Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome

An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.

Serpins are important regulators of proteolytic pathways with an anti-protease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an inter-molecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of a number of pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39, and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of pre-formed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for rational design of ligands that is able to dynamically influence α1-AT polymerisation

Phylogeny and chromosomal diversification in the <i>Dichroplus elongatus</i> species group (Orthoptera, Melanoplinae)

In an attempt to track the chromosomal differentiation in the Dichroplus elongatus species group, we analyzed the karyotypes of four species with classical cytogenetic and mapping several multigene families through fluorescent in situ hybridization (FISH). We improved the taxon sampling of the D. elongatus species group adding new molecular data to infer the phylogeny of the genus and reconstruct the karyotype evolution. Our molecular analyses recovered a fully resolved tree with no evidence for the monophyly of Dichroplus. However, we recovered several stable clades within the genus, including the D. elongatus species group, under the different strategies of tree analyses (Maximum Parsimony and Maximum Likelihood). The chromosomal data revealed minor variation in the D. elongatus species group's karyotypes caused by chromosome rearrangements compared to the phylogenetically related D. maculipennis species group. The karyotypes of D. intermedius and D. exilis described herein showed the standard characteristics found in most Dichroplini, 2n = 23/24, X0♂ XX♀, Fundamental number (FN) = 23/24. However, we noticed two established pericentric inversions in D. intermedius karyotype, raising the FN to 27♂/28♀. A strong variation in the heterochromatic blocks distribution was evidenced at interespecific level. The multigene families' mapping revealed significant variation, mainly in rDNA clusters. These variations are probably caused by micro chromosomal changes, such as movement of transposable elements (TEs) and ectopic recombination. These observations suggest a high genomic dynamism for these repetitive DNA sequences in related species. The reconstruction of the chromosome character "variation in the FN" posits the FN = 23/24 as the ancestral state, and it is hypothesized that variations due to pericentric inversions has arisen independently three times in the evolutionary history of Dichroplus. One of these independent events occurred in the D. elongatus species group, where D. intermedius is the unique case with the highest FN described in the tribe Dichroplini.Centro de Estudios Parasitológicos y de VectoresFacultad de Ciencias Naturales y Muse

Cross-sectional relationship between physical fitness components and functional performance in older persons living in long-term care facilities

BACKGROUND: The age-related deterioration of physiological capacities such as muscle strength and balance is associated with increased dependence. Understanding the contribution of physical fitness components to functional performance facilitates the development of adequate exercise interventions aiming at preservation of function and independence of older people. The aim of the study was to investigate the relationship between physical fitness components and functional performance in older people living in long-term care facilities. METHODS: Design cross-sectional study Subjects 226 persons living in long-term care facilities (mean age: 81.6 ± 5.6). Outcome measures Physical fitness and functional performance were measured by performance-based tests. RESULTS: Knee and elbow extension strength were significantly higher in men (difference = 44.5 and 50.0 N, respectively), whereas women were more flexible (difference sit & reach test = 7.2 cm). Functional performance was not significantly different between the genders. In men, motor coordination (eye-hand coordination) and measures of strength were the main contributors to functional performance, whereas in women flexibility (sit and reach test) and motor coordination (tandem stance and eye-hand coordination) played a major role. CONCLUSION: The results of this study show that besides muscle strength, fitness components such as coordination and flexibility are associated with functional performance of older people living in long-term care facilities. This suggests that men and women living in long-term care facilities, differ considerably concerning the fitness factors contributing to functional performance. Women and men may, therefore, need exercise programs emphasizing different fitness aspects in order to improve functional performance

Signs and symptoms of temporomandibular disorders and oral parafunctions in urban Saudi arabian adolescents: a research report

BACKGROUND: The aim of this study was to evaluate the prevalence of signs and symptoms of temporomandibular disorders (TMD) and oral parafunction habits among Saudi adolescents in the permanent dentition stage. METHODS: A total of 385 (230 females and 155 males) school children age 12–16, completed a questionnaire and were examined clinically. A stratified selection technique was used for schools allocation. RESULTS: The results showed that 21.3% of the subjects exhibited at least one sign of TMD and females were generally more affected than males. Joint sounds were the most prevalent sign (13.5%) followed by restricted opening (4.7%) and opening deviation (3.9%). The amplitude of mouth opening, overbite taken into consideration, was 46.5 mm and 50.2 mm in females and males respectively. TMJ pain and muscle tenderness were rare (0.5%). Reported symptoms were 33%, headache being the most frequent symptom 22%, followed by pain during chewing 14% and hearing TMJ noises 8.7%. Difficulty during jaw opening and jaw locking were rare. Lip/cheek biting was the most common parafunction habit (41%) with females significantly more than males, followed by nail biting (29%). Bruxism and thumb sucking were only 7.4% and 7.8% respectively. CONCLUSION: The prevalence of TMD signs were 21.3% with joint sounds being the most prevalent sign. While TMD symptoms were found to be 33% as, with headache being the most prevalent. Among the oral parafunctions, lip/cheek biting was the most prevalent 41% followed by nail biting 29%

Observational Evidence of For-Profit Delivery and Inferior Nursing Home Care: When Is There Enough Evidence for Policy Change?

This research was financially supported by the Social Sciences and Humanities Research Council

Calibrating ADL-IADL scales to improve measurement accuracy and to extend the disability construct into the preclinical range: a systematic review

<p>Abstract</p> <p>Background</p> <p>Interest in measuring functional status among nondisabled older adults has increased in recent years. This is, in part, due to the notion that adults identified as 'high risk' for functional decline portray a state that is potentially easier to reverse than overt disability. Assessing relatively healthy older adults with traditional self-report measures (activities of daily living) has proven difficult because these instruments were initially developed for institutionalised older adults. Perhaps less evident, are problems associated with change scores and the potential for 'construct under-representation', which reflects the exclusion of important features of the construct (e.g., disability). Furthermore, establishing a formal hierarchy of functional status tells more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring older adults: if the sequence task difficulty is accelerated or out of order it may indicate the need for interventions.</p> <p>Methods</p> <p>This review identified studies that employed item response theory (IRT) to examine or revise functional status scales. IRT can be used to transform the ordinal nature of functional status scales to interval level data, which serves to increase diagnostic precision and sensitivity to clinical change. Furthermore, IRT can be used to rank items unequivocally along a hierarchy based on difficulty. It should be noted that this review is not concerned with contrasting IRT with more traditional classical test theory methodology.</p> <p>Results</p> <p>A systematic search of four databases (PubMed, Embase, CINAHL, and PsychInfo) resulted in the review of 2,192 manuscripts. Of these manuscripts, twelve met our inclusion/exclusion requirements and thus were targeted for further inspection.</p> <p>Conclusions</p> <p>Manuscripts presented in this review appear to summarise gerontology's best efforts to improve construct validity and content validity (i.e., ceiling effects) for scales measuring the early stages of activity restriction in community-dwelling older adults. Several scales in this review were exceptional at reducing ceiling effects, reducing gaps in coverage along the construct, as well as establishing a formal hierarchy of functional decline. These instrument modifications make it plausible to detect minor changes in difficulty for IADL items positioned at the edge of the disability continuum, which can be used to signal the onset of progressive type disability in older adults.</p