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101.
A current development trend in research on intelligent systems is to optimize a general intelligent prediction system into an individuation intelligent prediction system that is applied in specialized fields. Protein structure prediction is a challenging international issue. In this paper, we propose a new intelligent prediction system model, designed as a multi-layer compound pyramid model, for predicting secondary protein structure. The model comprises four independent intelligent interfaces and several knowledge discovery methods. The model penetrates throughout the domain knowledge, with the effective attributes chosen by Causal Cellular Automata. Furthermore, a high pure structure database is constructed for training. On the RS126 dataset, the overall state per-residue accuracy, Q3, reached 83.99%, while on the CB513 dataset, Q3 reached 85.58%. Meanwhile, on the CASP8 sequences, the results are superior to those produced by other methods, such as Psipred, Jpred, APSSP2 and BehairPred. These results confirm that our method has a strong generalization ability, and that it provides a model for the construction of other intelligent systems. 相似文献
102.
Novel technology of purification of copper electrolyte 总被引:10,自引:1,他引:10
The effects of arsenic with different valence states on the purification of copper electrolyte were studied and a novel technology of purification of copper electrolyte by copper arsenite was proposed. The results show that the purification performance of As(Ⅲ) compounds is better than that of As(Ⅴ) compounds. The purification technology by copper arsenite has the advantages of simple operation, high purification performance and low cost in comparison with other technologies and its appropriate purification conditions are that copper arsenite concentration is 18 g/L, reaction temperature is 65 ℃ and reaction time is 8 h. The removal rates of Sb and Bi are 53.22% and 58.67% respectively under these conditions. The purification principle show that a kind of yellow precipitate mainly composed of arsenic, antimony ( Ⅴ ), bismuth and oxygen forms in electrolyte after copper arsenite is added, and consequently antimony and bismuth are removed from electrolyte. 相似文献
103.
Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure–activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1–phenyl/R2–indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl–ethyl to pyridyl–propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach. 相似文献
104.
Amir Mohammadzadeh Pter P. Lakatos Mihly Balogh Ferenc Zdor Dvid rpd Kardi Zoltn S. Zdori Kornl Kirly Anna Rita Galambos Szilvia Barsi Pl Riba Sndor Benyhe Lszl Kles Tams Tbi va Szk Laszlo G. Harsing Jr. Mahmoud Al-Khrasani 《International journal of molecular sciences》2021,22(5)
The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. 相似文献
105.
Jang Mi Han Jae Kyung Sohng Woo-Haeng Lee Tae-Jin Oh Hye Jin Jung 《International journal of molecular sciences》2021,22(5)
We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA. 相似文献
106.
Zhen Zeng Hui Yi Chew Jazmina G. Cruz Graham R. Leggatt James W. Wells 《International journal of molecular sciences》2021,22(6)
T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8+ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models. 相似文献
107.
Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory. 相似文献
108.
Improved Controlled Release and Brain Penetration of the Small Molecule S14 Using PLGA Nanoparticles
Vanesa Nozal Elisa Rojas-Prats Ins Maestro Carmen Gil Daniel I. Perez Ana Martinez 《International journal of molecular sciences》2021,22(6)
Phosphodiesterase 7 (PDE7) is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), an important cellular messenger. PDE7’s role in neurotransmission, expression profile in the brain and the druggability of other phosphodiesterases have motivated the search for potent inhibitors to treat neurodegenerative and inflammatory diseases. Different heterocyclic compounds have been described over the years; among them, phenyl-2-thioxo-(1H)-quinazolin-4-one, called S14, has shown very promising results in different in vitro and in vivo studies. Recently, polymeric nanoparticles have been used as new formulations to target specific organs and produce controlled release of certain drugs. In this work, we describe poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles loaded with S14. Their preparation, optimization, characterization and in vivo drug release profile are here presented as an effort to improve pharmacokinetic properties of this interesting PDE7 inhibitor. 相似文献
109.
在减缓金属腐蚀的研究中,为了缓解在酸性溶液、碱性溶液以及大气、土壤等介质中金属腐蚀较为严重的问题,对咪唑啉类缓蚀剂进行了工艺条件优化.采用静态失重法研究了碳钢在加入了缓蚀剂的盐酸溶液中的缓蚀性能.在最佳合成条件下苯甲酸与二乙烯三胺最佳摩尔比为1∶1.3,催化剂质量分数为1.2%,环化时间为1 h,咪唑啉中间体与氯化苄的最佳摩尔比为1∶1.1,季铵化反应时间为1 h,季铵化反应温度为70 ℃,缓蚀剂的最佳质量分数为1%,最终缓蚀率可以达到99.37%. 相似文献
110.
采用苯酚、邻苯二酚、愈创木酚和紫丁香酚为木质素单体模化物,利用两段裂解反应器-在线气相色谱仪(GCs)进行热解实验和产物分析,采用多色谱柱对无机气体(IGs)、C1~C5烃(C1~C5 LHs)、非芳基含氧化合物、酚和芳烃进行定量分析,以确定羟基和甲氧基对木质素热解过程中开环反应及产物分布的影响. 结果显示:羟基和甲氧基可以提高模化物的转化率,且羟基和甲氧基的存在影响芳基开环反应、芳基取代反应和重排反应间的竞争关系,使热解产物分布存在明显差异. 4种模化物热解产物主要是芳环的开环反应产物,包括IGs(质量分数为27.29%~33.56%)和C1~C5烃(20.46%~39.51%). 一氧化碳产率(23.82%~29.18%)随羟基数增加而升高,随甲氧基数增加而降低;二氧化碳产率(0.19%~9.61%)随甲氧基数增加而升高. 羟基和甲氧基的存在降低了C1~C5烃的质量选择性,促进了烷基苯、大分子化合物和焦炭的形成. 相似文献