOTE) to create three synthetic datasets with different distributions based on the refined version of collected dataset to investigate impact of different sample sizes on accuracy of malware detection. Using SMOTE datasets we could achieve over 96% detection accuracy and false alarm of less than 4%. All malware classification experiments are tested using cross validation technique. Our results reflect that increasing sample size in synthetic datasets has direct positive effect on detection accuracy while increases false alarm rate in compare to the original dataset

Functionals of the Brownian motion, localization and metric graphs

We review several results related to the problem of a quantum particle in a random environment. In an introductory part, we recall how several functionals of the Brownian motion arise in the study of electronic transport in weakly disordered metals (weak localization). Two aspects of the physics of the one-dimensional strong localization are reviewed : some properties of the scattering by a random potential (time delay distribution) and a study of the spectrum of a random potential on a bounded domain (the extreme value statistics of the eigenvalues). Then we mention several results concerning the diffusion on graphs, and more generally the spectral properties of the Schr\"odinger operator on graphs. The interest of spectral determinants as generating functions characterizing the diffusion on graphs is illustrated. Finally, we consider a two-dimensional model of a charged particle coupled to the random magnetic field due to magnetic vortices. We recall the connection between spectral properties of this model and winding functionals of the planar Brownian motion.Comment: Review article. 50 pages, 21 eps figures. Version 2: section 5.5 and conclusion added. Several references adde

In Situ Loading of Basic Fibroblast Growth Factor Within Porous Silica Nanoparticles for a Prolonged Release

Basic fibroblast growth factor (bFGF), a protein, plays a key role in wound healing and blood vessel regeneration. However, bFGF is easily degraded in biologic systems. Mesoporous silica nanoparticles (MSNs) with well-tailored porous structure have been used for hosting guest molecules for drug delivery. Here, we report an in situ route to load bFGF in MSNs for a prolonged release. The average diameter (d) of bFGF-loaded MSNs is 57 ± 8 nm produced by a water-in-oil microemulsion method. The in vitro releasing profile of bFGF from MSNs in phosphate buffer saline has been monitored for 20 days through a colorimetric enzyme linked immunosorbent assay. The loading efficiency of bFGF in MSNs is estimated at 72.5 ± 3%. In addition, the cytotoxicity test indicates that the MSNs are not toxic, even at a concentration of 50 μg/mL. It is expected that the in situ loading method makes the MSNs a new delivery system to deliver protein drugs, e.g. growth factors, to help blood vessel regeneration and potentiate greater angiogenesis

A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA

It is well recognized that base sequence exerts a significant influence on the properties of DNA and plays a significant role in protein–DNA interactions vital for cellular processes. Understanding and predicting base sequence effects requires an extensive structural and dynamic dataset which is currently unavailable from experiment. A consortium of laboratories was consequently formed to obtain this information using molecular simulations. This article describes results providing information not only on all 10 unique base pair steps, but also on all possible nearest-neighbor effects on these steps. These results are derived from simulations of 50–100 ns on 39 different DNA oligomers in explicit solvent and using a physiological salt concentration. We demonstrate that the simulations are converged in terms of helical and backbone parameters. The results show that nearest-neighbor effects on base pair steps are very significant, implying that dinucleotide models are insufficient for predicting sequence-dependent behavior. Flanking base sequences can notably lead to base pair step parameters in dynamic equilibrium between two conformational sub-states. Although this study only provides limited data on next-nearest-neighbor effects, we suggest that such effects should be analyzed before attempting to predict the sequence-dependent behavior of DNA

New insights into measurement variability in glaucomatous visual fields from computer modelling.

To develop a model to simulate visual fields (VFs) in glaucoma patients, and to characterize variability of the Mean Deviation (MD) VF summary measurement using real VFs and simulations