Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies ...have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.
Large peridotite massifs are scattered along the 1500km length of the Yarlung-Zangbo Suture Zone (southern Tibet, China), the major suture between Asia and Greater India. Diamonds occur in the ...peridotites and chromitites of several massifs, together with an extensive suite of trace phases that indicate extremely low fO sub(2) (SiC, nitrides, carbides, native elements) and/or ultrahigh pressures (UHP) (diamond, TiO sub(2) II, coesite, possible stishovite). New physical and isotopic (C, N) studies of the diamonds indicate that they are natural, crystallized in a disequilibrium, high-T environment, and spent only a short time at mantle temperatures before exhumation and cooling. These constraints are difficult to reconcile with previous models for the history of the diamond-bearing rocks. Possible evidence for metamorphism in or near the upper part of the Transition Zone includes the following: (1) chromite (in disseminated, nodular and massive chromitites) containing exsolved pyroxenes and coesite, suggesting inversion from a high-P polymorph of chromite; (2) microstructural studies suggesting that the chromitites recrystallized from fine-grained, highly deformed mixtures of wadsleyite and an octahedral polymorph of chromite; (3) a new cubic Mg-silicate, with the space group of ringwoodite but an inverse-spinel structure (all Si in octahedral coordination); (4) harzburgites with coarsely vermicular symplectites of opx + Cr-Al spinel plus or minus cpx; reconstructions suggest that these are the breakdown products of majoritic garnets, with estimated minimum pressures to>13GPa. Evidence for a shallow pre-metamorphic origin for the chromitites and peridotites includes the following: (1) trace-element data showing that the chromitites are typical of suprasubduction-zone (SSZ) chromitites formed by magma mixing or mingling, consistent with Hf-isotope data from magmatic (375Ma) zircons in the chromitites; (2) the composition of the new cubic Mg-silicate, which suggests a low-P origin as antigorite, subsequently dehydrated; (3) the peridotites themselves, which carry the trace element signature of metasomatism in an SSZ environment, a signature that must have been imposed before the incorporation of the UHP and low-fO sub(2) phases. A proposed P-T-t path involves the original formation of chromitites in mantle-wedge harzburgites, subduction of these harzburgites at c. 375Ma, residence in the upper Transition Zone for >200 Myr, and rapid exhumation at c. 170-150Ma or 130-120Ma. Os-isotope data suggest that the subducted mantle consisted of previously depleted subcontinental lithosphere, dragged down by a subducting oceanic slab. Thermomechanical modeling shows that roll-back of a (much later) subducting slab would produce a high-velocity channelized upwelling that could exhume the buoyant harzburgites (and their chromitites) from the Transition Zone in<10 Myr. This rapid upwelling, which may explain some characteristics of the diamonds, appears to have brought some massifs to the surface in forearc or back-arc basins, where they provided a basement for oceanic crust. This model can reconcile many apparently contradictory petrological and geological datasets. It also defines an important, previously unrecognized geodynamic process that may have operated along other large suture zones such as the Urals.
Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and ...promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments (PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.
Hybrid halide perovskites such as methylammonium lead iodide (CH3NH3PbI3) exhibit unusually low free‐carrier concentrations despite being processed at low‐temperatures from solution. We demonstrate, ...through quantum mechanical calculations, that an origin of this phenomenon is a prevalence of ionic over electronic disorder in stoichiometric materials. Schottky defect formation provides a mechanism to self‐regulate the concentration of charge carriers through ionic compensation of charged point defects. The equilibrium charged vacancy concentration is predicted to exceed 0.4 % at room temperature. This behavior, which goes against established defect conventions for inorganic semiconductors, has implications for photovoltaic performance.
Missing ion action: Schottky defects are found to be a dominant mode of equilibrium stoichiometric disorder in the photovoltaic material CH3NH3PbI3. This behavior can explain the previous finding that “the compounds show intense color, but there is no significant conductivity”.
Aims
Vibrio alginolyticus was frequently isolated from diseased farmed fish in the coaster waters of Hainan Island over the past two decades. In this study, we attempted to identify candidates of ...virulent strain‐specific DNA regions for this pathogen.
Methods and Results
Suppression subtractive hybridization (SSH) and PCR were successively performed between the typical virulent strain and avirulent strain of V. alginolyticus, in which they shared 99·54% homology of 16S rDNAs. Out of 2873 subtracted clones, nine clones were finally indicated to harbour virulent strain‐specific DNA fragments. The receivable functions of the major fragments in the nine clones were believed to encode methyl‐accepting chemotaxis protein (n = 1), type VI secretion system‐associated FHA domain protein TagH (n = 1), diguanylate cyclase (n = 1), AraC family transcriptional regulator (n = 1), ABC‐type uncharacterized transport system permease component (n = 1) and hypothetical proteins (n = 4). Two hypothetical proteins contain several disordered regions.
Conclusions
Some specific DNA regions existed in the virulent strain of V. alginolyticus, and the SSH assay could be a highly sensitive method for identifying virulent regions in pathogens.
Significance and Impact of the Study
This report is the first to describe the identification of virulent strain‐specific DNA regions in the V. alginolyticus genome, which is helpful in developing virulent strain‐specific rapid detection methods and is a pivotal precondition for clarifying the molecular virulence mechanism of V. alginolyticus.
Summary
We conducted a meta-analysis to qualitatively summarize the evidence of the association between abdominal obesity and hip fracture risk. The results indicated that abdominal obesity as ...measured by waist circumference and waist-hip ratio might be associated with an increased risk of hip fracture.
Introduction
Epidemiological investigations evaluating the association of abdominal obesity with hip fracture risk have yielded conflicting results. Therefore, a meta-analysis was conducted to qualitatively summarize the evidence of the associations between waist circumference, waist-hip ratio, and hip circumference and the risk of hip fracture, respectively.
Methods
PubMed, Embase, and Web of Science were searched for relevant articles published up to March 2017. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. Dose-response relationship was assessed by restricted cubic spline.
Results
Seven studies involving 180,600 participants for hip circumference, six studies involving 199,828 participants for waist-hip ratio, and five studies involving 170,796 participants for waist circumference were finally included in this meta-analysis. The combined RRs with 95% CIs of hip fracture for the highest versus lowest category of waist circumference, waist-hip ratio, and hip circumference were 1.58 (95% CI 1.20–2.08), 1.32 (95% CI 1.15–1.52), and 0.87 (95% CI 0.74–1.02), respectively. For dose-response analysis, a nonlinear relationship was found (
P
nonlinearity
< 0.001) between waist circumference and the risk of hip fracture, and a linear relationship (
P
nonlinearity
= 0.911) suggested that the risk of hip fracture increased about 3.0% (1.03 (1.01–1.04)) for each 0.1 unit increment of waist-hip ratio.
Conclusions
This meta-analysis suggested that abdominal obesity as measured by waist circumference and waist-hip ratio might be associated with an increased risk of hip fracture. From a public health perspective, indicators of abdominal obesity may be usable predictors of hip fracture risk.
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