In the early stages of immobilization, upregulation of IL-1β/TGF-β1 via macrophages may promote fibroblast differentiation that could affect muscle contracture. The soleus muscle became hypoxic in the later stages of immobilization, suggesting that hypoxia influences the progression of muscle contracture.
Our study identifies the prevalence of HBV virus (HBV) screening and vaccination among Asian Americans, and ethnic differences for factors associated with screening and vaccination behaviors. In 2009–2010 we recruited 877 Korean, Chinese, and Vietnamese Americans 18 years of age and above through several community organizations, churches and local ethnic businesses in Maryland for a health education intervention and a self-administered survey. Prevalence of HBV screening, screening result and vaccinations were compared by each ethnic group. We used logistic regression analysis to understand how sociodemographics, familial factors, patient-, provider-, and resource-related barriers are associated with screening and vaccination behaviors, using the total sample and separate analysis for each ethnic group. Forty-seven percent of participants reported that they had received HBV screening and 38% had received vaccinations. Among the three groups, the Chinese participants had the highest screening prevalence, but lowest self-reported infection rate; Vietnamese has the lowest screening and vaccination prevalence. In multivariate analysis, having better knowledge of HBV, and family and physician recommendations was significantly associated with screening and vaccination behaviors. Immigrants who had lived in the US for more than a quarter of their lifetime were less likely to report ever having been screened (OR = 0.39, 95% CI: 0.28–0.55) or vaccinated (OR = 0.62, 95% CI: 0.44–0.88). In ethnic-specific analysis, having a regular physician (OR = 4.46, 95% CI: 1.62–12.25) and doctor's recommendation (OR = 2.11, 95% CI: 1.05–4.22) are significantly associated with Korean's vaccination behaviors. Health insurance was associated with vaccination behaviors only among Vietnamese (OR = 2.66, 95% CI: 1.21–5.83), but not among others.
BackgroundHyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms.MethodsWe analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice.ResultsSocial deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction.ConclusionsThese findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0243-3) contains supplementary material, which is available to authorized users.
The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cell metabolism, growth, and proliferation. The overactivation of mTOR has been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor rapamycin improved social interaction deficits in mouse models of TSC. Prenatal exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that are exposed to VPA in utero have been used as an animal model of ASD. Activation of the mTOR signaling pathway was recently observed in rodents that were exposed to VPA in utero, and rapamycin ameliorated social interaction deficits. The present study investigated the effect of rapamycin on social interaction deficits in both adolescence and adulthood, and gene expressions in mice that were exposed to VPA in utero. We subcutaneously injected 600 mg/kg VPA in pregnant mice on gestational day 12.5 and used the pups as a model of ASD. The pups were intraperitoneally injected with rapamycin or an equal volume of vehicle once daily for 2 consecutive days. The social interaction test was conducted in the offspring after the last rapamycin administration at 5–6 weeks of ages (adolescence) or 10–11 weeks of age (adulthood). Whole brains were collected after the social interaction test in the adulthood, and microarray and Western blot analyses were performed. Mice that were exposed to VPA and treated with vehicle exhibited a decrease in social interaction compared with control mice that were treated with vehicle. Rapamycin treatment in VPA-exposed mice improved social deficits. Mice that were exposed to VPA and treated with vehicle exhibited the aberrant expression of genes in the mTOR signaling pathway, and rapamycin treatment recovered changes in the expression of some genes, including Fyb and A330094K24Rik. Rapamycin treatment suppressed S6 phosphorylation in VPA-exposed mice. Aberrant gene expression was associated with social interaction deficits in VPA-exposed mice. Rapamycin may be an effective treatment for non-syndromic ASD in adolescent and adult patients who present impairments in the mTOR signaling pathway.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0423-2) contains supplementary material, which is available to authorized users.
Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4 0 -(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (()-1. An efficient and scalable synthesis of (()-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum's acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step SuzukiÀMiyaura couplingÀbromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.
The present study indicated that a decrease in muscle extensibility depended on collagen overexpression in immobilized rat soleus muscles. Muscle Nerve 57: 672-678, 2018.
The total syntheses of (+)-schizandrin (1), (+)-gomisin A (2), and (+)-isoschizandrin (3) having natural configurations were accomplished. Optically pure butyrolactones ((-)-9, (-)-31) were transformed to a-benzylidenebutyrolactones ((+)-10, (+)-32, (+)-35). By a highly efficient iron(III) perchlorate-mediated oxidative coupling reaction of 10, 32, and 35, the key intermediates with biphenyl skeletons ((-)-ll, (-)-33) were constructed with high stereoselectivity. Several methods for the stereoselective introduction of the C6-hydroxyl group were examined. For the synthesis of schizandrin and gomisin A, the Mukaiyama hydration reaction of (-)-ll and (-)-33 provided the desired products with satisfactory selectivity. For the synthesis of isoschizandrin, the stereoselective epoxidation of allylic alcohol (+)-48 was successfully utilized taking advantage of its conformational features.
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