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Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.

Well-structured Energy Management Maturity Models (EMMMs) are advanced and easy-to-use energy management (EM) approaches for energy management systems (EnMSs), providing both qualitative metrics and improvement guidelines. And the metrics serve the most valuable role. To furnish the users in different contexts (regional or industrial) with optimal applicability, an EMMM should deliver the most specific, precise, and valid metrics. It requires the latest explorations of this domain to evolve from the existing prototypes and keep improving the theoretical hypotheses about EM maturation, particularly for emerging economies like China. Accordingly, this study attempts to propose a highly practice-based Energy Management Maturity Model for China (EMMM-China), intending to make twofold contributions to this domain. For the methodological perspective, this study has demonstrated a set of highly referable strategies to felicitously formulate a model’s metrics. A solid knowledge base for deducing hypotheses, encompassing both EM imperfections and good practices, was crucially constructed by taking in empirical experience from scientific literature and over 70 domestic cases. On this basis, five maturity levels and four maturation phases were justifiably defined. To validate the reliability of the model, three industrial cases were repeatedly assessed by EMMM-China in a longitudinal study design. And for the outcome perspective, EMMM-China serves as a new ISO 50001-based model for global users. The High Level Structure (HLS) of ISO 50001:2018 and numerous widely recognized success factors for EM were both adopted. With extended knowledge that goes beyond EnMS standards, EMMM-China enables long-term applicability to even certified organizations. The proposed model is believed to work on China and other emerging economies as a referable meta-approach.

Heat shock protein 90 (Hsp90) as a molecular target for oncology therapeutics has attracted much attention in the last decade. The Hsp90 multichaperone complex has important roles in the growth and/or survival of cancer cells. Cdc37, as a cochaperone, associates kinase clients to Hsp90 and promotes the development of malignant tumors. Disrupting the Hsp90-Cdc37 interaction provides an alternative strategy to inhibit the function of Hsp90 for cancer therapy. Celastrol, as a natural product, can disrupt the Hsp90-Cdc37 interaction and induce degradation of kinase clients. The study conducted here attempted to elucidate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors and to improve the druglike properties. 23 celastrol derivatives were designed, synthesized, and the biological activities and physicochemical properties were determined. The derivative CEL20 showed improved Hsp90-Cdc37 disruption activity, anti-proliferative activities as well as druglike properties. Additionally, CEL20 induced clients degradation, cell cycle arrest and apoptosis in Panc-1 cells. This study can provide reference for the discovery of novel Hsp90-Cdc37 disruptors.

In recent years, wildlife conservation has attracted great public attention. However, substantial distinctions can be found in the prevailing concepts of wildlife conservation, particularly with the recent notion that emphasizes animal rights. Wildlife welfare and wildlife rights are not synonymous, with welfare more compatible with the reasonable and legal utilization of wildlife. The key to scientific wildlife conservation is the appropriate awareness and appreciation of the relationship between wildlife conservation and utilization and the theoretical basis of holism. Nevertheless, rational biases regarding the public's understanding of wildlife conservation and the spread of information via social media still exist. As such, expansion of the concept of scientific wildlife conservation requires the application of several measures. Wildlife conservation researchers should be regarded as the most important disseminators of scientifically-based information, with education in schools and universities of growing importance. Furthermore, the media should shoulder the social responsibility for the accurate dissemination of conservation information.

In this paper, we used orthogonal experiment method and Computational Fluid Dynamics (CFD) technology to simulate the thermal environment of the iron and steel workshop. By comparing and analyzing the temperature distribution and air flow of workshops with different window structures, we obtained an optimization of natural ventilation design for industrial workshop. The research results can be used for the structure design or reformation of industrial workshops as reference.

Plasma spray zirconia gradient thermal barrier coating (TBC) and the traditional double-layer structure thermal barrier coating were both studied in this paper. NiCoCrAlY alloy powder was used as bottom bonding materials, 8YSZ (8mol% yttrium stabilized zirconia) was used as top layer materials and the different proportions mixed powder of 8YSZ and NiCoCrAlY was used as gradient layers materials. Bonding strength of thickness gradient coating was measured by tensile experiment. Thermal cycle experiment was carried on to test the thermal shock resistance of TBC. The microstructure after thermal shock experiment was observed to analyze the failure mechanism of TBC. The research result shows that the bonding strength and thermal shock resistance of gradient TBC are much better than the traditional double-layer structure TBC. With the increasing of top layer thickness, thermal shock life of TBC substantially reduces. With the decreasing of ZrO2 composition proportion in gradient layer, thermal shock life of TBC significantly rises. This result has important significance for the future study of thick TBC.

Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure–activity and structure–property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.

BACKGROUND: The effects of age, gender, and seasonal variation on human levels of 25‐hydroxyvitamin D (25(OH)D) are not well understood. In this study, we aimed to investigate 25(OH)D status according to these factors in a Korean population. METHODS: A total of 303,943 serum 25(OH)D levels were measured using an electrochemiluminescence immunoassay between October 2011 and May 2014. Potential participants were ineligible for the study if they had significant renal, hepatic, or thyroid dysfunction, as well as any major ongoing disease that could influence serum 25(OH)D levels. RESULTS: A total of 95,137 subjects (49,662 men and 45,475 women) were included in this study. The mean 25(OH)D levels were higher in men (42.4 nmol/l) than in women (32.9 nmol/l, P < 0.001). Among the men and women, 73.0% and 88.9%, respectively, had 25(OH)D levels 75 nmol/l. The highest mean 25(OH)D value was noted in individuals aged ≥70 for both genders. The proportion of those with 25(OH)D levels

Background Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described. Methods We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000–2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. Results A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p Conclusions The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain.