الملخص
Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).
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OBJECTIVE To analyze the main components of Chelidonii Herba-Corydalis Rhizoma （CHCR）， and to predict pharmacodynamic substances against estrogen receptor （ER） -positive breast cancer and their potential targets and signaling pathways， followed by verifying experiments. METHODS The ethanol extract of CHCR was analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS/MS）. The network pharmacology analysis was performed for the screened components. The network diagram of CHCR “active components-target-pathway” was constructed， and the enrichment pathway in vitro was validated. RESULTS A total of 58 chemical components were identified， including 57 alkaloids and 1 organic acid. A total of 38 active ingredients were screened from the network pharmacology， and 38 core targets were found in the protein-protein interaction network of “component-disease” intersection targets； 258 gene ontology entries and 137 Kyoto encyclopedia of genes and genomics pathways were obtained， mainly including estrogen signal pathway， phosphatidylinositol-3-kinase/protein kinase B （PI3K/Akt） signal pathway， etc. The results of validation test showed that the median inhibitory concentration of CHCR to MCF-7 cells was 693 μg/mL； 150， 300， 600 μg/mL CHCR could significantly reduce the expressions of phosphorylated PI3K， phosphorylated Akt， ERα protein and ESR1 mRNA （P＜0.01）. CONCLUSIONS The anti-ER-positive breast cancer effect of CHCR may be related to the regulation of ER and PI3K/Akt pathways， which has the characteristics of multi-component and multi-target effects.
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The theory of "liver opens at the eyes" was first seen in Yellow Emperor's Internal Canon of Medicine， which is the ancient people's summary of the connection between the liver and the eyes. The theory of "liver opens at the eyes" suggests the characteristic of "co-damage and co-recover of liver and eyes". It has been found in clinical practice that liver diseases and eye diseases often occur together， and "liver and eyes co-recover" is an ideal choice. The key to achieving "liver and eyes co-recover" is to analyze its pharmacological material basis and mechanism. With the development of modern medicine， more and more evidence indicates that the liver and eyes have complex and close relationships in physiological and pathological aspects. In a pathological state， there is a phenomenon of "liver and eyes co-damage"， and after the intervention of traditional Chinese medicine， "liver and eyes co-recover" occurs. "Liver and eyes co-damage and co-recover" can be explained through the "co-material basis and co-action mechanism". On this basis， the research group tentatively proposed that the liver and eyes had "four common characteristics" （4CCs）， namely "co-damage， co-recover， co-material basis， and co-action mechanism" from the theoretical connotation of traditional Chinese medicine， clinical practice， and molecular biology. Additionally， the group also took the intervention of Prunella vulgaris， traditional Chinese medicine， for removing liver fire and improving eyesight on immune liver injury （ILI） and allergic conjunctivitis （AC） as examples to analyze 4CCs. This project aims to deeply analyze the scientific connotation of the theory of "liver opens at the eyes"， reveal the common characteristics and biological essence of liver and eyes， explore a new research paradigm of "liver and eyes co-recover"， and provide a reference for the study of common problems of multi-organ associated diseases.
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Pulmonary arterial hypertension is a clinical syndrome characterized by pulmonary vascular remodeling causing increased vascular resistance, which will lead to right heart failure and even death if left untreated. The pathogenesis of pulmonary arterial hypertension has not yet been clarified, and clinical treatments have not been effective in improving prognosis or reducing mortality. To investigate the pathogenesis of pulmonary arterial hypertension and to develop and evaluate more effective and safer drug treatments, establishing related animal disease models is very important. This paper outlines the pathological characteristics of pulmonary arterial hypertension and summarizes the various types of animal models of pulmonary arterial hypertension, as well as describes the progress of the application of these models in three therapeutic pathways and related drug research in the past five years, with a view to providing a reference for the selection of animal models of pulmonary arterial hypertension and research applications.
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Long non-coding RNA(LncRNA)is a class of RNA that cannot encode translated proteins with more than 200 nucleotides in length.It can be involved in the regulation of X chromosome silencing,chromatin modification,transcriptional activa-tion,transcriptional interference and other regulatory processes by binding to DNA,RNA or proteins.In recent years,more and more studies have confirmed that LncRNA plays an important role in the occurrence,development,invasion and metastasis of gastric cancer. At the same time,many studies have demonstrated LncRNA as the target of traditional Chinese medicine for the development and pro-gression of anti-gastric cancer.This review introduces the mechanism of LncRNA in the development and progression of gastric canc-er,and as a target for traditional Chinese medicine treatment prospects.
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Objective To construct expression vectors of calmodulin(CaM)mutants N2 and C2,and to express,purify,and identify the mutant proteins,in order to study the interactions between CaM and calcium channels. Methods The cDNA of N?lobe and C?lobe of CaM were used to prepare the cDNA of N2 and C2. Next,the recombinant cDNAs were cloned into a pGEX?6p?3 plasmid,and the recombinant plasmids were trans?ferred into E.coli BL21 cells. The transfected BL21 cells were stimulated with IPTG. The fusion proteins were extracted by ultrasonication and puri?fied by using GS?4B beads. Finally,protein activity was identified by the pull?down assay. Results Both the restriction digestion map and the DNA sequence identification results confirmed that the recombinant plasmids were successfully constructed. SDS?PAGE results showed high purity and concentration of N2 and C2 proteins. Their activities and binding abilities with the calcium channel fragment were confirmed by the pull?down assay.Conclusion In this study,expression vectors of N2 and C2 are successfully constructed,and physiologically active N2 and C2 CaM mutant proteins are obtained.
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Objective To examine whether Tim-3 plays a protective role in paraquat poisoning induced excessive immune response and tissue damage based on the critical roles of Tim-3 controlling inflammatory response.Methods A paraquat poisoning model was established in wild type and in Tim-3 transgenic C57BL/6 mice by intraperitoneal injection of paraquat (40 mg/kg) .In addition, C57BL/6 mice with paraquat poisoning were injected with Tim-3 soluble protein( sTim-3) or control protein to see the effect of Tim-3 blocking on the progression of paraquat poisoning.Samples were collected at 6 and 24 h after paraquat injection respectively and were examined for tissue damage, cytokine expression and paraquat metabolism.Results After paraquat poisoning, there was significantly attenuated tissue damage in the lungs and kidneys and decreased TNF-α,IL-6 and IL-1 beta expression in the PBMCs or in the serum from Tim-3 transgenic mice compared to wild type mice.The serum concentration of paraquat in Tim-3 transgenic mice was also significantly decreased.However, in sTim-3 treated paraquat poisoning mice, there was significantly increased cytokine expression and tissue damage compared to control protein treated mice.The in vitro data showed that Tim-3 signaling negatively regulated macrophages mediated inflammatory response.Conclusion Tim-3 plays a critical role in maintaining the homeostasis after paraquat poisoning. Further investigation on the regulatory roles of Tim-3 in inflammation will shed new light on the pathogenesis of paraquat poisoning and provide new therapeutic strategies.
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The system applies H.264 compression coding technology and uses TCP/IP protocol to transmit data. It transfers the video information, cardio-spectrograms, blood oxygen and blood pressure spectrum to the medical area and the visiting area for families that outside of ICU intensively. The patients' information is transmitted to the medical staffs intensively, then making the relevant backups, so people can avoid many potential medical disputes.
الموضوعات
Humans , Blood Pressure , Data Compression , Heart , Intensive Care Units , Monitoring, Physiologic , Technology , Video Recordingالملخص
Objective To investigate the relationship between uric acid levels and lipid metabolism in Uyghur and Han people who underwent physical examination.Methods From February 2012 to February 2013,8 197 blood samples were collected for the tests of serum uric acid and some other relevant lipid metabolism indicators in the First Affiliated Hospital of Xinjiang Medical Uni-versity.Results The uric acid level of Han was higher than that of Uyghur people(P <0.05),the levels of uric acid has gradually increased with the growing age both in the Uygur and Han people.The uric acid and high-density lipoprotein and apolipoprotein-A showed negative correlation between Uyghur and Han(P <0.05),however,the uric acid and other factors showed positive correla-tion(P <0.05).Conclusion There is ethnic differences in the level of uric acid and the prevalence of hyperuricemia in people who underwent physical examination of Urumqi,there are correlations between uric acid levels and the lipid metabolism.
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A cardiac stimulator for rapid atrial pacing animal model was designed in this paper. According to the needs of clinical research, output pulse parameters of the cardiac stimulator can be designed. The cardiac stimulator will be controlled through magnet. Efficiency of the cardiac stimulator was validated by animal experiments.