Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.

BACKGROUND: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research

Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling

Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling

The spatial dynamics of chlorophyll-a and sea surface temperature in a coastal zone as revealed by high resolution remote sensing

In this paper, we examined the spatial dynamics of chlorophyll-a and SST of a bay in the south-western Scottish coast through analysis of a series of Airborne Thematic Mapper images that were acquired on two dates throughout an ebb tide. Changes in patterns of chlorophyll-a and SST were determined through two complimentary statistical procedures: firstly, by geostatistics (variogram analysis), which provided information on changes in the scale-dependency of the variation; and secondly, by maximum cross correlation, which provided information on the displacement of pattern at a local scale. Geostatistics and maximum cross correlation were effective for quantifying spatial dynamics, but qualitative interpretation was also necessary. Complex spatial dynamics were found over a wide range of spatial and temporal scales, associated with the creation and dissipation of eddies, the convergence and divergence of fronts, and the creation of geostrophic boundary currents. All these dynamics were superimposed on the synoptic tidal flow. Patterns of chlorophyll-a differed markedly from those of SST, indicating the non-conservative aspect of algal populations and the 3-dimensional aspect of the velocity field

Spatial dynamics of estuarine water surface temperature from airborne remote sensing.

This paper examines the applicability of airborne remote sensing to the characterization and quantification of the spatial dynamics of water surface temperature (WST) within estuaries. For this, a series of successive airborne Thematic Mapper thermal images was acquired of Kirkcudbright Bay, an estuary in the United Kingdom, on two dates. Spatial dynamics were determined by two techniques: (1) qualitatively, which involved interpreting features �by eye�; and (2) by the velocimetric technique of maximum cross correlation (MCC). Qualitatively, complex spatial dynamics were identified over a wide range of spatial and temporal scales, associated with the creation and dissipation of eddies, and the convergence and divergence of fronts, all of which were superimposed on the synoptic tidal flow. MCC was effective for producing synoptic velocity fields, but the minimum cell size was constrained by image noise, limiting the ability to analyze small-scale spatial dynamics. The effectiveness of MCC was related to the ratio of spatially correlated variance to spatially independent variance, as estimated from the variogram. Suggestions for optimizing the application of airborne remote sensing to estuarine spatial dynamics are presented

Vaccinia virus immunomodulator A46: destructive interactions with MAL and MyD88 shown by negative-stain electron microscopy

Vaccinia virus A46 is an anti-inflammatory and non-anti-apoptotic, two-domain member of the poxviral Bcl-2-like protein family that inhibits the cellular innate immune response at the level of the Toll/interleukin-1 receptor (TIR) domain-containing TLR adaptor proteins MAL, MyD88, TRAM, and TRIF. The mechanism of interaction of A46 with its targets has remained unclear. The TIR domains of MAL and MyD88 have been shown to signal by forming filamentous assemblies. We show a clear concentration-dependent destruction of both of these assemblies by A46 by means of negative-stain electron microscopy from molar ratios of 1:15 for MAL and 1:30 for MyD88. Using targeted mutagenesis and protein-protein crosslinking, we show that A46 interacts with MAL and MyD88 through several facets, including residues on helices α1 and α7 and the C-terminal flexible region. We propose a model in which A46 targets the MAL and MyD88 signalosome intra-strand interfaces and gradually destroys their assemblies in a concentration-dependent manner

Nature’s path to thinking about others and the surrounding environment

Research has shown differences in pro-social and pro-environmental attitudes after exposure to different physical environments. It is unclear whether these perspective shifts are associated with changes in conscious thoughts and feelings about other people and the environment. In Study 1, we used a within-subject design to measure social and environmental thought content throughout one-hour environmental explorations of a nature conservatory and an indoor mall. At three survey time points, participants (N = 86, undergraduates and community members) reported whom they were thinking about and how connected they felt to the physical and social environment. Using Bayesian multi-level models, we found that while visiting the conservatory, participants were less likely to think about themselves, felt closer to people nearby and around the world, and felt higher connectedness to their social and physical environment. In Study 2, we used a correlational design to investigate the association between perceived naturalness of city parks and feelings of connection to nearby others and the physical environment while visiting. Participants (N = 303, Chicago residents) reported feeling higher levels of connection to nearby people and the physical environment when they were visiting city parks rated as more natural. These studies further our understanding of the ways in which natural environments influence conscious thoughts and feelings about the social and physical environment

o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2

AbstractToll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MALTIR). We show that o-vanillin binds to MALTIR and inhibits its higher-order assembly in vitro. Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell