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811.
Trattnig SM Harpsøe K Thygesen SB Rahr LM Ahring PK Balle T Jensen AA 《The Journal of biological chemistry》2012,287(30):25241-25254
The ligand-gated ion channels in the Cys-loop receptor superfamily mediate the effects of neurotransmitters acetylcholine, serotonin, GABA, and glycine. Cys-loop receptor signaling is susceptible to modulation by ligands acting through numerous allosteric sites. Here we report the discovery of a novel class of negative allosteric modulators of the 5-HT(3) receptors (5-HT(3)Rs). PU02 (6-[(1-naphthylmethyl)thio]-9H-purine) is a potent and selective antagonist displaying IC(50) values of ~1 μM at 5-HT(3)Rs and substantially lower activities at other Cys-loop receptors. In an elaborate mutagenesis study of the 5-HT(3)A receptor guided by a homology model, PU02 is demonstrated to act through a transmembrane intersubunit site situated in the upper three helical turns of TM2 and TM3 in the (+)-subunit and TM1 and TM2 in the (-)-subunit. The Ser(248), Leu(288), Ile(290), Thr(294), and Gly(306) residues are identified as important molecular determinants of PU02 activity with minor contributions from Ser(292) and Val(310), and we propose that the naphthalene group of PU02 docks into the hydrophobic cavity formed by these. Interestingly, specific mutations of Ser(248), Thr(294), and Gly(306) convert PU02 into a complex modulator, potentiating and inhibiting 5-HT-evoked signaling through these mutants at low and high concentrations, respectively. The PU02 binding site in the 5-HT(3)R corresponds to allosteric sites in anionic Cys-loop receptors, which emphasizes the uniform nature of the molecular events underlying signaling through the receptors. Moreover, the dramatic changes in the functional properties of PU02 induced by subtle changes in its binding site bear witness to the delicate structural discrimination between allosteric inhibition and potentiation of Cys-loop receptors. 相似文献
812.
Here, molecular dynamics (MD) simulations are performed to study the differences of binding channel shapes of TTR with two inhibitors, flufenamic acid (FLU) and one kind of N-phenyl phenoxazine (BPD). The asymmetries of global structure including the central binding channel are found to be intrinsic. Moreover, the conformational changes of the binding channel are responsible for negative cooperativity (NC) or independent cooperativity (IC) of ligands. The results suggested a possible binding mechanism addressing NC of FLU and IC of BPD. For FLU, when the first ligand binds with TTR, it leads to expansion of the second binding site which may weaken the interaction of the second FLU with TTR. But for BPD, the first ligand's binding changes the second site's shape slightly, the second ligand has similar binding ability with TTR in the second site like the first binding event. 相似文献
813.
One fifth to one third of all patients diagnosed with schizophrenia are resistant to drug treatment, which makes it a major clinical challenge. Genetic studies have focused on the association between treatment resistant schizophrenia (TRS) and a number of candidate genes, including serotonin and dopamine system genes. We explored associations between carefully characterized TRS and DAT–VNTR, SERT-PR and SERT-in2 polymorphisms. There were 173 patients enrolled in the study that were clinically evaluated using Positive and Negative Syndrome Scale and Clinical Global Impressions Scales and divided into two groups based on treatment resistance (92 patients in TRS group). Patients with a combination of SERT-in2 ll and DAT 9/10, 9/11, 9/9 and 6/6 genotypes were more likely to have TRS, compared to those with 10/10 or 10/12 genotype (OR = 5.1; 95% CI = 1.6–16.8). In the group of patients with DAT 10/10 or 10/12 genotype, those who also shared SERT-in2 ls or ss genotype were more likely to have TRS, compared to ll genotype carriers (OR = 2.7; 95% CI = 1.0–7.0). The model in which interaction between SERT-in2 and DAT polymorphisms is linked to TRS can possibly explain contradictory previous results regarding role of DAT and SERT in TRS, but further research is needed. 相似文献
814.
Jérémie Pérès Lionel Thollon Jérome Delotte Yannick Tillier Christian Brunet Kambiz Kayvantash 《Computer methods in biomechanics and biomedical engineering》2014,17(9):958-964
Trauma during pregnancy especially occurring during car crashes leads to many foetal losses. Numerical modelling is widely used in car occupant safety issue and injury mechanisms analysis and is particularly adapted to the pregnant woman. Material modelling of the gravid uterus tissues is crucial for injury risk evaluation especially for the abruption placentae which is widely assumed as the leading cause of foetal loss. Experimental studies on placenta behaviour in tension are reported in the literature, but none in compression to the authors' knowledge. This lack of data is addressed in this study. To complement the already available experimental literature data on the placenta mechanical behaviour and characterise it in a compression loading condition, 80 indentation tests on fresh placentae are presented. Hyperelastic like mean experimental stress versus strain and corridors are exposed. The results of the experimental placenta indentations compared with the tensile literature results tend to show a quasi-symmetrical behaviour of the tissue. An inverse analysis using simple finite element models has permitted to propose parameters for an Ogden material model for the placenta which exhibits a realistic behaviour in both tension and compression. 相似文献
815.
816.
González-Martínez SC Burczyk J Nathan R Nanos N Gil L Alía R 《Molecular ecology》2006,15(14):4577-4588
Understanding population-scale processes that affect allele frequency changes across generations is a long-standing interest in genetic, ecological and evolutionary research. In particular, individual differences in female reproductive success and the spatial scale of gene flow considerably affect evolutionary change and patterns of local selection. In this study, a recently developed maximum-likelihood (ML) method based on established offspring, the Seedling Neighbourhood Model , was applied and exponentially shaped dispersal kernels were fitted to both genetic and ecological data in a widespread Mediterranean pine, Pinus pinaster Aiton. The distribution of female reproductive success in P. pinaster was very skewed (about 10% of trees mothered 50% of offspring) and significant positive female selection gradients for diameter (γ = 0.7293) and cone crop (γ = 0.4524) were found. The selective advantage of offspring mothered by bigger trees could be due to better-quality seeds. These seeds may show more resilience to severe summer droughts and microsite variation related to water and nutrient availability. Both approaches, ecological and of parentage, consistently showed a long-distance dispersal component in saplings that was not found in dispersal kernels based on seed shadows, highlighting the importance of Janzen-Connell effects and microenvironmental variation for survival at early stages of establishment in this Mediterranean key forest tree. 相似文献
817.
818.
The handling of individual cells, which has attracted increasing attention, is a key technique in cell engineering such as gene introduction, drug injection, and cloning technology. Alternating current (AC) electrokinetics has shown great potential for microfluidic functions such as pumping, mixing, and concentrating particles. The non-uniform electric field gives rise to Joule heating and dielectrophoresis (DEP). The motion of particles suspended in the medium can be influenced directly, by means of dielectrophoretic effects, and indirectly, via fluid flow through a viscous drag force that affects the particles. Thus alternating current electrothermal effect (ACET) induced flow and DEP force can be combined to manipulate and trap single particles and cells. This study presents a microfluidic device which is capable of specifically guiding and capturing single particles and cells by ACET fluid flow and the negative dielectrophoretic (nDEP) trap, respectively. The experiment was operated at high frequencies (5–12 MHz) and in a culture medium whose high conductivity (σ = 1.25 S/m) is of interest to biochemical analysis and environmental monitoring, which are both prone to producing ACET and nDEP. Manipulation of particle motion using ACET-induced fluid flow to the target trap is modeled numerically and is in good agreement with the experimental results. 相似文献
819.
820.
Jubala CM Lamerato-Kozicki AR Borakove M Lang J Gardner LA Coffey D Helm KM Schaack J Baier M Cutter GR Bellgrau D Modiano JF 《Cancer immunology, immunotherapy : CII》2009,58(2):171-185
The survival of naive T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naive T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naive B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance. 相似文献