Facilitated Hyperpolarization Signaling in Vascular Smooth Muscle-overexpressing TRIC-A Channels

The TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation-specific channels and likely mediate counterion movements to support efficient Ca²⁺ release from the sarco/endoplasmic reticulum. Vascular smooth muscle cells (VSMCs) contain both TRIC subtypes and two Ca²⁺ release mechanisms; incidental opening of ryanodine receptors (RyRs) generates local Ca²⁺ sparks to induce hyperpolarization and relaxation, whereas agonist-induced activation of inositol trisphosphate receptors produces global Ca²⁺ transients causing contraction. Tric-a knock-out mice develop hypertension due to insufficient RyR-mediated Ca²⁺ sparks in VSMCs. Here we describe transgenic mice overexpressing TRIC-A channels under the control of a smooth muscle cell-specific promoter. The transgenic mice developed congenital hypotension. In Tric-a-overexpressing VSMCs from the transgenic mice, the resting membrane potential decreased because RyR-mediated Ca²⁺ sparks were facilitated and cell surface Ca²⁺-dependent K⁺ channels were hyperactivated. Under such hyperpolarized conditions, L-type Ca²⁺ channels were inactivated, and thus, the resting intracellular Ca²⁺ levels were reduced in Tric-a-overexpressing VSMCs. Moreover, Tric-a overexpression impaired inositol trisphosphate-sensitive stores to diminish agonist-induced Ca²⁺ signaling in VSMCs. These altered features likely reduced vascular tonus leading to the hypotensive phenotype. Our Tric-a-transgenic mice together with Tric-a knock-out mice indicate that TRIC-A channel density in VSMCs is responsible for controlling basal blood pressure at the whole-animal level.     

3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation

Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC₅₀ values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values.     

基于Apache Spark机器学习的生态安全格局构建方法

区域生态安全格局构建往往是通过对各类环境因子不同层次、不同深度的分析以生成规划结果,少有学者直接对生态安全格局与环境因子之间的关系进行分析,研究通用模型。利用大数据计算框架Apache Spark机器学习库的Logistic Regression(LR)模型对佛山市高明、三水和顺德区已有生态安全格局规划数据与岩性、土壤、用地类型、NDVI、海拔、坡度、道路距离、河流距离、年均降雨量、人口密度等多个变量的相互关系进行了训练学习,得到回归模型,用以预测广东省生态安全格局,结果显示:1)基于Spark-LR的保障生态安全格局模型(GSPM)精度达到90.58%,其预测的广东省保障安全格局高概率区比例为50.56%,在实际应用中,有一定的参考价值;2)总体上GSPM预测的生态安全格局分布与已有规划类似,但是模型容易受到样点分布均匀性的影响;3)GSPM预测结果更加切合生态资源保护的需求,而常规方法构建的结果则需要进一步优化;4)Spark-LR机器学习对生态安全格局中城市扩张的预测具有一定的优势。     

Chemical analysis of silica doped hydroxyapatite biomaterials consolidated by a spark plasma sintering method

Silica (SiO(2)) and the silicate-based biomaterials play an important role due to their in vitro and in vivo biological response. The present study synthesized a novel nano-structured amorphous silica doped hydroxyapatite (HA) via an aqueous precipitation route. HA was prepared with 0, 1, 3 and 5 wt% silica, which are comparable to the measured silicon content of natural bone. After spray drying into micron sized powders, the silica doped HA (SiHA) powders were consolidated at 1000 degrees C with a dwell time of 3 min using a spark plasma sintering (SPS) technique. X-ray diffraction analysis showed a main apatite phase with minor secondary beta-tricalcium phosphate (beta-TCP) was observed in the as-consolidated SiHA compacts. Substitution of PO(4)(3-) by SiO(4)(4-) in the apatite structure resulting in a small increase in the lattice parameters in both a-axis and c-axis of the unit cell were identified by X-ray photoelectron spectrometer (XPS) analysis and Raman spectrometer investigation. The cell culture in vitro investigation demonstrated that the presence of silicon in the SPS consolidated compacts contributed to the relatively high cell proliferation ability when compared with phase pure HA.