The credibility of 38 global climate models (GCMs) participating in the Coupled Model Intercomparison Project Phase 5 (CMIP5) is assessed to simulate the spatiotemporal variability of the summer ...monsoon season (SMS) precipitation over the central Himalayas in and around Nepal in the present climate (1971–2000). The evolution of precipitation during 3 tri-decadal periods of the 21st century (2011–2040, 2041–2070 and 2070–2099) under 2 warming scenarios: representative concentration pathways (RCP) 4.5 and RCP8.5, are analyzed based on the systematically selected best models and their multi-model mean. Most of the models capture the annual cycle. However, most are deficient in their simulation of spatial distribution of SMS mean climatology and interannual variability (IAV). Models consistently project a considerable increase in seasonal mean precipitation in the middle and late 21st century under both warming scenarios. However, there is inconsistency in projections of the change in IAV of seasonal mean precipitation in all future periods. The increase in the seasonal mean is contributed to mainly by intensification of moderate to heavy precipitation events and the enhanced frequency and length of active spells. Increased precipitation could be attributed to the increase in moisture flux convergence and enhanced low level circulation. Inconsistency in the spatial distribution of the future projections of SMS precipitation change by the best models indicates the uncertainty of the projections and suggests careful interpretation of projections is required in the study of regional climate change and its consequences.
HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly ...disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti-androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.
Computed, high-resolution, spatial distributions of solvation energy and entropy can provide detailed information about the role of water in molecular recognition. While grid inhomogeneous solvation ...theory (GIST) provides rigorous, detailed thermodynamic information from explicit solvent molecular dynamics simulations, recent developments in the 3D reference interaction site model (3D-RISM) theory allow many of the same quantities to be calculated in a fraction of the time. However, 3D-RISM produces atomic-site, rather than molecular, density distributions, which are difficult to extract physical meaning from. To overcome this difficulty, we introduce a method to reconstruct molecular density distributions from atomic-site density distributions. Furthermore, we assess the quality of the resulting solvation thermodynamics density distributions by analyzing the binding site of coagulation Factor Xa with both GIST and 3D-RISM. We find good qualitative agreement between the methods for oxygen and hydrogen densities as well as direct solute-solvent energetic interactions. However, 3D-RISM predicts lower energetic and entropic penalties for moving water from the bulk to the binding site.
Although pregnant women’s fish consumption is beneficial for the brain development of the fetus due to the docosahexaenoic acid (DHA) in fish, seafood also contains methylmercury (MeHg), which ...adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women’s sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups’ body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20- epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women’s intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.
► Progesterone protected hippocampal cells from the toxic effects of tributyltin. ► The neuroprotective effect was independent from a progesterone receptor. ► The protective effect was mediated by ...allopregnanolone, a metabolite of progesterone. ► The neuroprotective effect of allopregnanolone was mediated by a GABAA receptor.
Increasing evidence shows that progesterone, a neuroactive steroid, has protective actions in central nervous system, but there is little evidence to show the protective mechanism of progesterone on neurotoxicity induced by environmental chemicals. In this study, we examined the effects of progesterone on neuronal injury induced by tributyltin (TBT) in rat hippocampal slices. Treatment with progesterone dose-dependently suppressed hippocampal neuronal injury induced by TBT. The neuroprotective action of progesterone was completely canceled with pretreatment by finasteride, a 5α-reductase inhibitor, but it was not affected by mifepristone, a progesterone receptor antagonist, or by SU-10603, a cytochrome P450 17α inhibitor. The content of allopregnanolone in the slices was significantly increased by treatment with progesterone, and this increment was greatly suppressed with a pretreatment of finasteride. Treatment with allopregnanolone attenuated neuronal injury induced by TBT in a dose-dependent manner. The neuroprotective effects not only of progesterone but also of allopregnanolone were canceled by bicuculline, a potent gamma-aminobutyric acid A (GABAA) receptor antagonist. Pretreatment with muscimol, a GABAA receptor agonist, attenuated hippocampal neuronal injury elicited by TBT. Taken together, allopregnanolone converted from progesterone in hippocampal slices could protect neurons from TBT-induced neurotoxicity due to a GABAA receptor-dependent mechanism. One of the physiological roles of neuroactive steroids might be neuroprotection from environmental chemicals.
Background & Aims: Helicobacter pylori CagA-positive strain is associated with gastric adenocarcinoma. CagA is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation at ...the EPIYA sites by Src family kinases (SFKs). Owing to homologous recombination within the 3′-region of the cagA gene, 4 distinct EPIYA sites, each of which is defined by surrounding sequences, are variably assembled in both number and order among CagA proteins from different clinical H pylori isolates. Tyrosine-phosphorylated CagA specifically binds and deregulates SHP-2 via the Western CagA-specific EPIYA-C or East Asian CagA-specific EPIYA-D site, and C-terminal Src kinase (Csk) via the EPIYA-A or EPIYA-B site. Here we investigated the influence of EPIYA-repeat polymorphism on the CagA activity. Methods: A series of EPIYA-repeat variants of CagA were expressed in AGS gastric epithelial cells and the ability of individual CagA to bind SHP-2 or Csk was determined by the sequential immunoprecipitation and immunoblotting method. Results: CagA proteins carrying multiple EPIYA-C or EPIYA-D sites bound and deregulated SHP-2 more strongly than those having a single EPIYA-C or EPIYA-D. Furthermore, the ability of CagA to bind Csk was correlated with the number of EPIYA-A and EPIYA-B sites. Because Csk inhibits SFK, CagA with greater Csk-binding activity more strongly inhibited Src-dependent CagA phosphorylation and more effectively attenuated induction of cell elongation caused by CagA–SHP-2 interaction. Conclusions: EPIYA-repeat polymorphism of CagA greatly influences the magnitude and duration of phosphorylation-dependent CagA activity, which may determine the potential of individual CagA as a bacterial virulence factor that directs gastric carcinogenesis.
Prenatal and postnatal biphasic increases in plasma testosterone levels derived from perinatal testes are considered critical for defeminizing/masculinizing the brain mechanism that regulates sexual ...behavior in male rats. Hypothalamic kisspeptin neurons are indispensable for stimulating GnRH and downstream gonadotropin, as well as the consequent testicular testosterone production/release in adult male rats. However, it is unclear whether kisspeptin is responsible for the increase in plasma testosterone levels in perinatal male rats. The present study aimed to investigate the role of Kiss1/kisspeptin in generating perinatal plasma LH and the consequent testosterone increase in male rats by comparing the plasma testosterone and LH profiles of wild-type (Kiss1+/+) and Kiss1 knockout (Kiss1–/–) male rats. A biphasic pattern of plasma testosterone levels, with peaks in the prenatal and postnatal periods, was found in both Kiss1+/+ and Kiss1–/– male rats. Postnatal plasma testosterone and LH levels were significantly lower in Kiss1–/– male rats than in Kiss1+/+ male rats, whereas the levels in the prenatal embryonic period were comparable between the genotypes. Exogenous kisspeptin challenge significantly increased plasma testosterone and LH levels and the number of c-Fos-immunoreactive GnRH neurons in neonatal Kiss1–/– and Kiss1+/+ male rats. Kiss1 and Gpr54 (kisspeptin receptor gene) were found in the testes of neonatal rats, but kisspeptin treatment failed to stimulate testosterone release in the cultured testes of both genotypes. These findings suggest that postnatal, but not prenatal, testosterone increase in male rats is mainly induced by central kisspeptin-dependent stimulation of GnRH and consequent LH release.
We propose the method of spatial decomposition analysis (SDA) based on three-dimensional integral equation (3D-IE) theory of molecular liquids to study and decompose the thermodynamics of proteins in ...solution into atomic level contributions. The 3D-IE theory maps the solvation thermodynamic properties, such as the solvation free energy and solvation entropy, onto the 3D space around the solute, including the excluded volume of the solute macromolecule, with the elementary volume contributions expressed in terms of the 3D total and direct correlation functions. The SDA thus breaks down the thermodynamic quantity into partial contributions of the solute fragments (functional groups or residues) by applying the proximity criterion to the 3D-IE mapping onto both the solvation shell outside the solute macromolecule and its excluded volume inside the van der Waals cores, the latter giving a major contribution to the solvation thermodynamics. This is distinct from the previous use of the proximity criterion applied to the 3D distribution functions in the solvation shell only. As SDA does not require perturbing the protein molecule to extract the contributions from the constituent residues, it can become an alternative to the computational “alanine scanning approach”. For illustration, we apply SDA to four miniproteins composed of 10−28 amino acid residues (chignolin, CLN025, Trp-cage, and FSD-1) and decompose their solvation free energy into the partial contributions of each residue. The present results show that SDA is capable of detecting a change in the protein thermodynamics due to mutations and local conformational changes. Furthermore, the SDA exhibits a convincing consistency with the experimental values of the whole-residue transfer free energies from water to 1-octanol. Thus, the SDA provides a meaningful decomposition of the protein thermodynamics which can bear a comparison with experimental measurements and therefore can serve as a valuable sensitive tool to analyze the protein thermodynamics at the atomistic resolution level. We envision that the SDA may also serve as a tool for quantitative structure−activity relationships (QSAR) to correlate and predict various solute properties in a fragment-based manner.
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