An optimality criterion for sizing members of heated structures with temperature constraints

A thermal optimality criterion is presented for sizing members of heated structures with multiple temperature constraints. The optimality criterion is similar to an existing optimality criterion for design of mechanically loaded structures with displacement constraints. Effectiveness of the thermal optimality criterion is assessed by applying it to one- and two-dimensional thermal problems where temperatures can be controlled by varying the material distribution in the structure. Results obtained from the optimality criterion agree within 2 percent with results from a closed-form solution and with results from a mathematical programming technique. The thermal optimality criterion augments existing optimality criteria for strength and stiffness related constraints and offers the possibility of extension of optimality techniques to sizing structures with combined thermal and mechanical loading

Obesity: Current and Potential Pharmacotherapeutics and Targets

Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed

Electrical Characteristics of Rat Skeletal Muscle in Immaturity, Adulthood and After Sciatic Nerve Injury, and Their Relation to Muscle Fiber Size

Localized impedance methods can provide useful approaches for assessing neuromuscular disease. The mechanism of these impedance changes remains, however, uncertain. In order to begin to understand the relation of muscle pathology to surface impedance values, 8 immature rats, 12 mature rats, and 8 mature rats that had undergone sciatic crush were killed. Tissue from the gastrocnemius muscle from each animal was measured in an impedance cell, and the conductivity and relative permittivity of the tissue calculated in both the longitudinal and transverse directions for frequencies of 2 kHz to 1 MHz. In addition, quantitative histological analysis was performed on the tissue. Significant elevations in transverse conductivity and transverse relative permittivity were found with animal growth, but longitudinal values showed no difference. After sciatic crush, both transverse and longitudinal conductivity increased significantly, with no change in the relative permittivity in either direction. The frequency dependence of the values also changed after nerve injury. In the healthy animals, there was a strong linear relation between measured conductivity and relative permittivity with cell area, but not for the sciatic crush animals. These results provide a first step toward developing a comprehensive understanding of how the electrical properties of muscle alter in neuromuscular disease states

Multidisciplinary approaches to the study of eating disorders and obesity: recent progress in research and development and future prospects

No description supplie

International consensus guidance for management of myasthenia gravis

Altres ajuts: Supported by a grant from the Myasthenia Gravis Foundation of America (MGFA).To develop formal consensus-based guidance for the management of myasthenia gravis (MG). In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide

The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tonz Syndrome

Kohlschutter-Tönz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. Rogdi, an essential protein, is highly conserved across metazoans, and mutations in Rogdi are linked to KTS. However, how certain mutations in Rogdi abolish its physiological functions and cause KTS is not known. In this study, we determined the crystal structure of human Rogdi protein at atomic resolution. Rogdi forms a novel elongated curved structure comprising the ?? domain, a leucine-zipper-like four-helix bundle, and a characteristic ??-sheet domain. Within the ?? domain, the N-terminal H1 helix (residues 19-45) pairs with the C-terminal H6 helix (residues 252-287) in an antiparallel manner, indicating that the integrity of the four-helix bundle requires both N- and C-terminal residues. The crystal structure, in conjunction with biochemical data, indicates that the ?? domain might undergo a conformational change and provide a structural platform for protein-protein interactions. Disruption of the four-helix bundle by mutation results in significant destabilization of the structure. This study provides structural insights into how certain mutations in Rogdi affect its structure and cause KTS, which has important implications for the development of pharmaceutical agents against this debilitating neurological disease

A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism

Clinical features of children and adults with a muscular dystrophy using powered indoor/outdoor wheelchairs (EPIOCs): disease features, comorbidities and complications of disability.

Purpose: To describe the clinical features of electric powered indoor/outdoor wheelchair users with a muscular dystrophy, likely to influence optimal prescription; reflecting features of muscular dystrophies, conditions secondary to disability and comorbidities impacting on equipment provision. Methods: cross-sectional retrospective case note review of recipients of electric powered indoor/outdoor wheelchairs provided by a specialist regional wheelchair service. Data on demography, diagnostic/clinical and wheelchair prescription were systematically extracted. Results: Fifty-one men and 14 women, mean age 23.7 (range 10-67, sd 12.95) years, were studied. Forty had Duchenne muscular dystrophy, 22 had other forms of muscular dystrophy and three were unclassified. Twenty-seven were aged under 19. Notable clinical features included problematic pain (10), cardiomyopathy (5) and ventilatory failure (4). Features related to disability were (kypho)scoliosis (20) and oedema/cellulitis (3) whilst comorbidities included back pain (5). Comparison of younger with older users revealed younger users had more features of muscular dystrophy affecting electric powered chair provision (56%) whilst older users had more comorbidity (37%). Tilt-in-space was prescribed for 81% of users, specialised seating for 55% and complex controls for 16%. Conclusions: Muscular dystrophy users were prescribed electric powered indoor/outdoor chairs with many additional features reflecting the consequences of profound muscle weakness. In addition to facilitating independence and participation, electric powered indoor/outdoor chairs have major therapeutic benefits

Mid-circuit qubit measurement and rearrangement in a 171^{171}Yb atomic array

Measurement-based quantum error correction relies on the ability to determine the state of a subset of qubits (ancillae) within a processor without revealing or disturbing the state of the remaining qubits. Among neutral-atom based platforms, a scalable, high-fidelity approach to mid-circuit measurement that retains the ancilla qubits in a state suitable for future operations has not yet been demonstrated. In this work, we perform imaging using a narrow-linewidth transition in an array of tweezer-confined $^{171}$Yb atoms to demonstrate nondestructive state-selective and site-selective detection. By applying site-specific light shifts, selected atoms within the array can be hidden from imaging light, which allows a subset of qubits to be measured while causing only percent-level errors on the remaining qubits. As a proof-of-principle demonstration of conditional operations based on the results of the mid-circuit measurements, and of our ability to reuse ancilla qubits, we perform conditional refilling of ancilla sites to correct for occasional atom loss, while maintaining the coherence of data qubits. Looking towards true continuous operation, we demonstrate loading of a magneto-optical trap with a minimal degree of qubit decoherence.Comment: 9 pages, 6 figure

Isolation, Characterization, and Stability of Discretely-Sized Nanolipoprotein Particles Assembled with Apolipophorin-III

Background: Nanolipoprotein particles (NLPs) are discoidal, nanometer-sized particles comprised of self-assembled phospholipid membranes and apolipoproteins. NLPs assembled with human apolipoproteins have been used for myriad biotechnology applications, including membrane protein solubilization, drug delivery, and diagnostic imaging. To expand the repertoire of lipoproteins for these applications, insect apolipophorin-III (apoLp-III) was evaluated for the ability to form discretely-sized, homogeneous, and stable NLPs. Methodology: Four NLP populations distinct with regards to particle diameters (ranging in size from 10 nm to.25 nm) and lipid-to-apoLp-III ratios were readily isolated to high purity by size exclusion chromatography. Remodeling of the purified NLP species over time at 4uC was monitored by native gel electrophoresis, size exclusion chromatography, and atomic force microscopy. Purified 20 nm NLPs displayed no remodeling and remained stable for over 1 year. Purified NLPs with 10 nm and 15 nm diameters ultimately remodeled into 20 nm NLPs over a period of months. Intra-particle chemical cross-linking of apoLp-III stabilized NLPs of all sizes. Conclusions: ApoLp-III-based NLPs can be readily prepared, purified, characterized, and stabilized, suggesting their utilit