ABSTRACT
SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.
ABSTRACT
OBJECTIVE@#To evaluate the relevant indicators affecting difficulty in the extraction of impacted mandibular third molars and score difficulty of different operation and risk indicators, so as to build an intuitive and accurate scale to help operators make more accurate analysis and prediction of difficulty before the operation.@*METHODS@#Based on literature and the clinical review, the difficulty indicators of tooth extraction were summarized. Firstly, 10 doctors from Peking University School and Hospital of Stomatology who had been engaged in alveolar surgery for a long time established an expert nominal group, and then rated whether the summarized indicators needed to be retained in the form of face-to-face questionnaires. A level 1 and 2 item frame for evaluating difficulty in the tooth extraction was formed after discussion; Then Delphi method was used to send a questionnaire to 30 experts by e-mail. After two rounds of scoring and modification, the scale of difficulty in the extraction of impacted mandibular third molars was formed.@*RESULTS@#The recycling rate of two rounds of questionnaires was 100.0%, which showed that the experts were very enthusiastic about the study; The authority coefficients (Cr) of the two rounds of Delphi expert consultation were both 0.92, which showed that the results were representative and authoritative. After two rounds of grading and revision, the variable coefficient (CV) decreased and the Kendall's concordance coefficient (W) increased, which were statistically significant: In the first round, the CV was 0.24 and W was 0.56 (P < 0.001), and in the second, the CV was 0.19 and W was 0.72 (P < 0.001), which indicated that there was a good convergence among the expert opinions. Finally, a scale of difficulty in the tooth extraction containing 12 items at level A and 37 items at level B was formed, including operation difficulty indicators, risk difficulty indicators and common difficulty indicators.@*CONCLUSION@#Based on comprehensive literature retrieval, the study has put forward the concept that difficulty in the extraction of impacted mandibular third molars is composed of operation difficulty and risk difficulty. Using Delphi method, the long-term clinical experience and professional knowledge of experts are transformed into quantitative indicators as a scoring scale. The scale has certain representativeness and authority.
Subject(s)
Humans , Delphi Technique , Mandible/surgery , Molar, Third/surgery , Tooth Extraction , Tooth, Impacted/surgeryABSTRACT
The recent discovery of activator compounds binding to an allosteric site on the NAD
ABSTRACT
RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an 'undruggable' feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.
ABSTRACT
OBJECTIVE@#This study aimed to compare the cartilage regeneration of the stromal vascular fraction (SVF) cells and adipose-derived mesenchymal stem cells (ASCs) cocultured with chondrocytes seeded on the scaffolds.@*METHODS@#The cellular morphologies and proliferation capabilities on the scaffolds were evaluated. The scaffolds with the cocul-ture of ASCs/SVF and chondrocytes were implanted into the full thickness cartilage defective rabbit joints for 10 weeks.@*RESULTS@#The cells seeded into the scaffolds showed good adhesion and proliferation. Implantation with SVF and chondrocytes revealed desirable in vitro healing outcomes.@*CONCLUSIONS@#The SVF cells were better than ASCs in terms of the formation of cartilage matrix in a coimplantation model. Without in vitro expansion, the SVF cells are good cell sources for cartilage repair.
Subject(s)
Animals , Rabbits , Adipose Tissue , Cartilage , Chondrocytes , Coculture Techniques , RegenerationABSTRACT
Shanghai Jiao Tong University established the first biomedical science in China in 2016. Learning the successful experience from international universities can promote the development of this major. According to the comparison of cultivation program and curriculum system in different top universities at home and abroad, it was showed that Oxford University focused on the pluralism development of students, University of Technology Sydney paid attention to the combination of basis and clinical practice, and the University of Hong Kong stressed the integration of clinical practice, science and research, and transformation. Through the exploration of the details of educational system this university, we found that we mainly focused on five innovation ideas: building the basic knowledge, strengthening comprehensive basic knowledge teaching, stimulating students' interests towards biomedical science, developing their ability and promoting innovative education and training. Based on analysis of those cases, it is showed that the development of biomedical science in China should solve problems in curriculum integration and practical education of science and research, so as to achieve the goal to cultivate more talents in this major and boost the development and advances in the field of biomedical science.
ABSTRACT
Shanghai Jiao Tong University established the first biomedical science in China in 2016. Learning the successful experience from international universities can promote the development of this major. According to the comparison of cultivation program and curriculum system in different top universities at home and abroad, it was showed that Oxford University focused on the pluralism development of students, University of Technology Sydney paid attention to the combination of basis and clinical practice, and the University of Hong Kong stressed the integration of clinical practice, science and research, and transformation. Through the exploration of the details of educational system this university, we found that we mainly focused on five innovation ideas: building the basic knowledge , strengthening comprehensive basic knowledge teaching, stimulating students' interests towards biomedical science, developing their ability and promoting innovative education and training . Based on analysis of those cases , it is showed that the development of biomedical science in China should solve problems in curriculum integration and practical education of science and research , so as to achieve the goal to cultivate more talents in this major and boost the development and advances in the field of biomedical science.
ABSTRACT
The research on distribution and quality suitability division of Desmodium styracifolium were formulated by Maxent and ArcGIS model based on the content of schaftoside and polysaccharide of D. styracifolium and its field research in the south and southwest areas of China (Guangdong, Guangxi, Hainan and Yunnan), and the most suitable habitats of distribution suitability and quality suitability were screened. The distribution suitability results indicated that average air temperature in April,mean temperature of coldest quarter, soil type, coldness index were found as the four dominant factors contributing to the plant distribution. The quality suitability results indicated that: ①Polysaccharide content and precipitation in April show significant positive correlation;Schaftoside content and mean temperature of April, mean temperature of coldest quarter show significant negative correlation. Schaftoside content shows significant negative correlation with the precipitation in October and November and the sunshine duration in April and May, while there is a significant positive correlation between schaftoside content and precipitation in April and temperature seasonality standard deviation, and a highly significant positive correlation was found between schaftoside content and precipitation in February and March. ②The quality zoning map was drawn depend on general content of polysaccharide and schaftoside as the index of quality. And this research provides scientific location basis for the production regionalization, cultivation bases selection and directive breeding of D. styracifolium.