Slow amyloid nucleation via α-helix-rich oligomeric intermediates in short polyglutamine-containing huntingtin fragments

The 17-amino-acid N-terminal segment (httNT) that leads into the polyglutamine (polyQ) segment in the Huntington\u27s disease protein huntingtin (htt) dramatically increases aggregation rates and changes the aggregation mechanism, compared to a simple polyQ peptide of similar length. With polyQ segments near or above the pathological repeat length threshold of about 37, aggregation of htt N-terminal fragments is so rapid that it is difficult to tease out mechanistic details. We describe here the use of very short polyQ repeat lengths in htt N-terminal fragments to slow this disease-associated aggregation. Although all of these peptides, in addition to httNT itself, form α-helix-rich oligomeric intermediates, only peptides with QN of eight or longer mature into amyloid-like aggregates, doing so by a slow increase in β-structure. Concentration-dependent circular dichroism and analytical ultracentrifugation suggest that the httNT sequence, with or without added glutamine residues, exists in solution as an equilibrium between disordered monomer and α-helical tetramer. Higher order, α-helix rich oligomers appear to be built up via these tetramers. However, only httNTQN peptides with N=8 or more undergo conversion into polyQ β-sheet aggregates. These final amyloid-like aggregates not only feature the expected high β-sheet content but also retain an element of solvent-exposed α-helix. The α-helix-rich oligomeric intermediates appear to be both on- and off-pathway, with some oligomers serving as the pool from within which nuclei emerge, while those that fail to undergo amyloid nucleation serve as a reservoir for release of monomers to support fibril elongation. Based on a regular pattern of multimers observed in analytical ultracentrifugation, and a concentration dependence of α-helix formation in CD spectroscopy, it is likely that these oligomers assemble via a four-helix assembly unit. PolyQ expansion in these peptides appears to enhance the rates of both oligomer formation and nucleation from within the oligomer population, by structural mechanisms that remain unclear. © 2011 Elsevier Ltd

Clinical Profile of Dengue Infection at a Teaching Hospital in South India

Abstract: Background: Dengue fever is the most important viral, mosquito borne infection (Aedes) Dengue Results: Dengue fever is the most important viral, mosquito borne infection (Aedes) in India. It has become a major epidemic in Indian subcontinent. Spread of the infection is now leading to increased recognition of typical clinical features of dengue infection. Dengue virus belongs to the family Flaviviridae. Conclusion: Dengue disease continues to involve newer areas, newer populations and is increasing in magnitude, epidemic after epidemic, no vaccine is ye

Incidence, Predictors, and Prognostic Impact of Late Bleeding Complications After Transcatheter Aortic Valve Replacement

AbstractBackgroundThe incidence and prognostic impact of late bleeding complications after transcatheter aortic valve replacement (TAVR) are unknown.ObjectivesThe aim of this study was to identify the incidence, predictors, and prognostic impact of major late bleeding complications (MLBCs) (≥30 days) after TAVR.MethodsClinical and echocardiographic outcomes of patients who underwent TAVR within the randomized cohorts and continued access registries in the PARTNER (Placement of Aortic Transcatheter Valves) trial were analyzed after stratifying by the occurrence of MLBCs. Predictors of MLBCs and their association with 30-day to 1-year mortality were assessed.ResultsAmong 2,401 patients who underwent TAVR and survived to 30 days, MLBCs occurred in 142 (5.9%) at a median time of 132 days (interquartile range: 71 to 230 days) after the index procedure. Gastrointestinal complications (n = 58 [40.8%]), neurological complications (n = 22 [15.5%]), and traumatic falls (n = 11 [7.8%]) were identified as the most frequent types of MLBCs. Independent predictors of MLBCs were the presence of low hemoglobin at baseline, atrial fibrillation or flutter at baseline or 30 days, the presence of moderate or severe paravalvular leak at 30 days, and greater left ventricular mass at 30 days. MLBCs were identified as a strong independent predictor of mortality between 30 days and 1 year (adjusted hazard ratio: 3.91; 95% confidence interval: 2.67 to 5.71; p < 0.001).ConclusionsMLBCs after TAVR were frequent and associated with increased mortality. Better individualized and risk-adjusted antithrombotic therapy after TAVR is urgently needed in this high-risk population. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894

Mother and child nutrition among the Chakhesang tribe in the state of Nagaland, North-East India

Despite the importance of the nutritional status and food systems of Indigenous Peoples, the subject has received very little attention, especially in North-East India. Therefore, a community-based cross-sectional descriptive study was carried out among Chakhesang mothers with children under 5 years of age to evaluate their nutritional status and prevalence of chronic diseases in the context of their dietary habits. From 558 households (HHs), 661 children and 540 mothers were covered using standard anthropometric measurements as well as blood collection for haemoglobin and vitamin A. Data were collected from mothers on HH socio-demographic particulars and infant and young child feeding practices. The results showed that the prevalence of underweight, stunting, and wasting among children <5 years of age was 14%, 22%, and 7%, respectively. The prevalence of anaemia and vitamin A deficiency was 26% and 33% among children <5 years, whereas it was 33% and 26%, respectively, among mothers. Hypertension was observed in 16% of women, whereas diabetes was seen in 0.8%. Approximately 35% and 24% of HHs suffered mild or moderate food insecurity, respectively, which was associated with literacy of the parents, per capita income, and family size. Utilization of the rich agrobiodiversity and wild foods by the Chakhesangs appears to be a strong reason for their better nutritional and health status as compared to the rest of India. Therefore, this Indigenous knowledge and food system must be documented and kept vital, especially in policies and intervention programmes addressing food and nutrition security among the Chakhesang

Pacemakers and Implantable Cardioverter Defibrillator

The history of cardiac pacing therapy must be viewed within the broader framework of electro-diagnosis and electro-therapy. Electro-therapy has a simple core concept: the use of an outside source of electricity to stimulate human tissue in various ways to produce a beneficial therapeutic effect. This has shown a prolonged, halting development through the ages, sometimes being looked upon as mysterious magic produced by complex machines. The field of paediatric open heart surgery gave a major impetus to the development of pacemakers since heart block often accompanied impeccably performed intra-cardiac repairs of congenital defects. This review deals various of aspects of pacemaker functioning, indications, contraindications and complications

Folding landscape of mutant huntingtin Exon1: Diffusible multimers, oligomers and fibrils, and no detectable monomer

Expansion of the polyglutamine (polyQ) track of the Huntingtin (HTT) protein above 36 is associated with a sharply enhanced risk of Huntington's disease (HD). Although there is general agreement that HTT toxicity resides primarily in N-terminal fragments such as the HTT exon1 protein, there is no consensus on the nature of the physical states of HTT exon1 that are induced by polyQ expansion, nor on which of these states might be responsible for toxicity. One hypothesis is that polyQ expansion induces an alternative, toxic conformation in the HTT exon1 monomer. Alternative hypotheses posit that the toxic species is one of several possible aggregated states. Defining the nature of the toxic species is particularly challenging because of facile interconversion between physical states as well as challenges to identifying these states, especially in vivo. Here we describe the use of fluorescence correlation spectroscopy (FCS) to characterize the detailed time and repeat length dependent self-association of HTT exon1-like fragments both with chemically synthesized peptides in vitro and with cell-produced proteins in extracts and in living cells. We find that, in vitro, mutant HTT exon1 peptides engage in polyQ repeat length dependent dimer and tetramer formation, followed by time dependent formation of diffusible spherical and fibrillar oligomers and finally by larger, sedimentable amyloid fibrils. For expanded polyQ HTT exon1 expressed in PC12 cells, monomers are absent, with tetramers being the smallest molecular form detected, followed in the incubation time course by small, diffusible aggregates at 6-9 hours and larger, sedimentable aggregates that begin to build up at 12 hrs. In these cell cultures, significant nuclear DNA damage appears by 6 hours, followed at later times by caspase 3 induction, mitochondrial dysfunction, and cell death. Our data thus defines limits on the sizes and concentrations of different physical states of HTT exon1 along the reaction profile in the context of emerging cellular distress. The data provide some new candidates for the toxic species and some new reservations about more well-established candidates. Compared to other known markers of HTT toxicity, nuclear DNA damage appears to be a relatively early pathological event