ALBERT

Description: Background: Procalcitonin is useful for the diagnosis of sepsis but its prognostic value regarding mortality is unclear. This prospective observational study was designed to study the prognostic value of procalcitonin in prediction of 28 day mortality in patients of sepsis. Fifty-four consecutive patients of sepsis, severe sepsis and septic shock defined using the 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS criteria from medical Intensive Care Unit (ICU) of a tertiary care center in New Delhi, India were enrolled from July 2011 to June 2013. Procalcitonin (PCT), C-reactive protein (CRP) measurements were recorded on day 1, day 7 and day 28 of follow up. Results: Procalcitonin value was a better predictor of all-cause short-term mortality than C-reactive protein. Those patients with Procalcitonin levels

Description: Background: In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. The aim of this study was to examine the in vitro effects of chronic glucolipotoxic conditions on cellular responses in pancreatic islets, including glucose and fat metabolism, Calcium mobilization, insulin secretion and insulin content. Results: Exposure of islets to chronic glucolipotoxic conditions decreased glucose stimulated insulin secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride accumulation increased significantly while fatty acid oxidation decreased. This general suppression in glucose metabolism correlated well with a decrease in mitochondrial number and activity, reduction in cellular ATP content and dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels and lower Calcium mobilization in response to glucose. Importantly, chronic glucolipotoxic conditions in vitro decreased insulin gene expression, insulin content, insulin granule docking (to the plasma membrane) and insulin secretion. Conclusions: Our results present an integrated view of the effects of chronic glucolipotoxic conditions on known and novel signaling events, in vitro, that results in reduced glucose responsiveness and insulin secretion.

Description: Background; With an ever-growing ageing population, dementia is fast becoming the chronic disease of the 21stcentury. Elderly people affected with dementia progressively lose their autonomy as they encounterproblems in their Activities of Daily Living (ADLs). Hence, they need supervision and assistancefrom their family members or professional caregivers, which can often lead to underestimated psychologicaland financial stress for all parties. The use of Ambient Assistive Living (AAL) technologiesaims to empower people with dementia and relieve the burden of their caregivers.The aim of this paper is to present the approach we have adopted to develop and deploy a systemfor ambient assistive living in an operating nursing home, and evaluate its performance and usabilityin real conditions. Based on this approach, we emphasise on the importance of deployments in realworld settings as opposed to prototype testing in laboratories.Methods; We chose to conduct this work in close partnership with end-users (dementia patients) and specialistsin dementia care (professional caregivers). Our trial was conducted during a period of 14 monthswithin three rooms in a nursing home in Singapore, and with the participation of eight dementiapatients and two caregivers. A technical ambient assistive living solution, consisting of a set of sensorsand devices controlled by a software platform, was deployed in the collaborating nursing home. Thetrial was preceded by a pre-deployment period to organise several observation sessions with dementiapatients and focus group discussions with professional caregivers. A process of ground truth andsystem's log data gathering was also planned prior to the trial and a system performance evaluationwas realised during the deployment period with the help of caregivers. An ethical approval wasobtained prior to real life deployment of our solution.Results; Patients' observations and discussions allowed us to gather a set of requirements that a system forelders with mild-dementia should fulfil. In fact, our deployment has exposed more concrete requirementsand problems that need to be addressed, and which cannot be identified in laboratory testing.Issues that were neither forecasted during the design phase nor during the laboratory testing surfacedduring deployment, thus affecting the effectiveness of the proposed solution. Results of the systemperformance evaluation show the evolution of system precision and uptime over the deploymentphases, while data analysis demonstrates the ability to provide early detection of the degradation ofpatients' conditions. A qualitative feedback was collected from caregivers and doctors and a set oflessons learned emerged from this deployment experience.Conclusion; Lessons learned from this study were very useful for our research work and can serve as inspirationfor developers and providers of assistive living services. They confirmed the importance of realdeployment to evaluate assistive solutions especially with the involvement of professional caregivers.They also asserted the need for larger deployments. Larger deployments will allow to conduct surveyson assistive solutions social and health impact, even though they are time and manpower consumingduring their first phases.

Description: Background Mutation of amino acid sequences in a protein may have diverse effects on its structure and function. Point mutations ofeven a single amino acid residue in the helices of thenon-redundant database may lead to sequentially identical peptides whichadopt different secondary structures in different proteins. However, variousphysico-chemical factors which govern the formation of these ambivalent helices generated by point mutationsof a sequence are not clearly known.Results Sequences generated by point mutations of helices are mapped on to theirnon-helical counterparts in the SCOP database. The results show thatshort helices are prone to transform into non-helical conformations upon pointmutations. Mutation of amino acid residues by helix breakerspreferentially yield non-helical conformations, while mutation withresidues of intermediate helix propensity display least preferences fornon-helical conformations. Differences in the solvent accessibility of themutating/mutated residues are found to be a major criteria for these sequencesto conform to non-helical conformations. Even with minimal differencesin the amino acid distributions of the sequences flanking the helicaland non-helical conformations, helix-flanking sequences are found bemore solvent accessible.Conclusions All types of mutations from helicalto non-helical conformations are investigated. The primary factorsattributing such changes in conformation can be: i) type/propensity ofthe mutating and mutant residues ii) solvent accessibility of the residue at the mutation siteiii) context/environment dependence of the flanking sequences. Theresults from the present study may be used to design de novoproteins via point mutations.

Description: Background: Resveratrol, a naturally occurring stilbene, has been categorized as phytoestrogen due to its capability to compete with natural estrogens for binding to estrogen receptor alpha (ERalpha) and thus modulating the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERalpha) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results: Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERalpha ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERalpha monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERalpha in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERalpha dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERalpha are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERalpha. Conclusions: Our Molecular Dynamics simulation of RES-ERalpha structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.

Description: Background: Gene expression in vertebrate cells may be controlled post-transcriptionally through regulatory elements in mRNAs. These are usually located in the untranslated regions (UTRs) of mRNA sequences, particularly the 3[prime]UTRs. Results: Scan for Motifs (SFM) simplifies the process of identifying a wide range of regulatory elements on alignments of vertebrate 3[prime]UTRs. SFM includes identification of both RNA Binding Protein (RBP) sites and targets of miRNAs. In addition to searching pre-computed alignments, the tool provides users the flexibility to search their own sequences or alignments. The regulatory elements may be filtered by expected value cutoffs and are cross-referenced back to their respective sources and literature. The output is an interactive graphical representation, highlighting potential regulatory elements and overlaps between them. The output also provides simple statistics and links to related resources for complementary analyses. The overall process is intuitive and fast. As SFM is a free web-application, the user does not need to install any software or databases. Conclusions: Visualisation of the binding sites of different classes of effectors that bind to 3[prime]UTRs will facilitate the study of regulatory elements in 3[prime] UTRs.

Description: Background: Procalcitonin is useful for the diagnosis of sepsis but its prognostic value regarding mortality is unclear. This prospective observational study was designed to study the prognostic value of procalcitonin in prediction of 28 day mortality in patients of sepsis. Fifty-four consecutive patients of sepsis, severe sepsis and septic shock defined using the 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS criteria from medical Intensive Care Unit (ICU) of a tertiary care center in New Delhi, India were enrolled from July 2011 to June 2013. Procalcitonin (PCT), C-reactive protein (CRP) measurements were recorded on day 1, day 7 and day 28 of follow up. Results: Procalcitonin value was a better predictor of all-cause short-term mortality than C-reactive protein. Those patients with Procalcitonin levels

Description: Background: Chronic inflammation-mediated beta-cell apoptosis is known to decrease beta-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic beta-cells. The G protein coupled receptor 40 (GPR40) is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect beta-cells from inflammation-induced apoptosis and restore glucose stimulated insulin secretion. Results: By exposing NIT1 insulinoma cells and rat islets to a cocktail of pro-inflammatory cytokines (TNFalpha and IL1beta), we mimicked inflammatory signaling as seen by JNK and NFkappaB activation and increased mRNA levels of TNFalpha, IL1beta and NOS2a. These changes were reversed by pharmacological activation of GPR40 by a specific, small molecule, CNX-011-67. Further, GPR40 activation reduced inflammation-mediated oxidative and endoplasmic reticulum (ER) stresses. Importantly, GPR40 activation decreased inflammation-induced apoptosis as measured by key markers. These impacts of GPR40 were mediated through activation of PLC, CaMKII, calcineurin and cAMP. Cell survival was also enhanced by GPR40 activation as seen from the increased phosphorylation of Akt/PKB and enhanced expression of BCL2 and PDX1 genes. Interestingly, GPR40 activation restored both, inflammation-mediated inhibition on insulin secretion and intracellular insulin content. Conclusions: In this study, we provide evidences that CNX-011-67, a GPR40 agonist, reduces inflammatory signaling and apoptosis in pancreatic beta-cell while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of beta-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and beta-cell survival.