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271.
A three-dimensional molecular model of the transmembrane domain of the 5-HT1A receptor (5-HT1AR) is presented in the context of a general strategy for modeling the macromolecular structure of a guanine nucleotide binding, regulatory protein coupled receptor (GPCR). The model of the 5-HT1AR rests on the definition of the putative residues of the ligand-binding site guided by criteria based on specific models proposed from structure-activity studies and on published results of modifications of GPCRs using methods of molecular biology. The resulting requirements for matching recognition sites in the agonist-binding pocket define the molecular details of the interaction between the agonist 5-HT and the human 5-HT1AR that includes: (1) the interaction between the protonated amine moiety and the conserved negative Asp-116, located in TMH 3; (2) the hydrogen bond between the hydroxyl group and Thr-199, located in TMH 5; and (3) the interaction complex between the aromatic ring portion of the ligand and the neutral form of His-192, located in TMH 5. Results from quantum mechanical calculations of the interaction between an agonist and the proposed recognition pocket of the 5-HT1AR model suggest a trigger of the receptor activation mechanism resulting from ligand binding. The antagonist-binding pocket of the human 5-HT1AR is inferred from the interaction sites of pindolol with the receptor model: (1) the ionic interaction between the protonated amine of the ligand and the side chain of the conserved Asp-116, located in TMH 3; and (2) the hydrogen bonds between the ether oxygen and the hydroxyl group of the ligand and Asn-385, located in TMH 7. Use of the model is proposed to facilitate the identification of the structural elements of agonists and antagonists that are key for their specific functions, in order to achieve the design of new compounds with predetermined pharmacological properties. 相似文献
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Transgenic tilapia were produced using a carp -actinlacZ gene construct and the transmission of the transgene to F1 progeny was followed. Of 36 founder fish analysed, 9 (25%) were found to be transgenic in at least one tissue and two of these were found to transmit the transgene to progeny. One male produced only three out of 28 transgene DNA positive progeny (10.7%) but none of these were found to express the transgene. The other male produced 243 out of 1601 (15.2%)lacZ expressing embryos; 40 of these were analysed by Southern blotting and all were found to be positive for the presence of the transgene but revealed two different patterns of transgene arrangement. Three different expression patterns were also observed and presumed to be a result of multiple integration events and resulting position effects. 相似文献
275.
Roland E. Willburger MD Ralf H. Wittenberg MD Karin S. Kleemeyer MD Romberg Hoos MD Francoise L. BrunnerFerber PhD Bernhard A. Peskar MD 《Prostaglandins & other lipid mediators》1996,52(4):327-338
The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthitis (RA, n=10) or osteoarthritis (OA, n=11) patients were incubated. Tepoxalin (10−7, 10−6, 10−5 M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71−33%, 6-keto-PGF1a to 37−20%, PGE2 to 29−6%. For RA: LTC4 to 56−22%, 6-keto-PGFa to 43−22%, PGE2 to 57−32%. Similarly, its metabolite (10−7, 10−5 M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA: LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (p<0.05) was achieved for all but 1 group (LTC4, metabolite at 10−7M vs tyrode).In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy. 相似文献
276.
Within the last 30 years, researchers have explored what role hypoxia might play in causing permeability changes in the pulmonary microvasculature. Since the data accumulated thus far are unclear, the effects of hypoxia on microvascular transport in the isolated, Ringer's perfused adult rabbit lung was observed and the following parameters were measured or computed for both oxygenated and hypoxic perfusates: pulmonary arterial (ra) and pulmonary venous (rv) resistances, pulmonary capillary filtration coefficients (Kf), and pulmonary capillary endothelial reflection coefficients () for NaCl and inulin. Separate reservoir bottles were used to create the desired oxygenated (aeration of solution with 95% O2-5% CO2) gas mixture or hypoxic (aeration of solution with 95% N2-5% CO2) gas mixture. A higher, but not significant, resistance value was found during the oxygenated state. A significant increase in the pulmonary capillary filtration coefficient during hypoxia (10.72 × 10–4±0.446 × 10–4 cm3/s cm H2O for the hypoxic perfusate and 8.80 × 10–4±0.384 × 10–4 cm3/s cm H2O for the oxygenated perfusate) was found and a significant difference between oxygenated and hypoxic pulmonary capillary reflection coefficients for inulin was computed (oxygenated solution revealed a finding of 0.120±0.003 and the hypoxic solution revealed 0.105±0.002). These findings imply a change in the microvascular permeability during hypoxia. According to the pore theory, a change in pore number, pore size, or both could have occurred. However, from the reflection coefficient data, a change in pore radius seems most likely. 相似文献
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Luke A. Smith MSc Jaedon D. Bem MSc Xiaojing Lv PhD Antonio Lauto PhD Ashour Sliow PhD Zhiyuan Ma MD David A. Mahns PhD Carolyn Berryman PhD Mark R. Hutchinson PhD Christophe Fumeaux PhD Giuseppe C. Tettamanzi PhD 《Bioelectromagnetics》2023,44(7-8):181-191
Electric-field stimulation of neuronal activity can be used to improve the speed of regeneration for severed and damaged nerves. Most techniques, however, require invasive electronic circuitry which can be uncomfortable for the patient and can damage surrounding tissue. A recently suggested technique uses a graft-antenna—a metal ring wrapped around the damaged nerve—powered by an external magnetic stimulation device. This technique requires no electrodes and internal circuitry with leads across the skin boundary or internal power, since all power is provided wirelessly. This paper examines the microscopic basic mechanisms that allow the magnetic stimulation device to cause neural activation via the graft-antenna. A computational model of the system was created and used to find that under magnetic stimulation, diverging electric fields appear at the metal ring's edges. If the magnetic stimulation is sufficient, the gradients of these fields can trigger neural activation in the nerve. In-vivo measurements were also performed on rat sciatic nerves to support the modeling finding that direct contact between the antenna and the nerve ensures neural activation given sufficient magnetic stimulation. Simulations also showed that the presence of a thin gap between the graft-antenna and the nerve does not preclude neural activation but does reduce its efficacy. 相似文献
280.
Yiqi Gao Tao Xue MD Biliang Chen MD Hong Yang MD Li Wei MD 《Developing world bioethics》2023,23(1):34-40
The recent advances in assisted reproductive technology, such as hormonal stimulation, IVF, and intracytoplasmic sperm injection (ICSI), have made it possible to circumvent many causes of male and female factor infertility. However, uterine infertility is still considered an ‘‘unconditionally infertile’’ condition. Owing to the continued advances in organ transplantation, microvascular anastomosis techniques, and immunosuppressive medicine, the transplantation of organs is no longer restricted to the ones necessary for continued life. Quality-of-life enhancing types of transplantation, such as uterine transplantation, in recent years, have also entered the clinical arena. This undoubtedly brings new hope to such women, but also creates ethical challenges. Selection of the donor, the impact on the recipient and offspring, as well as challenges to moral and social norms are issues that cannot be ignored. In the present review, the ethical issues of transplantation of the uterus will be discussed in light of recent progress in the procedure. 相似文献