Thyroxine-thyroid hormone receptor interactions

ABSTRACTThyroid hormone (TH) actions are mediated by nuclear receptors (TRs α and β) that bind triiodothyronine (T3, 3,5,3′-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T4, 3,5,3′,5′-tetraiodo-l-thyronine) with lower affinity. T4 contains a bulky 5′ iodine group absent from T3. Because T3 is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5′ substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T4 affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T4 complexes adopt a conformation that differs from TR-T3 complexes in solution. Nonetheless, T4 behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T3 does not contribute to agonist activity. We determined x-ray crystal structures of the TRβ LBD in complex with T3 and T4 at 2.5-Å and 3.1-Å resolution. Comparison of the structures reveals that TRβ accommodates T4 through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5′ iodine and complete the coactivator binding surface. While T3 is the major active TH, our results suggest that T4 could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5′ extension should be considered in TR ligand design

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Preserving the Chesapeake: Law, Ecology, and the Bay

This event was co-sponsored by the Merhige Center for Environmental Studies, the Allen Chair of Law, the Virginia State Bar, and the Miller Center of Public Affairs. The “Historical Background” session, held from 9:30 - 10:30 a.m., was presented by the Hon. Governor Gerald L. Baliles, Director of the Miller Center of Public Affairs and 65th Governor of the Commonwealth of Virginia; Gerald McCarthy, Executive Director of the Virginia Environmental Endowment; and Russell W. Baxter, Deputy Director of the Virginia Department of Conservation and Recreation. Rodney A. Smolla, Dean of the University of Richmond School of Law, served as moderator. The “Current State of the Bay” session, held on Friday, October 20, 2006 from 10:45 - 11:45 a.m., was presented by Jonathan Z. Cannon, Director of the Center for Environmental and Land Use Law at the University of Virginia School of Law; Erin Ryan, of the Marshall-Wythe School of Law at the College of William and Mary; and Richard Batiuk, Associate Director for Science of the Chesapeake Bay Program Office, United States Environmental Protection Agency. Joel Eisen, University of Richmond School of Law, served as moderator. The Keynote was given from 11:45 a.m. - 1:15 p.m. by L. Preston Bryant, Secretary of Natural Resources of the Commonwealth of Virginia. The “Regulatory Efforts” session, held 1:15-2:15 p.m., was presented by Kathy R. Frahm, Director of the Division of Policy at the Virginia Department of Environmental Quality; Joseph J. Tannery, Virginia Staff Attorney for the Chesapeake Bay Foundation; David E. Evans, Partner at McGuireWoods LLP; and Mark Smith, Environmental Scientist with the Water Protection Division, U.S. Environmental Protection Agency. The “Future and Solutions” session, held from 2:30-3:45 p.m., was presented by Nikki Rovner, Deputy Secretary of Natural Resources for the Commonwealth of Virginia; Timothy G. Hayes, Partner at Hunton & Williams LLP; Clyde Wilbur, Principal of Greeley & Hanson; and Alexandra Dunn, General Counsel for the National Association of Clean Water Agencies. Carl W. Tobias, Williams Professor of Law University of Richmond School of Law, served as moderator

Comparative molecular biological analysis of membrane transport genes in organisms

Comparative analyses of membrane transport genes revealed many differences in the features of transport homeostasis in eight diverse organisms, ranging from bacteria to animals and plants. In bacteria, membrane-transport systems depend mainly on single genes encoding proteins involved in an ATP-dependent pump and secondary transport proteins that use H+ as a co-transport molecule. Animals are especially divergent in their channel genes, and plants have larger numbers of P-type ATPase and secondary active transporters than do other organisms. The secondary transporter genes have diverged evolutionarily in both animals and plants for different co-transporter molecules. Animals use Na+ ions for the formation of concentration gradients across plasma membranes, dependent on secondary active transporters and on membrane voltages that in turn are dependent on ion transport regulation systems. Plants use H+ ions pooled in vacuoles and the apoplast to transport various substances; these proton gradients are also dependent on secondary active transporters. We also compared the numbers of membrane transporter genes in Arabidopsis and rice. Although many transporter genes are similar in these plants, Arabidopsis has a more diverse array of genes for multi-efflux transport and for response to stress signals, and rice has more secondary transporter genes for carbohydrate and nutrient transport

Genome-wide association analysis reveals QTL and candidate mutations involved in white spotting in cattle

International audienceAbstractBackgroundWhite spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein–Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein–Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date.ResultsUsing imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region.ConclusionsOur findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics

Muslim communities learning about second-hand smoke:a pilot cluster randomised controlled trial and cost-effectiveness analysis

Background: In the United Kingdom, men of Bangladeshi and Pakistani origin have higher smoking rates than the general population. This makes non-smokers in their households more vulnerable to second-hand smoke (SHS) exposure than the general population. Aims: The aim of this study was to investigate the feasibility of implementing and pilot testing the effectiveness and cost-effectiveness of a 'Smoke-free Homes' (SFH) intervention in Islamic religious settings to encourage families of Bangladeshi and Pakistani origin to apply smoking restrictions in their homes. Methods: We allocated Islamic religious settings (clusters) to either receive SFH-an educational intervention-or to a control arm. Within each cluster, we recruited households with at least one smoker and one non-smoker. SHS exposure among non-smokers was measured using salivary cotinine. Results: Seven (50%) clusters were randomised to each trial arm. A total of 468 households were assessed for eligibility and 62% (n=289) were eligible, of which 74% (n=213) agreed to participate in the trial. Six of the seven intervention clusters delivered the intervention, and all clusters were retained throughout the trial. In all, 81% (n=172) of households provided data at follow-up. No evidence of a difference in log cotinine level was observed (adjusted mean difference -0.02, 95% confidence interval (CI) -1.28-1.23, P=0.97) between the two trial arms. The direct mean cost of delivering the intervention was £18.18 per household (range £3.55-42.20). Conclusions: It was possible to recruit, randomise and retain Islamic religious settings and participant households. However, some of the original assumptions, in particular our ability to collect primary outcome data, need to be revisited before a definitive trial

Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma

Tuberculosis (TB) granulomas are organized collections of immune cells comprised of macrophages, lymphocytes and other cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro-inflammatory cytokine, tumor necrosis factor-α (TNF). To characterize mechanisms that control TNF availability within a TB granuloma, we developed a multi-scale two compartment partial differential equation model that describes a granuloma as a collection of immune cells forming concentric layers and includes TNF/TNF receptor binding and trafficking processes. We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads. Using our model, we then demonstrated that the organization of immune cells within a TB granuloma as well as TNF/TNF receptor binding and intracellular trafficking are two important factors that control TNF availability and may spatially coordinate TNF-induced immunological functions within a granuloma. Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry. To further elucidate the role of TNF in the process of granuloma development, our modeling and experimental findings on TNF-associated molecular scale aspects of the granuloma can be incorporated into larger scale models describing the immune response to TB infection. Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy