Glycogen Synthase Kinase-3: A Promising Therapeutic Target for Fragile X Syndrome

Recent advances in understanding the pathophysiological mechanisms contributing to fragile X syndrome (FXS) have increased optimism that drug interventions can provide significant therapeutic benefits. FXS results from inadequate expression of functional fragile X mental retardation protein (FMRP). FMRP may have several functions, but it is most well-established as an RNA binding protein that regulates translation, and it is thought that by this mechanism FMRP is capable of affecting numerous cellular processes by selectively regulating protein levels. The multiple cellular functions regulated by FMRP suggest that multiple interventions may be required for reversing the effects of deficient FMRP. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3) may contribute to the therapeutic treatment of FXS is reviewed here. Lithium, a GSK3 inhibitor, improved function in the Drosophila model of FXS. In mice lacking FMRP expression (FX mice), GSK3 is hyperactive in several brain regions. Significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in patients with FXS also found improvements in several measures of behavior. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS

Regulation of Cell Survival Mechanisms in Alzheimer's Disease by Glycogen Synthase Kinase-3

A pivotal role has emerged for glycogen synthase kinase-3 (GSK3) as an important contributor to Alzheimer's disease pathology. Evidence for the involvement of GSK3 in Alzheimer's disease pathology and neuronal loss comes from studies of GSK3 overexpression, GSK3 localization studies, multiple relationships between GSK3 and amyloid β-peptide (Aβ), interactions between GSK3 and the microtubule-associated tau protein, and GSK3-mediated apoptotic cell death. Apoptotic signaling proceeds by either an intrinsic pathway or an extrinsic pathway. GSK3 is well established to promote intrinsic apoptotic signaling induced by many insults, several of which may contribute to neuronal loss in Alzheimer's disease. Particularly important is evidence that GSK3 promotes intrinsic apoptotic signaling induced by Aβ. GSK3 appears to promote intrinsic apoptotic signaling by modulating proteins in the apoptosis signaling pathway and by modulating transcription factors that regulate the expression of proteins involved in apoptosis. Thus, GSK3 appears to contribute to several neuropathological mechanisms in Alzheimer's disease, including apoptosis-mediated neuronal loss

Drop weight impact behaviour of sandwich panels with metallic micro lattice cores

The paper addresses the low velocity, drop weight behaviour of small (100 mm by 100 mm) sandwich panels with CFRP skins. The main point of interest is the core material, and the focus of the paper is in the use of body centred cubic (BCC) micro lattice cores made from Ti 6Al 4V titanium alloy and 316L stainless steel manufactured using selective laser melting. The mechanical behaviour of the micro lattice core is compared to that of conventional aluminium honeycomb. The paper discusses the manufacture and characterisation of the core materials, the measurement of core properties from strut tensile tests, block compression tests and the drop weight impact performance of the panels. Impact performance is expressed in terms of panel penetration. It is shown that the current Ti 6Al 4V BCC micro lattice cores are competitive with aluminium honeycomb, but that there is scope for improvement in Ti 6Al 4V micro strut mechanical properties. The SLM manufacturing process gives lattice structures with open cell architecture, which is an advantage for aerospace applications, and the SLM process can be used to realise a variety of cell lattice geometries

Interim Report: Air-Cooled Condensers for Next Generation Geothermal Power Plants Improved Binary Cycle Performance

As geothermal resources that are more expensive to develop are utilized for power generation, there will be increased incentive to use more efficient power plants. This is expected to be the case with Enhanced Geothermal System (EGS) resources. These resources will likely require wells drilled to depths greater than encountered with hydrothermal resources, and will have the added costs for stimulation to create the subsurface reservoir. It is postulated that plants generating power from these resources will likely utilize the binary cycle technology where heat is rejected sensibly to the ambient. The consumptive use of a portion of the produced geothermal fluid for evaporative heat rejection in the conventional flash-steam conversion cycle is likely to preclude its use with EGS resources. This will be especially true in those areas where there is a high demand for finite supplies of water. Though they have no consumptive use of water, using air-cooling systems for heat rejection has disadvantages. These systems have higher capital costs, reduced power output (heat is rejected at the higher dry-bulb temperature), increased parasitics (fan power), and greater variability in power generation on both a diurnal and annual basis (larger variation in the dry-bulb temperature). This is an interim report for the task ‘Air-Cooled Condensers in Next- Generation Conversion Systems’. The work performed was specifically aimed at a plant that uses commercially available binary cycle technologies with an EGS resource. Concepts were evaluated that have the potential to increase performance, lower cost, or mitigate the adverse effects of off-design operation. The impact on both cost and performance were determined for the concepts considered, and the scenarios identified where a particular concept is best suited. Most, but not all, of the concepts evaluated are associated with the rejection of heat. This report specifically addresses three of the concepts evaluated: the use of recuperation, the use of turbine reheat, and the non-consumptive use of EGS make-up water to supplement heat rejectio

Air-Cooled Condensers for Next Generation Geotherm

This report summarizes the efforts performed unde

Simulation of Air-Cooled Organic Rankine Cycle Geo

This document describes simulations that were dev

Determination of Elastic Modulus Value for Selectively Laser Melted Titanium Alloy Micro-Struty

Experimental method in determination of elastic modulus (E value) for micro scale specimen can be a debated issue, in the aspect of reliability and robustness of the results. Attention shall be given to the limiting factors which influence the techniques and procedure, such as the sample’s size, properties and geometries. It is also important to incorporate the microstructural effects toward producing a more understandable results. Analysis of tensile property for titanium alloy (Ti-6Al-4V) micro-struts manufactured from selective laser melting (SLM) rapid prototyping technology is presented in this paper. The result is found comparable to a standard value and will be used in future analysis of micro-lattice performance as core material in sandwich structure

Cultures of caste and rural development in the social network of a south Indian village

Cultures of caste in much of rural India have become entangled with institutions of rural development. In community-driven development, emphasis on “local resource persons” and “community spokespersons” has created new opportunities for brokerage and patronage within some villages, which interact with existing forms of authority and community afforded by caste identity and intra-caste headmanship. In this article, we study how these entangled cultures of caste and development translate into social network structures using data on friendship ties from a south Indian village. We find that although caste continues to be important in shaping community structures and leadership in the village’s network, its influence varies across different communities. This fluidity of caste’s influence on community network structures is argued to be the result of multiple distinct yet partially overlapping cultural-political forces, which include sharedness afforded by caste identity and new forms of difference and inequality effected through rural development

The United States Army Ocular Teleconsultation program 2004 through 2009

PURPOSE: To describe the United States Army Ocular Teleconsultation program and all consultations received from its inception in July 2004 through December 2009. DESIGN: Retrospective, noncomparative, consecutive case series. METHODS: All 301 consecutive ocular teleconsultations received were reviewed. The main outcome measures were differential diagnosis, evacuation recommendations, and origination of consultation. Secondary measures included patient demographics, reason for consultation, and inclusion of clinical images. RESULTS: The average response time was 5 hours and 41 minutes. Most consultations originated from Iraq (58.8%) and Afghanistan (18.6%). Patient care-related requests accounted for 94.7% of consultations; nonphysicians submitted 26.3% of consultations. Most patients (220/285; 77.2%) were United States military personnel; the remainder included local nationals and coalition forces. Children accounted for 23 consultations (8.1%). Anterior segment disease represented the largest grouping of cases (129/285; 45.3%); oculoplastic problems represented nearly one quarter (68/285; 23.9%). Evacuation was recommended in 123 (43.2%) of 285 cases and in 21 (58.3%) of 36 cases associated with trauma. Photographs were included in 38.2%, and use was highest for pediatric and strabismus (83.3%) and oculoplastic (67.6%) consultations. Consultants facilitated evacuation in 87 (70.7%) of 123 consultations where evacuation was recommended and avoided unnecessary evacuations in 28 (17.3%) of 162 consultations. CONCLUSIONS: This teleconsultation program has brought valuable tertiary level support to deployed providers, thereby helping to facilitate appropriate and timely referrals, and in some cases avoiding unnecessary evacuation. Advances in remote diagnostic and imaging technology could further enhance consultant support to distant providers and their patients