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Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design. Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40–MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

Background Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies. Methods Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A “click” chemistry labeling method is developed for the detection of O-GlcNAcylated tau. Results Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity. Conclusion The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer’s disease and other neurodegenerative tauopathies.

Feedback from differentiated cells may keep precursor cells in check, controlling proliferation and differentiation. One such mechanism is now shown to control neuron numbers in the olfactory epithelium.

LONDON Chile is asking its creditor banks to lend it as much as $1 billion this year, banking sources said, to help the country offset weak world prices for its principal export, copper.

There is evidence that human influence may be forcing the global ecosystem towards a rapid, irreversible, planetary-scale shift into a state unknown in human experience. Forecasting the biological impact of global change Most forecasts of how the biosphere will change in response to human activity are rooted in projecting trajectories. Such models tend not anticipate critical transitions or tipping points, although recent work indicates a high probability of those taking place. And, at a local scale, ecosystems are known to shift abruptly between states when critical thresholds are passed. These authors review the evidence from across ecology and palaeontology that such a transition is being approached on the scale of the entire biosphere. They go on to suggest how biological forecasting might be improved to allow us to detect early warning signs of critical transitions on a global, as well as local, scale. Localized ecological systems are known to shift abruptly and irreversibly from one state to another when they are forced across critical thresholds. Here we review evidence that the global ecosystem as a whole can react in the same way and is approaching a planetary-scale critical transition as a result of human influence. The plausibility of a planetary-scale ‘tipping point’ highlights the need to improve biological forecasting by detecting early warning signs of critical transitions on global as well as local scales, and by detecting feedbacks that promote such transitions. It is also necessary to address root causes of how humans are forcing biological changes.

Systemic analyses of psychological functioning in families of children with autism have typically shown that parents report different experiences (e.g., stress) and that siblings may also be affected. The purpose of the present research was more explicitly to address relationships between child, partner, and parent variables. Parents of 48 children with autism (41 mother-father pairs) reported on child characteristics, and their own stress and mental health. Mothers were found to report both more depression and more positive perceptions than fathers. Regression analyses revealed that paternal stress and positive perceptions were predicted by maternal depression; maternal stress was predicted by their children's behavior problems (not adaptive behavior or autism symptoms) and by their partner's depression. The future testing of the mechanisms underlying these results is discussed. In addition, the need is emphasized for more systemic analyses to understand the psychological functioning of children with autism and their siblings and parents.

We present optical and infrared photometry of the unusual Type Ia supernova 2000cx. With the data of Li et al. and Jha, this constitutes the largest data set ever assembled for a Type Ia SN, more than 600 points inUBVRIJHK. We confirm the finding of Li et al. regarding the unusually blueB−Vcolors as SN 2000cx entered the nebular phase. ItsI‐band secondary hump was extremely weak given itsB‐band decline rate. TheV minusnear‐infrared colors likewise do not match loci based on other slowly declining Type Ia SNe, althoughV−Kis the least “abnormal.” In several ways, SN 2000cx resembles other slow decliners, given itsB‐banddeclinerate [ \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $\\Delta m_{15}( B) =0.93$ \\end{document} ], the appearance of Feiiilines and weakness of Siiiin its premaximum spectrum, theV−Kcolors, and postmaximumV−Hcolors. If the distance modulus derived from surface brightness fluctuations of the host galaxy is correct, we find that the rate of light increase prior to maximum, the characteristics of the bolometric light curve, and the implied absolute magnitude at maximum are all consistent with a subluminous object with \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $\\Delta m_{15}( B) \\approx 1.6{\\mbox{--}} 1.7$ \\end{document} having a higher than normal kinetic energy.

Bioluminescence resonance energy transfer (BRET) between Renilla luciferase and yellow fluorescent protein has been adapted to serve as a real-time reporter on protein-protein interactions in live plant cells by using the Arabidopsis Constitutive photomorphogenesis 1 (COP1) protein as a model system. COP1 is a repressor of light signal transduction that functions as part of a nuclear E3 ubiquitin ligase. COP1 possesses a leucine-rich nuclear-exclusion signal that resides in a domain implicated in COP1 dimerization. BRET was applied in conjunction with site-directed mutagenesis to explore the respective contributions of the nuclear-exclusion and dimerization motifs to the regulation of COP1 activity in vivo. One specific mutant protein, COP1 L105 A, showed increased nuclear accumulation but retained the ability to dimerize, as monitored by BRET, whereas other mutations inhibited both nuclear exclusion and COP1 dimerization. Mutant rescue and overexpression experiments indicated that nuclear exclusion of COP1 protein is a rate-limiting step in light signal transduction.

We show that the bipartite logarithmic entanglement negativity (EN) of quantum spin models obeys an area law at all nonzero temperatures. We develop numerical linked cluster (NLC) expansions for the `area-law' logarithmic entanglement negativity as a function of temperature and other parameters. For one-dimensional models the results of NLC are compared with exact diagonalization on finite systems and are found to agree very well. The NLC results are also obtained for two dimensional XXZ and transverse-field Ising models. In all cases, we find a sudden onset (or sudden death) of negativity at a finite temperature above which the negativity is zero. We use perturbation theory to develop a physical picture for this sudden onset (or sudden death). The onset of EN or its magnitude are insensitive to classical finite-temperature phase transitions, supporting the argument for absence of any role of quantum mechanics at such transitions. On approach to a quantum critical point at \\(T=0\\), negativity shows critical scaling in size and temperature.