Heat shock genes-integrating cell survival and death

Heat shock induced gene expression and other cellular responses help limit the damage caused by stress and thus facilitate cellular recovery. Cellular damage also triggers apoptotic cell death through several pathways. This paper briefly reviews interactions of the major heat shock proteins with components of the apoptotic pathways. Hsp90, which acts as a chaperone for unstable signal transducers to keep them poised for activation, interacts with RIP and Akt and promotes NF-κB mediated inhibition of apoptosis; in addition it also blocks some steps in the apoptotic pathways. Hsp70 is mostly anti-apoptotic and acts at several levels like inhibition of translocation of Bax into mitochondria, release of cytochrome c from mitochondria, formation of apoptosome and inhibition of activation of initiator caspases. Hsp70 also modulates JNK, NF-κB and Akt signaling pathways in the apoptotic cascade. In contrast, Hsp60 has both anti- and pro-apoptotic roles. Cytosolic Hsp60 prevents translocation of the pro-apoptotic protein Bax into mitochondria and thus promotes cell survival but it also promotes maturation of procaspase-3, essential for caspase mediated cell death. Our recent in vivo studies show that RNAi for the Hsp60D in Drosophila melanogaster prevents induced apoptosis. Hsp27 exerts its anti-apoptotic influence by inhibiting cytochrome c and TNF-mediated cell death. αβ crystallin suppresses caspase-8 and cytochrome c mediated activation of caspase-3. Studies in our laboratory also reveal that absence or reduced levels of the developmentally active as well as stress induced non-coding hsrω transcripts, which are known to sequester diverse hnRNPs and related nuclear RNA-binding proteins, block induced apoptosis in Drosophila. Modulation of the apoptotic pathways by Hsps reflects their roles as "weak links" between various "hubs" in cellular networks. On the other hand, non-coding RNAs, by virtue of their potential to bind with multiple proteins, can act as "hubs" in these networks. In view of the integrative nature of living systems, it is not surprising that stress-induced genes, generally believed to primarily function in cell survival pathways, inhibit or even promote cell death pathways at multiple levels to ensure homeostasis at cell and/or organism level. The heat shock genes obviously do much more than merely help cells survive stress

Cost Estimation Tool for Commercial Software Development Industries

ABSTRACT: As cost associated to the software development is increasing continuously, there is a need to direct attention at better understanding of development process and calibrating previous models and methods making them applicable to existing environment such as proposing hybrid tools using the techniques based on existing models. The main aim of this paper is to improve the cost estimation accuracy of applications at all the phases of a software development lifecycle by calibrating COCOMO using a function point as a size measure instead of SLOC being used in COCOMO model. Here we have discussed the working of proposed software estimation tool that is a hybrid implementation of various software estimation and measurement techniques helping an organization to determine metrics such as Effort, Time and Cost, essential for improving turnaround time. This tool also works towards utilizing these metrics for project planning, scheduling and tracking

A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by ER aminopeptidase 1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12mer progressed at a considerable rate, albeit still slower than in solution. Results from thermodynamic, kinetic and computational analyses suggested that this 12mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissociation. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from pre-formed MHCI complexes as efficiently as ERAP1. A pseudopeptide analogue with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1-MHCI-peptide complex. Similarly, no interactions between ERAP1 and purified peptide loading complex (PLC) were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degradation and that trimming in solution, along with the dynamic nature of peptide binding to MHCI, are sufficient to explain ERAP1 processing of antigenic peptide precursors

A Review: Protein Interaction & Behavior Assessment in Host Cells after Novel Drug Compound Administration using Systems Biology Approach

To understand complex biological systems requires the integration of experimental and computational research; in other words systems biology approach. Computational biology, through via different software helps in exploration more than one gene expression at a time and also understanding the connectivity, Systems Biology provides a powerful foundation from which to address critical scientific questions head-on. The reviews in this Insight cover many different aspects of this energetic field, although all, in one way or another, illuminate the functioning of modular circuits, including their robustness, design and manipulation. Computational systems biology addresses questions fundamental to our understanding of life, yet progress here will lead to practical innovations in medicine, drug discovery and engineering, In this study we have evaluated th

Formation of primordial black holes from warm inflation

Primordial Black Holes (PBHs) serve as a unique probe to the physics of the early Universe, particularly inflation. In light of this, we study the formation of PBHs by the collapse of overdense perturbations generated during a model of warm inflation. For our model, we find that the primordial curvature power spectrum is red-tilted (spectral index ns1) for the small PBH scales (large k), with a sufficiently large amplitude of the primordial curvature power spectrum required to form PBHs. These features originate because of the inflaton's coupling with the other fields during warm inflation. We discuss the role of the inflaton dissipation to the enhancement in the primordial power spectrum at the PBH scales. We find that for some parameter range of our warm inflation model, PBHs with mass ?103 g can be formed with significant abundance. Such tiny mass PBHs have a short lifetime ?10?19 s and would have evaporated into Hawking radiation in the early Universe. Further in this study, we discuss the evaporation constraints on the initial mass fraction of the generated PBHs and the possibility of Planck mass PBH relics to constitute the dark matter.by Richa Ary

Gravitino production in a thermal Universe revisited

We study the production of spin 1/2 gravitinos in a thermal Universe. Taking into account supersymmetry breaking due to the finite thermal energy density of the Universe, there is a large enhancement in the cross section of production of these gravitino states. We consider gravitinos with zero temperature masses of 0.1 eV, 1 keV, 100 GeV and 30 TeV as representative of gauge mediated, gravity mediated and anomaly mediated supersymmetry breaking scenarios. We find that the abundance of gravitinos produced in the early Universe is very high for gravitinos of mass 1 keV and 100 GeV. The gravitino abundances can be sufficiently suppressed if the reheat temperature is less than 100 GeV and 4\times10^4 \gev respectively. However such low reheat temperatures will rule out many models of baryogenesis including those via leptogenesis.by Richa Arya, Namit Mahajan, Raghavan Rangaraja

An epidemiological profile of otorhinolaryngological disorders in the patients attending ENT OPD of H.N.B Base teaching hospital of VCSGGRMS & R I, Srinagar, Pauri, Garhwal

Background: ENT diseases are amongst most common causes for patient to report to hospital in both rural and urban setups. Since India is developing country with growing economy, its health system is still evolving. This study was done to assimilate the data on patients reporting to ENT OPD in past year so that the future treatment and trend of diseases could be studied and managed. It will help in further reconstruction of health care system of Pauri, Garhwal region. Objective: study conducted to determine the disease pattern and presentations of patients attending OPD of ENT department over a period of 1 year & to study the variation in the disease patterns between the genders & the age group in this region of the country. Material & Method: This was a retrospective record based study was carried in the department of ENT. It included patients who had attended the OPD of ENT department of H.N.B Base teaching hospital of VCSGGRMS&RI, Srinagar, Pauri Garhwal between 15th July 2014 to 14th July 2015. Results: In this Study, we observed that males of younger age group constituted the maximum percentage. Among all the cases presenting to the OPD complaints were of ear being impacted wax, (H61.2) second was CSOM (H66.1-2). It was noticed that throat complaint was third complaint leading to OPD visits, in which acute pharyngitis was commonest. Conclusion: Impacted wax or cerumen is most common disease for seeking medical advice in our centre

Hsp60D-A novel modifier of polyglutamine-mediated neurodegeneration in Drosophila

Background: Several dominant neurodegenerative disorders result from alleles carrying expanded stretch of polyglutamine (polyQ) tracts in the encoded proteins, which become toxic and form insoluble cytoplasmic and/or nuclear aggregates or "inclusion bodies" in the affected neuronal cells. Purpose: Present study identified Hsp60D, a member of the Drosophila Hsp60 family, as a novel modifier of neurodegeneration in fly models of polyQ disorders, viz., Spinocerebellar Ataxia type 3 (SCA3, caused by mutated MJDtr-Q78 allele) or the 127Q model. Methods: Immunostaining of third instar larval eye discs was carried out and the eye discs of 50-hours old pupae of different genotypes were stained with Phalloidin-Rhodamine to examine the organization of actin filaments in ommatidial units. The nail polish imprints of adult eye surfaces were examined and the assay was performed using a glass Y-maze. Results: We showed that the reduction in the cellular levels of Hsp60D protein through directed RNAi in the polyQ expressing developing eye cells not only improved external eye morphology, retinal structure and vision, but also reduced the number of inclusion bodies and the associated expression of Hsp70. Conclusion: Our results suggest that Hsp60D may be required for folding of polypeptides with polyQ stretches so that in its absence, due to targeted RNAi, the expanded polyQ polypeptides fail to fold in a manner that can produce the toxic inclusion bodies

Life in High Salt Concentrations with Changing Environmental Conditions: Insights from Genomic and Phenotypic Analysis of Salinivibrio sp.

Life in salt pans with varying chemical compositions require special adaptation strategies at both the physiological and molecular level. The Marakkanam salt pan in South India is characterized with a high fluctuation in salinity (19–490 ppt), Ultravioletradiation, and heavy metal concentrations. Several bacterial species have been isolated and identified in the view of phylogenetic analysis and for the subsequent production of industrially important enzymes. However, limited information exists on the genomic basis of their survival under variable environmental conditions. To this extent, we sequenced the whole genome of the Salinivibrio sp. HTSP, a moderately halophilic bacterium. We analysed the physiological and genomic attributes of Salinivibrio sp. HTSP to elucidate the strategies of adaptation under various abiotic stresses. The genome size is estimated to be 3.39 Mbp with a mean G + C content of 50.6%, including 3150 coding sequences. The genome possessed osmotic stress-related coding sequences, and genes involved in different pathways of DNA repair mechanisms and genes related to the resistance to toxic metals were identified. The periplasmic stress response genes and genes of different oxidative stress mechanisms were also identified. The tolerance capacity of the bacterial isolates to heavy metals, UV-radiation, and salinity was also confirmed through appropriate laboratory experiments under controlled conditions

Survival of Inoculated Vibrio spp., Shigatoxigenic Escherichia coli, Listeria monocytogenes, and Salmonella spp. on Seaweed (Sugar Kelp) During Storage

Bacteria including Vibrio spp. persist in coastal waters and can contaminate edible seaweeds. Pathogens such as Listeria monocytogenes, shigatoxigenic Escherichia coli (STEC), and Salmonella have been associated with and present serious health risks in minimally processed vegetables including seaweeds. This study evaluated the survival of four pathogens inoculated onto two product forms of sugar kelp subjected to different storage temperatures. The inoculation comprised of a cocktail of two Listeria monocytogenes and STEC strains, two Salmonella serovars, and two Vibrio species. STEC and Vibrio were grown and applied in salt-containing media to simulate preharvest contamination, whereas L. monocytogenes and Salmonella inocula were prepared to simulate postharvest contamination. Samples were stored at 4°C and 10°C for 7 days, and 22°C for 8 h. Microbiological analyses were performed periodically (1, 4, 8, 24 h, etc.) to evaluate the effects of storage temperature on pathogen survival. Pathogen populations decreased under all storage conditions, but survival was greatest for all species at 22°C, with STEC exhibiting significantly less reduction (1.8 log CFU/g) than Salmonella, L. monocytogenes, and Vibrio (3.1, 2.7, and 2.7 log CFU/g, respectively) after storage. The largest population reduction (5.3 log CFU/g) was observed in Vibrio stored at 4°C for 7 days. Regardless of storage temperature, all pathogens remained detectable at the end of the study duration. Results emphasize the need for strict adherence to temperature control for kelp as temperature abuse may support pathogen survival, especially STEC, during storage, and the need for prevention of postharvest contamination, particularly with Salmonella