Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6-[³H]-2,4-dioxo-3,4-dihydrothieno.3,2-d] pyrimidin1(2H)- yl) propanoic acid ([³H]-NF608)

The kainic acid receptors belong to the class of ionotropic glutamate receptors and comprise five subunits named GluK1-5. Radioligands are essential tools for use in binding assays aimed at ligand-receptor structure-activity-relationship studies. Previous work has led to the synthesis of GluK1 radioligands [3H]-SYM2081, [3H]-UBP310 and [3H]-ATPA, however all strategies were work-intensive and thus not attractive. Herein, we report the synthesis of [3H]-NF608 and subsequent pharmacological evaluation at homomeric recombinant rat GluK1 receptors. Binding affinities of a series of standard GluK1 ligands were shown to be in line with previously reported affinities obtained by use of already reported radioligands

A study on African vernacular mosque: A lesson from tradition

Mosques as a symbol of Islamic cities have a significant place in Islamic Architecture and it prompts architects to create admirable, magnificent buildings. While several studies have done on features and prototypes in this field but mainly it leaded to exaggerate dominance of dome as inseparable component of mosques. Although dome construction is costly, it is not that much adaptable to different climates and even it is not a good culture indicator of different countries, still there is a strong insist on presence of dome in mosques everywhere. This paper aims to study African mosque example which deeply relied on vernacular architecture. Various styles of design in Mali as case study investigated in terms of material, design concept, to arrive at concrete results

Association of a Workplace Sales Ban on Sugar-Sweetened Beverages With Employee Consumption of Sugar-Sweetened Beverages and Health.

ImportanceReductions in sugar-sweetened beverage (SSB) intake can improve health, but are difficult for individuals to achieve on their own.ObjectivesTo evaluate whether a workplace SSB sales ban was associated with SSB intake and cardiometabolic health among employees and whether a brief motivational intervention provides added benefits to the sales ban.Design, setting, and participantsThis before-after study and additional randomized trial conducted from July 28, 2015, to October 16, 2016, at a Northern California university and hospital assessed SSB intake, anthropometrics, and cardiometabolic biomarkers among 214 full-time English-speaking employees who were frequent SSB consumers (≥360 mL [≥12 fl oz] per day) before and 10 months after implementation of an SSB sales ban in a large workplace, with half the employees randomized to receive a brief motivational intervention targeting SSB reduction.InterventionsThe employer stopped selling SSBs in all workplace venues, and half the sample was randomized to receive a brief motivational intervention and the other half was a control group that did not receive the intervention. This intervention was modeled on standard brief motivational interventions for alcohol used in the workplace that promote health knowledge and goal setting.Main outcomes and measuresOutcomes included changes in SSB intake, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and measures of abdominal adiposity. The primary associations tested were the correlation between changes in SSB intake and changes in HOMA-IR.ResultsAmong the 214 study participants, 124 (57.9%) were women, with a mean (SD) age of 41.2 (11.0) years and a baseline mean (SD) body mass index of 29.4 (6.5). They reported a mean daily intake of 1050 mL (35 fl oz) of SSBs at baseline and 540 mL (18 fl oz) at follow-up-a 510-mL (17-fl oz) (48.6%) decrease (P < .001). Reductions in SSB intake correlated with improvements in HOMA-IR (r = 0.16; P = .03). Those not randomized to receive the brief intervention reduced their SSB intake by a mean (SD) of 246.0 (84.0) mL (8.2 [2.8] fl oz), while those also receiving the brief intervention reduced SSB intake by 762.0 (84.0) mL (25.4 [2.8] fl oz). From baseline to follow-up, there were significant reductions in mean (SE) waist circumference (2.1 [2.8] cm; P < .001).Conclusions and relevanceThis study's findings suggest that the workplace sales ban was associated with a reduction in SSB intake and a significant reduction in waist circumference among employees within 10 months. The randomized clinical trial portion of this study found that targeting those at high risk with a brief motivational intervention led to additional improvements. Workplace sales bans may offer a promising new private-sector strategy for reducing the health harms of SSB intake.Trial registrationClinicalTrials.gov identifier: NCT02585336

Planning, implementation and scientific goals of the Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) field mission

The Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) field mission based at Ellington Field, Texas, during August and September 2013 employed the most comprehensive airborne payload to date to investigate atmospheric composition over North America. The NASA ER-2, DC-8, and SPEC Inc. Learjet flew 57 science flights from the surface to 20 km. The ER-2 employed seven remote sensing instruments as a satellite surrogate and eight in situ instruments. The DC-8 employed 23 in situ and five remote sensing instruments for radiation, chemistry, and microphysics. The Learjet used 11 instruments to explore cloud microphysics. SEAC4RS launched numerous balloons, augmented AErosol RObotic NETwork, and collaborated with many existing ground measurement sites. Flights investigating convection included close coordination of all three aircraft. Coordinated DC-8 and ER-2 flights investigated the optical properties of aerosols, the influence of aerosols on clouds, and the performance of new instruments for satellite measurements of clouds and aerosols. ER-2 sorties sampled stratospheric injections of water vapor and other chemicals by local and distant convection. DC-8 flights studied seasonally evolving chemistry in the Southeastern U.S., atmospheric chemistry with lower emissions of NOx and SO2 than in previous decades, isoprene chemistry under high and low NOx conditions at different locations, organic aerosols, air pollution near Houston and in petroleum fields, smoke from wildfires in western forests and from agricultural fires in the Mississippi Valley, and the ways in which the chemistry in the boundary layer and the upper troposphere were influenced by vertical transport in convective clouds

Access to Autism Spectrum Disorder Services for Rural Appalachian Citizens

Background: Low-resource rural communities face significant challenges regarding availability and adequacy of evidence-based services. Purposes: With respect to accessing evidence-based services for Autism Spectrum Disorder (ASD), this brief report summarizes needs of rural citizens in the South-Central Appalachian region, an area notable for persistent health disparities. Methods: A mixed-methods approach was used to collect quantitative and qualitative data during focus groups with 33 service providers and 15 caregivers of children with ASD in rural southwest Virginia. Results: Results supported the barriers of availability and affordability of ASD services in this region, especially relating to the need for more ASD-trained providers, better coordination and navigation of services, and addition of programs to assist with family financial and emotional stressors. Results also suggested cultural attitudes related to autonomy and trust towards outside professionals that may prevent families from engaging in treatment. Implications: Relevant policy recommendations are discussed related to provider incentives, insurance coverage, and telehealth. Integration of autism services into already existing systems and multicultural sensitivity of providers are also implicated

Food supply confers calcifiers resistance to ocean acidification

Invasion of ocean surface waters by anthropogenic CO emitted to the atmosphere is expected to reduce surface seawater pH to 7.8 by the end of this century compromising marine calcifiers. A broad range of biological and mineralogical mechanisms allow marine calcifiers to cope with ocean acidification, however these mechanisms are energetically demanding which affect other biological processes (trade-offs) with important implications for the resilience of the organisms against stressful conditions. Hence, food availability may play a critical role in determining the resistance of calcifiers to OA. Here we show, based on a meta-analysis of existing experimental results assessing the role of food supply in the response of organisms to OA, that food supply consistently confers calcifiers resistance to ocean acidification.This work was funded by grants from the Danish Environmental Protection Agency within the Danish 486 Cooperation for Environment in the Arctic (DANCEA), ASSEMBLE grant agreement no. 227799 from European Community and from the Spanish Ministry of Economy and Competitiveness (ESTRESX, number CTM2012-32603). N.A.L. acknowledges support from grants Fondecyt 1140938 and NC 1200286 (Millennium Nucleus Project MUSELS) and L.R. was supported by BECAS CHILE fellowship program from Comisión Nacional de Investigación Científica y Tecnológica de Chile (CONICYT)Peer Reviewe

Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry.

The Sondheimer dialkyne is extensively used in double strain-promoted azide-alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications

Serum neurofilament light chain – A potential biomarker for polyneuropathy in type 2 diabetes?

AimsTo investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN).MethodsWe performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage.Results39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI’s 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73).ConclusionsS-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated to the severity of the nerve damage underlying DPN

Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society