HEAT SHOCK PROTEINS: NOVEL THERAPEUTIC TARGETS AGAINST INSULIN RESISTANCE AND TYPE 2 DIABETES

Impaired insulin action, termed insulin resistance, is characteristic of type 2 diabetes, obesity and aging. Given the rising epidemic of diabetes, efforts to understand the mechanisms of insulin resistance and discover effective therapeutic interventions are urgent. Considerable evidence now implicates oxidative stress in the patho-physiology of insulin resistance, a condition prevalent in the elderly and obese. Oxidative stress is known to activate several signaling cascades. This includes pathways that activate the stress kinases c-Jun N-terminal kinase (JNK) and the inhibitor of kappa B kinase beta (IKK beta), which interact with and inhibit the insulin signaling cascade. The heat shock proteins HSP72 and HSP25 have been recently identified as natural inhibitors of JNK and IKK beta, respectively, and therefore represent novel therapeutic targets against insulin resistance. Overexpression of HSPs has been shown to protect against obesity-induced insulin resistance as well as age-related muscle damage. Skeletal muscle, the largest glucose disposing tissue, also contains large amounts of inducible HSPs. We hypothesized that heat shock protein overexpression in skeletal muscle could protect against insulin resistance in obesity and aging. We tested this hypothesis using aged male Fischer 344 rats (24-month-old) as the aging model of insulin resistance and male Wistar rats given a high fat diet (60% calories from fat) as the model of diet induced-insulin resistance. We examined the role of HSPs in insulin resistance by inducing HSP expression with both in vitro and in vivo heat treatments and anti-oxidant administration. Our results showed that reduced HSP expression in the aging muscles is associated with a higher degree of stress kinase activation and insulin resistance in fast-twitch muscles compared to slow-twitch muscles. Increasing HSP72 expression in the muscles of young and old animals via heat treatment inhibited JNK activation. Heat-mediated JNK inhibition was specific to HSP72 induction, as determined by HSP72-inhibition studies, and was mediated by a direct interaction between HSP72 and JNK. In contrast to the muscle, brain sections from aging rats showed a robust increase in HSP25 expression, suggesting a tissue-specific regulation of HSPs in aging. In the high fat diet model, alpha-lipoic acid (LA), a potent antioxidant, was administered to relieve oxidative stress associated with high fat feeding. LA treatment improved insulin signaling and glucose transport, reduced stress kinase activation and increased HSP expression. As another method of HSP-induction, heat treatment, given in parallel with a high fat diet, improved glucose tolerance, reduced hyperinsulinemia, and reduced epididymal fat storage. In skeletal muscles, heat treatment induced HSP72 expression, improved insulin sensitivity, and reduced stress kinase activities. Heat treatment also enhanced mitochondrial function in fast-twitch muscles, normalizing the compensatory changes in mitochondrial protein expression seen with high fat feeding. Studies in L6 myotubes showed that heat treatment improved oxygen consumption and fatty acid oxidation. Mechanistically, our results indicate that heat shock proteins can 1). improve insulin sensitivity, 2). directly inhibit stress kinase activities, and 3). protect and enhance mitochondrial function. Our studies provide strong evidence that HSP induction in skeletal muscle could be a potential therapeutic treatment for age-related and obesity-induced insulin resistance

Evaluation of the immunogenicity of liposome encapsulated HVR1 and NS3 regions of genotype 3 HCV, either singly or in combination

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus displays a high rate of mutation and exists as a quasispecies in infected patients. In the absence of an effective universal vaccine, genotype-specific vaccine development represents an alternative. We have attempted to develop a genotype 3 based, liposome encapsulated HCV vaccine with hypervariable region-1 (HVR1) and non-structural region-3 (NS3) components.</p> <p>Results</p> <p>HCV RNA extracted from serum samples of 49 chronically infected patients was PCR amplified to obtain HVR1 region. These amplified products were cloned to obtain 20 clones per sample in order to identify the quasispecies pattern. The HVR1 consensus sequence, along with three variants was reverse transcribed to obtain peptides. The peptides were checked for immunoreactivity individually, as a pool or as a single peptide tetramer interspersed with four glycine residues. Anti-HCV positivity varied from 42.6% (tetramer) to 92.2% (variant-4) when 115 anti-HCV positive sera representing genotypes 1, 3, 4 and 6 were screened. All the 95 anti-HCV negatives were scored negative by all antigens. Mice were immunized with different liposome encapsulated or Al(OH)₃adjuvanted formulations of HVR1 variants and recombinant NS3 protein, and monitored for anti-HVR1 and anti-NS3 antibody titres, IgG isotypes and antigen specific cytokine levels. A balanced Th1/Th2 isotyping response with high antibody titres was observed in most of the liposome encapsulated antigen groups. The effect of liposomes and aluminium hydroxide on the expression of immune response genes was studied using Taqman Low Density Array. Both Th1 (IFN-gamma, Il18) and Th2 (Il4) genes were up regulated in the liposome encapsulated HVR1 variant pool-NS3 combination group. In-vitro binding of the virus to anti-HVR1 antibodies was demonstrated.</p> <p>Conclusion</p> <p>The optimum immunogen was identified to be combination of peptides of HVR1 consensus sequence and its variants along with pNS3 encapsulated in liposomes, which could generate both cellular and humoral immune responses in mice deserving further evaluation in a suitable cell culture system/non-human primate model.</p

Emotion Based Music Player - XBeats

This paper showcases the development of an Android platform based application named XBeats which acts as a Music Player working on Image Processing fundamentals to capture, analyze and present music as per the emotion or mood of the user using this application. The Android application was developed using the Android SDK software and OpenCV software was used to implement facial recognition algorithms and cascades. The unique aspect of this project is that it focuses on facial recognition on the Android platform unlike that on Computer systems which use commonly available softwares for the same. This paper also provides comparison between use of various classification algorithms used for facial detection

Queue-length synchronization in a communication networks

We study synchronization in the context of network traffic on a $2-d$ communication network with local clustering and geographic separations. The network consists of nodes and randomly distributed hubs where the top five hubs ranked according to their coefficient of betweenness centrality (CBC) are connected by random assortative and gradient mechanisms. For multiple message traffic, messages can trap at the high CBC hubs, and congestion can build up on the network with long queues at the congested hubs. The queue lengths are seen to synchronize in the congested phase. Both complete and phase synchronization is seen, between pairs of hubs. In the decongested phase, the pairs start clearing, and synchronization is lost. A cascading master-slave relation is seen between the hubs, with the slower hubs (which are slow to decongest) driving the faster ones. These are usually the hubs of high CBC. Similar results are seen for traffic of constant density. Total synchronization between the hubs of high CBC is also seen in the congested regime. Similar behavior is seen for traffic on a network constructed using the Waxman random topology generator. We also demonstrate the existence of phase synchronization in real Internet traffic data.Comment: 13 Pages, 15 figure

Hot Dip Aluminising of Steel Wire- Laboratory Scale Investigations and Pilot Plant Studies

Protective quality of aluminium due to its adherent surface oxide film is well known. In hot-dip aluminising the use is made of this protective nature of aluminium by coating the steel base by dipping it in molten aluminium bath there-by getting an outer aluminium layer & an iron-aluminium layer at the interface. The interfacial alloy layer though possessing good atmospheric corrosion and resistance to oxidation at high temperature is brittle in nature and such must be kept to a minimum of thickness where the end use of aluminised product is for deep drawing, forming etc. Hot-dip aluminium coating on steel base comprising the outer aluminium layer and an alloy layer in the interface should possess both atmospheric & high temperature corrosion resistance

Neural Structures within Human Meniscofemoral Ligaments: A Cadaveric Study.

Aim. To investigate the existence of neural structures within the meniscofemoral ligaments (MFLs) of the human knee. Methods. The MFLs from 8 human cadaveric knees were harvested. 5 μm sections were H&E-stained and examined under light microscopy. The harvested ligaments were then stained using an S100 monoclonal antibody utilising the ABC technique to detect neural components. Further examination was performed on 60–80 nm sections under electron microscopy. Results. Of the 8 knees, 6 were suitable for examination. From these both MFLs existed in 3, only anterior MFLs were present in 2, and an isolated posterior MFL existed in 1. Out of the 9 MFLs, 4 demonstrated neural structures on light and electron microscopy and this was confirmed with S100 staining. The ultrastructure of these neural components was morphologically similar to mechanoreceptors. Conclusion. Neural structures are present in MFLs near to their meniscal attachments. It is likely that the meniscofemoral ligaments contribute not only as passive secondary restraints to posterior draw but more importantly to proprioception and may therefore play an active role in providing a neurosensory feedback loop. This may be particularly important when the primary restraint has reduced function as in the posterior cruciate ligament—deficient human knee

Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice

Deficiency of ACE2 in macrophages has been suggested to promote the development of an inflammatory M1 macrophage phenotype. We evaluated effects of ACE2 deficiency in bone-marrow-derived stem cells on adipose inflammation and glucose tolerance in C57BL/6 mice fed a high fat (HF) diet. ACE2 activity was increased in the stromal vascular fraction (SVF) isolated from visceral, but not subcutaneous adipose tissue of HF-fed mice. Deficiency of ACE2 in bone marrow cells significantly increased mRNA abundance of F4/80 and TNF-α in the SVF isolated from visceral adipose tissue of HF-fed chimeric mice, supporting increased presence of inflammatory macrophages in adipose tissue. Moreover, deficiency of ACE2 in bone marrow cells modestly augmented glucose intolerance in HF-fed chimeric mice and increased blood levels of glycosylated hemoglobin. In summary, ACE2 deficiency in bone marrow cells promotes inflammation in adipose tissue and augments obesity-induced glucose intolerance