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关键词： Alzheimer's disease   amyloid beta   FTD mutation   phosphorylation   post-translational modification   TREM2  

摘要： Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid beta peptides (A beta). A beta peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct A beta variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of A beta affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric A beta, and that phosphorylation of A beta increases this interaction. Phosphorylation of A beta also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated A beta variants in distinct aggregation states and reduces the accumulation and deposition of these toxic A beta species in preclinical models of Alzheimer's disease.

关键词： Integro-differential equation   composite trapezoidal rule   post-processing technique   uniform convergence  

摘要： In this paper, a singularly perturbed Volterra integro- differential equation is being surveyed. On a piecewise-uniform Shishkin mesh, a fitted mesh finite difference approach is applied using a composite trapezoidal rule in the case of integral component and a finite difference operator for the derivative component. The proposed technique acquires a uniform convergence in accordance with the perturbation parameter. To improve the accuracy of the computed solution, an extrapolation, specifically Richardson extrapolation, is used measured in the discrete maximum norm and almost second-order convergence is attained. Further numerical results are provided to assist the theoretical estimates.

关键词： G-expectation   Reflected backward SDE   Approximate Skorohod condition  

摘要： In this paper, we study the reflected backward stochastic differential equations driven byG-Brownian motion with two reflecting obstacles, which means that the solution lies between two prescribed processes. A new kind ofapproximate Skorohod conditionis proposed to derive the uniqueness and existence of the solutions. The uniqueness can be proved by a priori estimates and the existence is obtained via a penalization method.

关键词： COVID-19   microbiota   immunity   immunological dark matter   inflammation   modelling  

摘要： Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19.

关键词： approximate controllability   approximating technique   finite delay   nonlinear equations   resolvent operator theory   semigroup theory  

摘要： In this paper, we apply the resolvent operator theory and an approximating technique to derive the existence and controllability results for nonlocal impulsive neutral integro-differential equations with finite delay in a Hilbert space. To establish the results, we take the impulsive functions as a continuous function only, and we assume that the nonlocal initial condition is Lipschitz continuous function in the first case and continuous functions only in the second case. The main tools applied in our analysis are semigroup theory, the resolvent operator theory, an approximating technique, and fixed-point theorems. Finally, we illustrate the main results with the help of two examples.

关键词： Calculus of Variations and Optimal Control   Optimization   Optimization   Theory of Computation   Applications of Mathematics   Engineering   general   Operations Research/Decision Theory  

摘要： In the Target-Attacker-Defender differential game, an Attacker missile strives to capture a Target aircraft. The Target tries to escape the Attacker and is aided by a Defender missile which aims at intercepting the Attacker, before the latter manages to close in on the Target. The conflict between these intelligent adversaries is naturally modeled as a zero-sum differential game. The Game of Degree when the Attacker is able to win the Target-Attacker-Defender differential game has not been fully solved, and it is addressed in this paper. Previous attempts at designing the players' strategies have not been proven to be optimal in the differential game sense. In this paper, the optimal strategies of the Game of Degree in the Attacker's winning region of the state space are synthesized. Also, the value function is obtained, and it is shown that it is continuously differentiable, and it is the solution of the Hamilton-Jacobi-Isaacs equation. The obtained state feedback strategies are compared to recent results addressing this differential game. It is shown that the correct solution of the Target-Attacker-Defender differential game that provides a semipermeable Barrier surface is synthesized and verified in this paper.

关键词： Heavy metals   Arbuscular mycorrhiza   Chromium   Metal translocation  

摘要： Chromium (Cr) is a nonessential element for plants that is extremely toxic at high concentrations. Zea mays L. is a species of plant that has developed adaptive mechanisms to increase its tolerance and absorption capacity for this metal. One effective mechanism is to form associations with arbuscular mycorrhizal fungi (AMF), which help the plant cope with stress from heavy metals such as Cr. However, it is still not clear which species of AMF are more efficient as bioremediating agents for plants of agricultural importance. Here, we evaluated the effect of Gigaspora gigantea and Rhizophagus irregularis as protective agents of maize plants in soils contaminated with Cr at concentrations of 0, 48.5, 97 and 194 mg kg(-1) under greenhouse conditions. Maize tolerance to Cr was corroborated, as well as increased absorption of this element by plants associated with both species of AMF. G. gigantea caused an increase in nitrogen content and greater translocation of Cr to the aerial part of the plant;R. irregularis registered an increase in the formation of arbuscules and vesicles with increasing metal concentration and greater retention of Cr in the roots of the plants. Based on these results, we can conclude that the analyzed species of fungi use different strategies, with similar effectiveness, to enhance the absorption capacity of Cr by the plant and influence the differential deposition of this metal in various parts of the plant.

关键词： Methylphenidate   Cognition   5-HT1A heteroreceptors   GABA   NMDA   Prefrontal cortex  

摘要： Methylphenidate (MPD), a psychostimulant, is a prescription medicine for treating attention deficit hyperactivity disorder (ADHD). Previously we have shown that moderate doses of MPD enhanced learning and memory while higher doses impaired it. To understand neurochemical mechanisms and receptors involved in memory enhancing and impairing effects of MPD, the present study concerns the effects of these doses of MPD on serotonin, 5-HT1A, GABA, and NMDA receptor mRNA expression in the prefrontal cortex (PFC). We found that low doses (2.5 mg/kg) of MPD improved performance in the water-maze test but higher doses (5 mg/kg) impaired memory retention. Animals showing improved performance had high 5-HT metabolism in the PFC while these levels were not affected in the group treated with higher MPD doses and exhibiting impaired memory. There was downregulation of 5-HT1A receptors in the PFC of rats treated with higher dose MPD, which didn't occur in low dose of MPD treated animals. Further, a decrease in GABA(A)receptor mRNA expression occurred in low doses of MPD treated animals and GluN2A expression was reduced in higher doses of MPD treated animals. The findings suggest that memory enhancing doses of MPD increase 5-HT and reduce GABA(A) receptor mRNA expression in the PFC to release excitatory glutamate neurons from the inhibitory influence of GABA. Conversely, higher dose of MPD downregulates 5-HT1A receptor mRNA expression to enhance inhibitory GABA influence on glutamate neurons and impair cognitive performance. The findings show an important role of 5-HT1A heteroreceptors in the PFC for improving therapeutic use of MPD and developing novel cognitive enhancers. (C) 2021 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

关键词： Cohomology   Weighted Densities  

摘要： We consider the spaces F-mu of polynomial mu-densities on the line as sl(2)-modules and then we compute the cohomological spaces H-diff(1) sl(2), D-lambda,D-mu), where mu is an element of R, (lambda) over bar = (lambda(1), ...,lambda(n)) is an element of R-n and D-lambda,D-mu is the space of n-ary differential operators from F-lambda 1 circle times ...circle times F-lambda n to F-mu.

关键词： placental insufficiency   intrauterine growth restriction   low birth weight   skeletal muscle   insulin resistance   mitochondria   lipid metabolism   Western diet   fetal programming   muscle vessels  

摘要： Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar "Western" diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male "lean" offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.