GPR40 受体苯丙酸类激动剂三维定量构效关系研究

苯丙酸类化合物是G蛋白偶联受体40(GPR40)潜在的生物活性药物。本文基于比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(CoMSIA),分别建立了40个已知活性的GPR40受体苯丙酸类激动剂的三维定量构效关系(3D-QSAR)模型,研究该类激动剂与生物活性之间的关系。CoMFA和CoMSIA模型的交叉验证系数(q~2)分别为0. 527和0. 500,拟合验证系数(r~2)分别为0. 901和0. 860,两个3D-QSAR模型预测值与实验值基本一致,表明模型具有良好的可信度和预测能力。根据两个3D-QSAR模型提供的立体场、静电场、疏水场、氢键供体场和氢键受体场所提供的信息提出优化该类抑制剂结构的药物设计思路,为指导设计更高活性的GPR40激动剂以及GRR40新分子激动活性的预测提供理论依据。     

基于高斯回归分析的水稻氮素敏感波段筛选及含量估算

水稻氮素含量的准确监测是稻田精准施肥的重要环节,水稻叶片氮素含量发生变化会引起叶片、冠层的光谱发射率发生变化,高光谱遥感是目前作物氮素无损监测的关键技术之一.以2018年—2019年湖北监利两年水稻氮肥试验为基础,分别获取水稻分蘖期、拔节期、孕穗期、扬花期、灌浆期五个生育期水稻叶片和冠层两个尺度的高光谱反射率数据及对应...     

Advanced machine learning based global optimizations for Pt nanoclusters

Pt-nanoclusters have attracted attention due to their extensive use as catalysts in various sectors and their catalytic capabilities, instigating a theoretical investigation to correlate structure and property. On the other hand, it is challenging to find stable and reliable structures to support experimental results at the nanoscale due to their fluxional nature at ambient temperature. The major objective of this work is to test the capability of stable and reliable structure findings at the nanocluster region by Gaussian Process Regression (GPR) model potentials on-the-fly within the evolutionary framework using the Bayesian optimization approach. The entire algorithm is called Global Optimizations by GPR (GO-GPR) learning. In this regard, the GO-GPR algorithm examined the potential energy surfaces of bare Pt_n-nanoclusters of sizes (n = 3–6, 7, 8, 10, 13). GO-GPR identified new low-lying isomers and global minimum structures are in correlation with earlier studies. In the case of Pt₁₃ and Pt₈ nano-clusters, the global minimum structure is close to the second lowest energy structure, implying that these clusters can have fluxional nature. In fact, a few experimental studies have shown that Pt₈ and Pt₁₃ are effective in catalyzing reactions.     

Postbiotics,Metabolic Signaling,and Cancer

Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.     

探地雷达测定地基土含水量的实验研究

利用室内模型槽,采用探地雷达开展了测定地基土含水量的室内实验研究。通过对探地雷达反射波法测定的介电常数和烘干法测定的含水量之间的曲线拟合,提出了实验用粉土的含水量与介电常数之间的经验公式。与实测含水量的对比分析表明,Topp公式在一定含水量范围内有良好的适用性,而本文提出的经验公式较Topp公式具有更宽的含水量适用范围和更高的预测精度;针对不同类型土建立相应的含水量和介电常数之间的经验公式是必要的,将有助于提高探地雷达测定地基土含水量的精度。     

Proteomics analysis of altered proteins in kidney of mice with aristolochic acid nephropathy using the fluorogenic derivatization–liquid chromatography–tandem mass spectrometry method

Aristolochic acid (AA) causes interstitial renal fibrosis, called aristolochic acid nephropathy (AAN). There is no specific indicator for diagnosing AAN, so this study aimed to investigate the biomarkers for AAN using a proteomics method. The C3H/He female mice were given ad libitum AA–distilled water (0.5 mg/kg/day) and distilled water for 56 days in the AA and normal groups, respectively. The AA‐induced proteins in the kidney were investigated using a proteomics study, including fluorogenic derivatization with 7‐chloro‐N‐[2‐(dimethylamino)ethyl]‐2,1,3‐benzoxadiazole‐4‐sulfonamide, followed by high‐performance liquid chromatography analysis and liquid chromatography tandem mass spectrometry with a MASCOT database searching system. There were two altered proteins, thrombospondin type 1 (TSP1) and G protein‐coupled receptor 87 (GPR87), in the kidney of AA‐group mice on day 56. GPR87, a tumorigenesis‐related protein, is reported for the first time in the current study. The renal interstitial fibrosis was certainly induced in the AA‐group mice under histological examination. Based on the results of histological examination and the proteomics study, this model might be applied to AAN studies in the future. TSP1 might be a novel biomarker for AAN, and the further role of GPR87 leading to AA‐induced tumorigenesis should be researched in future studies.     

Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.     

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson’s Disease and Amyotrophic Lateral Sclerosis

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB₁) and type-2 (CB₂) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson’s disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.     

超前探测中探地雷达应用与结果的处理分析

在隧道施工中,由于地质条件的复杂性和勘察工作的局限性,往往造成地质勘查成果与开挖后的情况不一致,这就要求在隧道施工工程中进行超前跟踪探测,确保隧道施工的安全。本文主要介绍SIR-3000探地雷达系统在郴(州)宁(远)高速公路芒头岭隧道超前预报中的应用概况,并采用空间域滤波和希尔伯特变换等方法对探测结果进行处理,根据处理结果对隧道掌子面前方溶洞、裂隙等地质情况进行预测。隧道后期的开挖情况证明了雷达预测结果的正确性,取得了较好的预测效果,同时也说明了采用空间滤波、希尔伯特变换等处理方法对改进实测数据质量方面的有用性。