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The high profit of regional investment is often accompanied by high risks, and the prior assessment of investment risks is conducive to avoid investment risks. However, the traditional evaluation methods usually only focus on individual risk factors, and it is difficult to evaluate and manage risks on the whole. Therefore, the study introduces deep learning algorithm, first build regional investment risk evaluation index system, then according to the characteristics of risk evaluation, design based on deep learning regional investment risk evaluation model, the final use parameter based migration learning algorithm and composite correlation coefficient to improve the evaluation model, solve the problem of insufficient training samples. The test results showed that the randomly selected 50 test samples with two different risk assessment models were 0.80 and 0.86, the deep learning algorithm tested 0.84, and the transfer learning improved model tested was 0.92, with the highest accuracy. This shows that the deep learning regional investment risk evaluation model improved by transfer learning effectively solves the problem of insufficient training data and improves the accuracy of prediction evaluation. In the field of venture capital, the model can help investors to evaluate and predict investment risks more accurately and improve the effect of investment decisions. [ABSTRACT FROM AUTHOR]

Sports injuries have been a common concern during athlete training as the number of Chinese athletes and their training intensity have increased. These injuries frequently impact critical locations, including the waist, shoulder, and wrist, impeding training progress and intensity. Inadequate training levels, a lack of understanding of preventive measures, inappropriate movements, insufficient warm-up exercises, low physical condition, and an inability to adjust to the environment all contribute to sports injuries. As a result, athlete training and recovery suffer. To address these issues, this study presents a neural network-based sports injury risk analysis system that uses blockchain and the Internet of Things (IoT). The suggested system combines a multi-sensor data fusion technique based on blockchain and IoT to evaluate and analyze sports injuries completely. The system has three unique roles: coach, team doctor, and athlete, each with its functional modules. Sensors collect data on athletes' recovery from sports injuries by collecting and analyzing inputs inside the human action system. The system then establishes the output values of a neural network and a risk level table, allowing for the estimation of athletes' risk levels based on the given table. Comparing the traditional technique and the sports injury rehabilitation monitoring system demonstrates that the technology can reliably detect players' injury locations in as little as 0.2 s. Furthermore, a thorough examination of the system's tracking and analysis accuracy reveals a recovery rate of approximately 94.39%, demonstrating minimal fluctuations and improved stability. The experimental findings reveal that combining blockchain, IoT, and neural network technologies makes the proposed sports injury rehabilitation monitoring system useful in quickly recognizing damage positions and enabling accurate tracking and analysis. [ABSTRACT FROM AUTHOR]

The aim was to develop a model to predict the adult height (AH) of idiopathic central precocious puberty (ICPP) girls who underwent gonadotropin-releasing hormone analog (GnRHa) treatment. Data analysis included 258 girls with ICPP. Among them, 101 girls who reached final AH (FAH) with GnRHa treatment were analyzed to verify three previous prediction models and develop a unique model based on multiple linear regression. The control group consisted of 41 untreated ICPP girls. Moreover, 116 girls treated with GnRHa who almost attained FAH were included for external validation. Based on our cohorts, all of the three previously published models underestimated the FAH with an R of 0.667, 0.793, and 0.664. The AH prediction model was built as follows: Calculated AH (cm) = 1.89630 * Height SDS + 2.29927 * Height SDS for bone age + 0.40776 * Target height + 100.16684 (R2 = 0.66 and adjusted R2 = 0.65). Internal validation showed a mean root mean squared error (RMSE) of 2.16 cm and a mean absolute error (MAE) of 1.64 cm. External validation showed that a significant error (> 1 SD) appeared only in 7 of 116 girls (6.0%). The model is displayed on the website: http://cpppredict.shinyapps.io/dynnomapp. Conclusion: A model for predicting the AH of girls with ICPP was developed incorporating the variables of height SDS, height SDS for bone age, and target height. The internal and external validation ensures an appropriate degree of discrimination and calibration of the prediction model. What is Known: • Uncertainty prevails as how to predict the adult height of patients with central precocious puberty following gonadotropin-releasing hormone analog treatment. • Previous models for predicting adult height of girls with idiopathic central precocious puberty have not been proven translational to the Chinese population. What is New: • This study develops a new model for predicting the adult height of idiopathic central precocious puberty girls who underwent gonadotropin-releasing hormone analog treatment. • The internal and external validation assures a good degree of discrimination and calibration of the prediction model in this study. [ABSTRACT FROM AUTHOR]

With the rapid development of science and technology in recent years, more and more researchers began to explore the basic disciplines of sports, namely, biomechanics and physiology, and further update and improve the traditional sports training theory. However, the developed countries, i.e., Europe and the United States, have dedicatedly worked on the effective role of physical training particularly in middle-class farmers in sports powers. They have realized that the continuous improvement of the physical training evaluation system is directly related to the reforming in the evaluation and monitoring methods of physical training. At the same time, there is a demand for athletes' physical fitness evaluation, which requires a large amount of data support during the evaluation. These data collection and analysis are difficult and consume a lot of manpower. Therefore, this paper uses artificial intelligence technology to design the sports athletes' physical fitness evaluation information management system to improve the comprehensiveness of system data collection and the accuracy of data analysis. Through the physical attenuation calculation and physical analysis of the system developed in this paper, data accuracy is high. The coach can make a training plan according to the physical consumption of athletes in sports training or competition, which can greatly improve the ability of athletes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide but lacks any acceptable therapy. The transcription factor glioma‐associated oncogene homologue 1 (GLI1) is a potentially important therapeutic target in liver fibrosis. This study investigates the anti‐fibrotic activities and potential mechanisms of the phytochemical, physalin B. Experimental Approach Two mouse models (CCl4 challenge and bile duct ligation) were used to assess antifibrotic effects of physalin B in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as in vitro liver fibrosis models. Liver fibrogenic genes, GLI1 and GLI1 downstream genes were examined using Western blot and quantitative real‐time PCR (qRT‐PCR). GLI1 acetylation and LAP2α–HDAC1 interaction were analysed by co‐immunoprecipitation. Key Results: In vivo, physalin B administration attenuated hepatic histopathological injury and collagen accumulation and decreased expression of fibrogenic genes. Physalin B dose‐dependently suppressed fibrotic marker expression in LX‐2 cells and mouse pHSCs. Mechanistic studies showed that physalin B inhibited GLI activity by non‐canonical Hedgehog signalling. Physalin B blocked formation of lamina‐associated polypeptide 2α (LAP2α)/histone deacetylase 1 (HDAC1) complexes, thus inhibiting HDAC1‐mediated GLI1 deacetylation. Physalin B up‐regulated acetylation of GLI1, down‐regulated expression of GLI1 and subsequently inhibited HSC activation. Conclusion and Implications: Physalin B exerted potent antifibrotic effects in vitro and in vivo by disrupting LAP2α/HDAC1 complexes, increasing GLI1 acetylation and inactivating GLI1. This indicates that the phytochemical physalin B may be a potential therapeutic candidate for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Cholestatic liver diseases comprise a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury. Regulation of bile acid (BA) synthesis and homeostasis is a promising strategy for the treatment of cholestatic liver disease. Limb expression 1-like protein (LIX1L) plays an important role in post-transcriptional gene regulation, yet its role in cholestatic liver injury remains unclear. LIX1L expression was studied in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), and 3 murine models of cholestasis (bile duct ligation [BDL], Mdr2 knockout [ Mdr2 -/- ], and cholic acid [CA] feeding). Lix1l knockout mice were employed to investigate the function of LIX1L in cholestatic liver diseases. Chromatin immunoprecipitation assays were performed to determine whether Egr-1 bound to the Lix1l promoter. MiRNA expression profiling was analyzed by microarray. An adeno-associated virus (AAV)-mediated hepatic delivery system was used to identify the function of miR-191-3p in vivo. LIX1L expression was increased in the livers of patients with PSC and PBC, and in the 3 murine models, as well as in BA-stimulated primary mouse hepatocytes. BA-induced Lix1l upregulation was dependent on Egr-1, which served as a transcriptional activator. LIX1L deficiency attenuated cholestatic liver injury in BDL and Mdr2 -/- mice. MiR-191-3p was the most reduced miRNA in livers of WT-BDL mice, while it was restored in Lix1l -/- -BDL mice. MiR-191-3p targets and downregulates Lrh-1 , thereby inhibiting Cyp7a1 and Cyp8b1 expression. AAV-mediated hepatic delivery of miR-191-3p significantly attenuated cholestatic liver injury in Mdr2 -/- mice. LIX1L deficiency alleviates cholestatic liver injury by inhibiting BA synthesis. LIX1L functions as a nexus linking BA/Egr-1 and miR-191-3p/LRH-1 signaling. LIX1L and miR-191-3p may be promising targets for the treatment of BA-associated hepatobiliary diseases. Bile acid homeostasis can be impaired in cholestatic liver diseases. Our study identified a novel mechanism of positive feedback regulation in cholestasis. LIX1L and miR-191-3p represent potential therapeutic targets for cholestatic liver diseases. [Display omitted] • LIX1L was upregulated in cholestatic liver specimens from both patients and mouse models. • Bile acids triggered upregulation of Egr-1, which induced LIX1L expression. • LIX1L deficiency alleviated cholestatic liver injury by inhibiting bile acid synthesis. • Overexpression of miR-191-3p using AAV protected against cholestatic liver injury in mouse models. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Tribbles homolog 2 (TRIB2) is an oncogene implicated in a variety of cancers, including liver cancer. However, the biological function and regulatory mechanism of TRIB2 in HSCs are poorly understood. In addition, little is known about its role in liver fibrosis progression to HCC. Here, we revealed the clinical significance of TRIB2 in liver fibrosis and HCC development. Methods: We investigated TRIB2 promoting liver fibrosis in vitro and in vivo. In mouse model of liver fibrosis and HCC, we measured hepatic fibrosis and HCC level through knockdown TRIB2 with shRNA. In addition, we performed western blotting, real‐time quantitative PCR, immunofluorescence and co‐immunoprecipitation assay to study TRIB2 function in LX‐2 cells. Results: TRIB2 expression was strongly upregulated in human fibrotic liver tissues and HCC tissues. TRIB2 colocalized with α‐smooth muscle actin (α‐SMA) in fibrotic and HCC liver tissues. Knockdown of TRIB2 inhibited HSC activation and liver fibrosis in vitro and in vivo. TRIB2 promoted Yes‐associated protein (YAP) stabilization, nuclear localization, and subsequent fibrotic gene expression independent of the MST‐LATS phosphorylation cascade in HSCs. TRIB2 interacted with YAP to recruit phosphatase 1A (PP1A), promoting PP1A‐mediated YAP dephosphorylation. TRIB2 knockdown potently attenuated the development of fibrosis‐associated liver cancer. Conclusions: TRIB2 is an attractive target for hepatic fibrosis and fibrosis‐associated liver cancer treatment. [ABSTRACT FROM AUTHOR]

Microencapsulated phase change materials (MEPCMs) have been widely used in many fields as thermal energy storage materials. This study reported a novel MEPCM with the functions of thermal energy storage, photothermal conversion, ultraviolet (UV) shielding, and superhydrophobicity, which was particularly suitable for intelligent textiles. The microcapsules based on an n-eicosane core and a CuO-doped polyurea shell with hierarchical structure were fabricated through a one-step interfacial polymerization. The morphology of the capsules and the hierarchical shell structure were identified through scanning and transmission electron microscopy. Thermal analysis indicated that the microcapsules had a high latent heat of 162.3 J/g and demonstrated a high thermal reliability. These microcapsules achieved a good photothermal conversion capability and can reduce UV radiation by approximately 30%. The water contact angle of the MEPCM was over 148° and showed a good superhydrophobic property. Cotton fabric coated with the prepared MEPCM was investigated. Results showed that it achieved a high phase change enthalpy of 36.8 J/g, an effective thermoregulation capability, and a large contact angle of 141.6°. [ABSTRACT FROM AUTHOR]

Abstract Background Studies have suggested that high-density lipoprotein (HDL) stimulates scavenger receptor class B type 1 (SR-B1) to promote hepatic uptake of cholesterol. SR-B1 is encoded by scavenger receptor class B member 1 (SCARB1) gene in human. A rare mutation in SCARB1 gene has been associated with coronary heart disease (CHD). A polymorphism rs5888 of SCARB1 gene has been linked to CHD risk in humans. Objectives The objective was to investigate the relationship between the SCARB1 gene polymorphism rs5888 and risk of CHD. Methods We searched databases of case-control studies and cohort studies on rs5888 polymorphism of SCARB1 gene and risk of CHD. Two reviewers independently screened literature, extracted data, and estimated potential bias of included studies. The quality of the studies was evaluated by recommendation of Newcastle-Ottawa Scale (NOS). Meta-analysis was performed with Stata 12.0 software. Results Seven studies including 6360 subjects (cases: 2456, controls: 3904) were included in the final data combination. Meta-analysis showed T allele had a lower risk of CHD as compared to C allele in allele model (T vs. C: OR = 0.87, 95% CI: 0.70 to 1.09, P = 0.229). Moreover, we found that T allele or TT/TC had a lower risk of CHD as compared to C/CC in male in allele model (T vs. C: OR = 0.79, 95% CI: 0.61 to 1.01). However, no significant association was observed in women in all allele models. Conclusions Our findings suggested that polymorphism rs5888 had negative association with CHD, especially in male. However, the conclusion needs further verification with high quality studies with larger sample size and rigorous designs. Highlights • A polymorphism rs5888 of SCARB1 gene has been linked to CHD risk in humans. • Exploring the relationship between rs5888 and coronary heart disease • Rs5888 have negative association with coronary heart disease, especially in male. [ABSTRACT FROM AUTHOR]

Background & aim Distinct metastasis accounts for the leading cause of mortality among patients with gastric cancer. The formation of pre-metastatic niche in the target organs provides permissive environments for the adhesion and subsequent growth of metastasized cancer cells. Targeting the pre-metastatic niche is a potential approach to prevent metastasis. Traditional Chinese medicine regimen called Jianpi Bushen therapy (JPBS) has been widely used in clinics to strengthen patients’ abilities to fight cancer. The present work is aimed to study the modulating effect of JPBS on the lungs expressions of Rac1, Cdc42, SDF-1, and FN in a murine gastric cancer model showing spontaneous lung metastasis. Methods Mice of strain 615 were inoculated with tumor cells derived from mouse forestomach carcinoma (MFC) to induce spontaneous lung metastasis, and were then treated with JPBS, JPBS combined with fluorouracil (5-FU), or 5-FU. Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN in lungs were determined using real-time PCR and immunohistochemistry, respectively. Serum levels of SDF-1 and FN were also measured using ELISA. Results Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN were significantly elevated in the lungs of model mice comparing to the counterpart mice received no tumor cell inoculation. JPBS treatment reduced protein expressions of Rac1, Cdc42, SDF-1 and FN in the lungs of model mice. The treatment could also suppress SDF-1 and FN in blood. For serum SDF-1 the level was further lower in model mice treated with combination therapy of JPBS and 5-FU. Conclusion The present work identified the potential roles of Rac1, Cdc42, SDF-1 and FN in the early onset of pre-metastatic niche of gastric cancer, and provided insights into the molecular mechanism by which Jianpi Bushen therapy prevent and suppress cancer metastasis. [ABSTRACT FROM AUTHOR]

The frequent presence of microcystin (MC) in eutrophic water bodies worldwide poses a serious threat to ecosystems. Biodegradation has been extensively investigated as a main pathway for MC attenuation, and an mlr -dependent mechanism of MC degradation have been elucidated in detail. However, the evolutionary origin and the distribution of mlr genes in MC-degrading bacteria is poorly understood. In this study, a novel Rhizobium sp. TH, which is the first α-proteobacterial MC-degrading bacterium other than Sphingomonadales, was isolated. Strain TH degraded MC via the mlr -dependent mechanism with a first-order rate constant of 0.18–0.29 h −1 under near-natural conditions. The partial length mlr gene cluster was sequenced, and the function of its key gene, mlrA , was verified by heterologous expression in Escherichia coli . Phylogenetic analyses show that the mlrA gene initially arose in α-proteobacteria by vertical evolution, and the two strains from β- and γ-proteobacteria acquired it by horizontal gene transfer. Therefore, the mlrA gene mainly exists in α-proteobacteria but is seldom present in other bacteria. A pair of primers matching well with mlrA sequences reported so far were designed and could be used to determine the MC-degrading mechanism for novel isolates or to screen for MC-degrading ability among environmental samples. [ABSTRACT FROM AUTHOR]

Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro‐inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single‐nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell‐cycle, and senescence‐associated pathways in naturally aged mice. Long‐term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence‐associated diseases. [ABSTRACT FROM AUTHOR]

• A new detrended combined climatologic deviation index was designed. • The new drought index successfully monitors the drought over China and captures drought recovery more quickly. • The droughts identified the new index were proved to be reliable by comparing with other drought indices and auxiliary data. Drought, as an extreme natural disaster event, can cause or exacerbate water, food, and national security hazards. However, because of differences in the regional characteristics and applicability of drought indices, a more comprehensive drought index is necessary for drought assessment over large areas. Here, we propose a new detrended combined climatologic deviation index (Detrended-CCDI), and monitor drought over China from 2002 to 2017 on the basis of pixels on pixels by Detrended-CCDI. Results show that Detrended-CCDI has recorded monthly drought distribution results for China from April 2002 to June 2017, which are similar to those recorded by the Gravity Recovery and Climate Experiment - Drought Severity Index (GRACE-DSI), the Palmer Drought Severity Index (PDSI), the Standardized Precipitation-Evapotranspiration Index (SPEI), and the China Flood and Drought Disaster Bulletin. Detrended-CCDI has a good drought monitoring capability and captures drought recovery more quickly. Three main drought characteristics identified by Detrended-CCDI is similar to those demonstrated by other indices. The drought trend obtained by Detrended-CCDI is similar to that obtained by GRACE-DSI, but is more accurate and can detect more trends associated with becoming wetter or drier than PDSI and SPEI. The drought frequency obtained using Detrended-CCDI was lower than those identified by other indices, due to Detrended-CCDI combines all water layer and precipitation data. The regional drought events obtained by Detrended-CCDI and GRACE-DSI were almost identical (kappa average > 0.8), higher than those obtained by other indices. Our findings provide scientific guidance for drought monitoring and assessment over China. [ABSTRACT FROM AUTHOR]

In view of the wide application of aluminum paste in the manufacture of electronic devices, it is important to thorough understanding and accurate control of the factors affecting electrical conductivity of aluminum electrodes and the related mechanisms. In this paper, we investigate the microstructural evolution of aluminum paste during sintering and analyze the effects of process parameters such as glass type and temperature on electrical conductivity of aluminum electrodes. The results demonstrate that differences in sintering temperature, glass type and content cause significant changes in the structural compactness and electrical conductivity of aluminum electrodes. At a certain temperature, part of the aluminum oxide film will break or peel off due to the difference in thermal expansion between aluminum particles and oxide film. At the same time, the melt glass has a certain fusion effect on the aluminum oxide film on the surface of the aluminum powder. The combined effect of these two factors can cause damage, thinning, peeling or removal of the oxide film on the surface of the aluminum powder, so that more conductive contact points (surfaces) are formed at the interface between the aluminum powder particles, and as a consequence, a coherent conductive network microstructure is formed at the aluminum electrode. With the increase of glass content in aluminum paste, the square resistance of aluminum electrode first decreases and then increases. Results of the study will provide reference for further study and application of electronic aluminum paste. [ABSTRACT FROM AUTHOR]

• Novel heat-storage coatings are prepared with microencapsulated phase change material. • The coatings can maintain good thermal stability after 200 heating-cooling cycles. • The obtained coatings hold excellent scrub resistance, and water resistance. • The prepared coatings can regulate indoor temperature effectively. Novel heat-storage composite coatings containing microencapsulated phase change material (MPCM) are prepared to enhance the thermal energy storage of the inner walls of an indoor environment. MPCMs with n-octadecane as core and polyurea as shell are synthesized via interface polymerization. They, along with the coatings, are characterized using Fourier transform infrared spectra (FTIR), SEM, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The SEM results show that MPCM can maintain its original morphology and be dispersed uniformly in the coatings with 30 wt% MPCM loads. Moreover, the latent heat capacity of MPCM and the heat-storage coatings are 151.89 J/g and 45.5 J/g, respectively. Other properties, such as thermal stability, temperature time lag, and film-forming are also tested, and the test results indicate excellent performances. After 200 heating-cooling cycles, MPCM and the heat-storage coatings still exhibit good thermal stability. Two reduced-scale test chambers enveloped by wall boards painted with and without MPCM coatings are tested under the same conditions and compared. Overall, the chamber with MPCM coatings can keep a stable temperature of 26-28 °C for approximately 77 min when the heating load is 80 W/m2. However, the chamber without PCM coating can only maintain such temperature for 13 min. Thus, the heat-storage coatings can improve the thermal comfort of indoor environments and have a high potential application in building thermal energy storage, especially for old buildings retrofit. [ABSTRACT FROM AUTHOR]

Abstract: Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of radiation-induced lung injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from radiation-induced oxidative injury. This study was designed to confirm the protective effect of Paeoniflorin against radiation-induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against radiation-induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against radiation-induced injury through the Nrf2/HO-1 pathway. [Copyright &y& Elsevier]

Chemical-based common feature pharmacophore modelling of Niemann Pick C1 Like 1 inhibitors was performed to provide some insights on the important pharmacophore features essential for Niemann Pick C1 Like 1 inhibition using Discovery Studio V2.5. After in-house database screening, a new series of substituted oxazolidinones, selected from the top ranked hits, have been synthesized and evaluated as novel cholesterol absorption inhibitors. All compounds demonstrated effect of different degrees in lowering the total cholesterol in serum, especially compounds 1a, 2a and 2d, the potency of which was comparable to that of ezetimibe. It was also found that 1a, 1d and 2d could raise high-density lipoprotein cholesterol levels markedly. Interestingly, compounds 2a-2f appeared to have the moderate potential to lower triglyceride levels, which were superior to that of normal cholesterol absorption inhibitors including ezetimibe. [ABSTRACT FROM AUTHOR]

Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1 was evaluated. The pharmacophore features of Hypo1 were different from the best pharmacophore model (Hypo1) of SGLT1 inhibitors we developed. Moreover, Hypo1 could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1 was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies. [ABSTRACT FROM AUTHOR]

Abstract: IL-15, a promising cytokine for treating cancer and viral diseases, is presented in trans by the IL-15 receptor (IL-15R) alpha-chain to the IL-15Rβγc complex displayed on the surface of T cells and natural killer (NK) cells. We previously reported that an asparagine to aspartic acid substitution at amino acid 72 (N72D) of IL-15 provides a 4–5-fold increase in biological activity compared to the native molecule. In this report, we describe Chinese hamster ovary (CHO) cell expression of a soluble complex (IL-15 N72D:IL-15RαSu/Fc) consisting of the IL-15 N72D superagonist and a dimeric IL-15Rα sushi domain-IgG1 Fc fusion protein. A simple but readily scalable affinity and ion exchange chromatography method was developed to highly purify the complex having both IL-15 binding sites fully occupied. The immunostimulatory effects of this complex were confirmed using cell proliferation assays. Treatment of mice with a single intravenous dose of IL-15N72D:IL-15RαSu/Fc resulted in a significant increase in CD8+ T cells and NK cells that was not observed following IL-15 treatment. Pharmacokinetic analysis indicated that the complex has a 25-h half-life in mice which is considerably longer than <40-min half-life of IL-15. Thus, the enhanced activity of the IL-15N72D:IL-15RαSu/Fc complex is likely the result of the increased binding activity of IL-15N72D to IL-15Rβγc, optimized cytokine trans-presentation by the IL-15RαSu domain, the dimeric nature of the cytokine domain and its increased in vivo half-life compared to IL-15. These findings indicate that this IL-15 superagonist complex could serve as a superior immunostimulatory therapeutic agent. [Copyright &y& Elsevier]

Abstract: G protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. Pharmacophore models were developed by using Discovery Studio V2.1 with a training set of 24 GPR119 agonists. The best hypothesis consisting of five features, namely, two hydrogen bond acceptors and three hydrophobic features, has a correlation coefficient of 0.969, cost difference of 62.68, RMS of 0.653, and configuration cost of 15.24, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of the 25 known GPR119 agonists in our test set with a correlation coefficient of 0.933. [Copyright &y& Elsevier]

A composite coating, containing 1.35 wt.%RE, 5.46 wt.%W, 3.82 wt.%B, 15 wt.%SiC and Ni was electrodeposited on the matrix by use of appropriate bath composition and process parameters. The addition of RE(CeO2) enhanced the hardness and wear resistance of the coating remarkably. The hardness and wear resistance of the coating increase with a rise in heat treatment temperature, and the hardness reaches the optimum value at 400 °C, while the coating has the best wear resistance at 500 °C. The wearing tests show that the wear resistance of the coating is four to five times as high as that of hard chromium, and the corrosion tests indicate that the corrosion resistance of the coating is superior to that of 1Cr18Ni9Ti stainless steel in various corrosive media, except for nitric acid. X-ray diffraction shows that the 1.35 wt.%RE–5.46 wt.%W–3.82 wt.%B–15 wt.%SiC–Ni as-deposited composite coating is mainly amorphous, except a few Ni, W, CeO2, B and SiC phases. [Copyright &y& Elsevier]

Sialomucin complex (SMC, rat Muc4) is a membrane mucin implicated in the protection of epithelia and the metastasis of some tumors. It is a heterodimeric complex, containing a mucin subunit with anti-adhesive activity and a transmembrane subunit with epidermal growth factor-like domains, one of which acts as an intramembrane ligand for ErbB2. Serum, insulin and insulin-like growth factor, but not epidermal growth factor, induce the expression of sialomucin complex in mammary epithelial cells. Induction correlates with sustained, but not transient, activation of extracellular-regulated protein kinase (ERK). MEK inhibitor U0126 blocked the induction, while activated MEK-1 transfected into a rat mammary adenocarcinoma cell line induced a sustained activation of ERK and up-regulated SMC/Muc4 expression. Northern and Western blotting indicated that up-regulation occurred concomitantly at the transcript and protein levels, both of which could be blocked by U0126. These results suggest that expression of SMC/Muc4 in mammary epithelial cells is regulated by selected growth factors through an ERK-dependent pathway at the transcript level. Oncogene (2000) 19, 4354–4361 [ABSTRACT FROM AUTHOR]

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT. [ABSTRACT FROM AUTHOR]

The stability and dispersion of Copper (Cu) powders in an aqueous medium impacts their performances. Thus the Cu powder suspensions were prepared by adding different stabilizers—sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), polyvinyl pyrrolidone (PVP), and hexadecyl trimethyl ammonium bromide (CTAB); the best surfactant was selected and its stability and dispersion were studied. The study systematically examined the effect of the stability of suspensions via sedimentation analysis, including solid–liquid ratio, the concentration of stabilizer, and dispersion time. The particle size, the stability of suspensions, phase composition, and microstructure of Cu powders were characterized by laser particle size analyzer, zeta potential, X-ray diffraction (XRD), transmission electron microscope (TEM), and scanning electron microscope (SEM). The results indicate that the stability of the suspension is improved with the addition of PVP due to the steric hindrance of PVP, and the growth and agglomeration of particles are retarded by the formation of a thick hydration layer with the optimizing concentrations, dispersion time, and solid–liquid ratio 10 g/L, 30 min, and 1:25, respectively. [ABSTRACT FROM AUTHOR]

The dynamic magnetic domain structure in magnetization and demagnetization process of hot-deformed and NdCu-diffused Nd2Fe14B magnets were in-situ observed by Lorentz transmission electron microscopy (LTEM). The demagnetization process of hot-deformed sample is dominated by domain-wall pinning, while that of NdCu-diffused sample is mainly the magnetization reversal of single grains or grain aggregations. This firstly observed result gives an explicit evidence to understand the coercivity mechanism of magnetically segregated magnet. The effect of magnetic field of TEM on decrease in domain wall energy was theoretically analyzed, which helps to understand the in-situ observation process of magnetic materials. [ABSTRACT FROM AUTHOR]

With the increasing worldwide application of the Prechtl general movements assessment (GMA) beyond its original field of the early prediction of cerebral palsy (CP), substantial knowledge has been gained on early neuromotor repertoires across a broad spectrum of diagnostic groups. Here, we aimed to profile the neuromotor functions of infants with Prader-Willi syndrome (PWS) and to compare them with two other matched groups. One group included infants with CP; the other included patients who were treated at the same clinic and turned out to have inconspicuous developmental outcomes (IOs). The detailed GMA, i.e., the motor optimality score-revised (MOS-R), was used to prospectively assess the infants' (N = 54) movements. We underwent cross-condition comparisons to characterise both within-group similarities and variations and between-group distinctions and overlaps in infants' neuromotor functions. Although infants in both the PWS and the CP groups scored similarly low on MOS-R, their motor patterns were different. Frog-leg and mantis-hand postures were frequently seen in the PWS group. However, a PWS-specific general movements pattern was not observed. We highlight that pursuing in-depth knowledge within and beyond the motor domain in different groups has the potential to better understand different conditions, improve accurate diagnosis and individualised therapy, and contribute to deep phenotyping for precision medicine. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have reported different opinions regarding the association between abdominal obesity and diabetic retinopathy (DR) in patients with diabetes mellitus (DM). In this study, we aimed to investigate this problem through a systematic review and meta-analysis to provide a basis for clinical interventions. Methods: A comprehensive search was conducted in the PubMed, Embase, and Web of Science databases up to May 1, 2022, for all eligible observational studies. Standardized mean differences (SMD) and 95% confidence intervals (CI) were evaluated using a random-effects model in the Stata software. We then conducted, publication bias assessment, heterogeneity, subgroup and sensitivity analyses. Results: A total of 5596 DR patients and 17907 non-DR patients were included from 24 studies. The results of the meta-analysis of abdominal obesity parameters showed statistically significant differences between DR and non-DR patients in both type 1 and type 2 diabetes. Waist circumference (WC) was higher in patients with DR than in the non-DR patients. In the waist-hip ratio (WHR) subgroup, the level of WHR was higher in patients with DR than that in non-DR patients. The association between abdominal obesity and mild to moderate nonproliferative DR or vision-threatening DR groups did not show any statistical difference. Subgroup analysis according to ethnicity showed that Caucasians had higher levels of combined abdominal obesity parameters than Asians. Conclusion: We found that abdominal obesity measured by WC and WHR is associated with DR in patients with type 1 and type 2 diabetes. This association is stronger in Caucasians than in Asians, where isolated abdominal obesity might be more related to DR. However, no correlation was found between abdominal obesity and varying degrees of diabetic retinopathy. Further prospective cohort studies with larger sample sizes are yet to be conducted to clarify our findings. [ABSTRACT FROM AUTHOR]

As a NPY-2 receptor agonist, PYY24-36-Leu31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin ( HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36-Leu31 to create long-acting and highly biologically active PYY24-36-Leu31 conjugates, and successfully find a novel, long-acting PYY24-36-Leu31 conjugate 8 that, when dosed every other day in diet induce obese ( DIO) mice for 2 weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis. [ABSTRACT FROM AUTHOR]

Recurrent hyperthyroidism is a special type of hyperthyroidism that is difficult to treat clinically. It is characterized by repeated recurrence after the cure of hyperthyroidism, causing serious physiological and psychological problems to patients. The theory of traditional Chinese medicine assumes that recurrent hyperthyroidism is closely related to emotional disorder. Sovereign fire and ministerial fire participate in the regulation of emotional activities. On the contrary, emotional disorder can lead to the imbalance between sovereign fire and ministerial fire. Zhu Danxi proposed that "disorderly heart is ministerial fire". The heart is easily disturbed by external factors, and anxiety leads to hyperactivity, resulting in reckless action of the ministerial fire. We believe that this is the core pathogenesis of recurrent hyperthyroidism. In addition, the course of recurrent hyperthyroidism is long, which is based on yin deficiency in the liver and kidney, while the ministerial fire is nourished by the yin of the liver and kidney, and the deficiency of yin fluid makes the ministerial fire more likely to act rashly. In terms of treatment, firstly, we should start with regulating emotions using psychological therapy and traditional skill method. Secondly, we should clear the sovereign and ministerial fire in order to restore balance. Yin should be nourished from beginning to end. The specific treatment should be based on medicines which have soft and quiet properties, so as to inhibit yang hyperactivity. According to the different affected viscera, the medicines that belong to the meridians should be selected. According to the combination of nature and flavor, fire should be reduced and yin should be protected. Finally, we must supplement qi in order to strengthen health. [ABSTRACT FROM AUTHOR]

Human interleukin-15 (hIL-15) and its receptor α (hIL-15Rα) are co-expressed in antigen presenting cells allowing trans-presentation of the cytokine to immune effector cells. We exploited the high-affinity interactions between hIL-15 and the extracellular hIL-15Rα sushi domain (hIL-15RαSu) to create a functional scaffold for the design of multispecific fusion protein complexes. Using single-chain T cell receptors (scTCRs) as recognition domains linked to the IL-15:IL-15Rα scaffold, we generated both bivalent and bispecific complexes. In these fusions, the scTCR domains retain the antigen-binding activity and the hIL-15 domain exhibits receptor binding and biological activity. As expected, bivalent scTCR fusions exhibited improved antigen binding due to increased avidity, whereas fusions comprising two different scTCR domains were capable of binding two cognate peptide/MHC complexes. Bispecific molecules containing scTCR and scCD8αβ domains also exhibit enhanced binding to peptide/MHC complexes, demonstrating that the IL-15:IL-15Rα scaffold displays flexibility necessary to support multi-domain interactions with a given target. Surprisingly, functional heterodimeric molecules could be formed by co-expressing the TCR α and β chains separately as fusions to the hIL-15 and hIL-15RαSu domains. Together, these properties indicate that the hIL-15 and hIL-15RαSu domains can be used as versatile, functional scaffold for generating novel targeted immune molecules. [ABSTRACT FROM AUTHOR]

Abstract: Flowerlike ZnO nanostructures were prepared by a PEG2000 and urea-assisted hydrothermal process at 140 °C. The samples were characterized by X-ray diffraction, transmission electron microscopy and photoluminescence spectrum. Results show that urea played a significant role in the formation of ZnO nanostructures. A preliminary explanation of the mechanism is proposed. [Copyright &y& Elsevier]

The effects of heat treatment temperature and time on the hardness and the wear resistance of RE (rare earth)-Ni-W-P-PTFE-SiC and RE-Ni-W-P-SiC composite coatings have been studied, and the results indicate that the hardness of the composite coatings is lower and the mass loss (i.e., rate of abrasion) is higher in the as-deposited state. The hardness rises and the rate of abrasion decreases with increasing heat treatment temperature; the abrasion rate is lowest and the hardness is highest at 400 °C. The hardness decreases and the rate of abrasion increases with a further rise in the temperature. The hardness and the wear resistance both increase with a rise in heat treatment time, and they reach their peak values after 2 h of heat treatment. The experimental results also show that the hardness of the coating decreases with an increase in PTFE quantity, and the wear rate diminishes correspondingly. X-ray diffraction indicates that the structure of the as-deposited RE-Ni-W-P-PTFE-SiC composite coating is of amorphous status. [Copyright &y& Elsevier]

• This study estimated groundwater storage information of China. • The groundwater storage was certificated to be reliable and accurate. • The causes of groundwater storage changes in different basins were analyzed. As an important freshwater resource, groundwater is of great significance to agriculture, industry, and daily life. The investigation of groundwater storage (GWS) in different regions of China is critical for water resource management and conservation. However, previous studies used different methods and data to monitor GWS in different regions of China, which made their results difficult to compare and cross validate. Here, we used a unified method by the Gravity Recovery and Climate Experiment (GRACE) satellite data and global models to study the variations of GWS in 10 major basins in China from April 2002 to December 2016. Results showed that GWS in the i) Songhua River basin (SRB), Liao River basin (LRB), Haihe River basin (HRB), Yellow River basin (YRB), Huaihe River basin (HHRB), and southeast basin (SEB) exhibited decreasing trends, ii) Yangtze River basin (YZRB) and Pearl River basin (PRB) presented increasing trends, and iii) southwest basin (SWB) and continental basin (CB) displayed both decreasing and increasing trends during the study period. These results were validated by comparing them with a large number of previous studies, which revealed that they were accurate and reliable. Comparing with the climate data and bulletin data, the analysis of causes for these trends indicated that drought and irrigation water-use led to a decline in GWS in several basins of northern China. The decreasing trend of GWS in the SEB was related to water use for production, whereas groundwater recharge from precipitation drove the increasing trends of GWS in the YZRB and PRB. In contrast, the wide geographical areas and complex factors of the SWB and CB led to the increasing–decreasing trends of GWS. This study enriches the GWS for China over the past decade, especially for SEB, PRB, and CB with rare GWS information. It will be helpful for the country's groundwater resource management and systematic water conservation. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the molecular characteristics of gastric adenocarcinoma of the fundic-gland type (GAFG) and explore the possible mechanism of tumor development. Samples from 10 Chinese patients with GAFG were collected at the Peking University International Hospital and Liaocheng People's Hospital between January 2015 and March 2022. The nucleic acid sequence of Epstein Barr virus-encoded RNA (EBV-EBER) was detected by in situ hybridization. Genetic mutation information for GNAS, KRAS, NRAS, BRAF, PIK3CA, TP53, APC, CTNNB1, HER2, MLH1, MSH2, MSH6, and PMS2 was obtained by Next-Generation Sequencing, and the relevant literature was reviewed. A total of eight instances of missense mutations were detected, consisting of seven cases with GNAS mutations, two cases with KRAS mutations, and one case with a TP53 mutation. Additionally, two patients had simultaneous missense mutations in GNAS and KRAS. Nonsynonymous mutations in APC, CTNNB1, NRAS, BRAF, PIK3CA, HER2, MLH1, MSH2, MSH6, or PMS2 were not observed in any cases. In addition, all tumors were EBER-negative. GAFG exhibits diversity at the molecular level, and GNAS mutations are more common than KRAS mutations, TP53 mutations, and microsatellite instability. To date, no association between EBV/HER2 and GAFG has been found. [ABSTRACT FROM AUTHOR]

This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC50 values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high‐fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development. This study describes the design, synthesis, and biological evaluation of a series of novel orally bioavailable small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compound 19 was obtained with EC50 values of 75 nM in in vitro cAMP assays and effectively lowered blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice as well as type 2 diabetic mice induced by streptozotocin and high‐fat diet, and had high potency to be a new lead. [ABSTRACT FROM AUTHOR]

DDX21, a DEAD-box protein, implicated in fundamental aspects of RNA metabolism such as gene transcription. DDX21 expression is dysregulated in cancer, but its specific contribution to tumor invasion and metastasis remains to be determined. Here, we demonstrate DDX21 down-regulation is associated with highly metastatic and poor prognosis human breast cancers. DDX21 overexpression inhibited, while DDX21 knockdown promoted epithelial-mesenchymal transition (EMT) in vitro and in vivo. Overexpression of Snail reversed DDX21 mediated inhibition of cell invasion. On the other hand, independent of its helicase activity, DDX21 suppressed Snail transcription by recruiting SUZ12 and EZH2, two core subunits of PRC2 (polycomb-repressive complex 2), to the Snail promoter. Furthermore, down-regulation of DDX21 is mediated by miR-218-5p. Surprisingly, Snail also modulates DDX21 transcription. Snail overexpression decreased DDX21 transcription, whereas Snail knockdown increased DDX21 expression. These novel observations demonstrate firstly, the antagonism/double negative feedback loop between DDX21 and Snail transcription, and secondly, the crucial role of miR-218-5p in promoting EMT, acting by decreasing the ratio of DDX21/Snail. Our results identify DDX21 as a breast cancer metastasis suppressor; blocking miR-218-5p will stabilize DDX21 and epigenetically suppress Snail expression and EMT. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic brain damage (HIBD) is one of the leading causes of neonatal mortality and permanent neurological disability worldwide and the effective treatment strategies are not yet available. It has been demonstrated that Chitosan oligosaccharide (COS) exerts protective effect in vitro ischemic brain injury. However, no information is available on possible effects of COS on neonatal HIBD. To investigate the hypothesis of the potential neuroprotective effect of COS on the brain injury due to HIBD, 7-day-old Sprague-Dawley rats were treated with left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 °C. After COS treatment, the cerebral damage was measured by behavior tasks, 2,3,5-triphenyltetrazolium chloride(TTC), Hematoxyline-Eosin(HE), Nissl and Fluoro-Jade B(FJB)staining. In addition, the oxidative stress were assayed with ipsilateral hemisphere homogenates. Immunofluorescence staining were used to examine the activation of the astrocyte and microglia. Expression of inflammatory-related proteins were analyzed by western-blot analysis. In this study we found that administration of COS ameliorated early neurological reflex behavior, significantly reduce brain infarct volume and attenuated neuronal cell injury and degeneration. Furthermore, COS markedly decreased the level of MDA, lactic acid and increased SOD, GSH-Px and T-AOC. COS attenuated hypoxic-ischemic induced up-regulation of expressions of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), meanwhile it dramatically increased the interleukin-10 (IL-10). These results suggest that COS exerts neuroprotection on hypoxic-ischemic brain damage in neonatal rats, it implies COS might be a potential therapeutic for the treatment of HIBD. [ABSTRACT FROM AUTHOR]

Influenza vaccination has been shown to be the most effective preventive measure to reduce influenza virus infection and its related morbidity and mortality. Young children aged 6–59 months are recommended as one of the priority groups for seasonal influenza vaccination in China. Our study was conducted to evaluate the level of influenza vaccination coverage during 2014–15 and 2015–16 influenza seasons among kindergarten children aged 2–7 years in Xining, a low-income city of north-western China, and to explore potential factors for noncompliance associated with influenza vaccination. The coverage rate of influenza vaccination was 12.2% (95 CI: 10.6–14.2%) in 2014–15 and 12.8% (95 CI: 11.1–14.7%) in 2015–16. The low coverage rate was found to be primarily associated with the lack of knowledge about influenza vaccine in children’s parents. The most common reason for vaccine declination was the concern about adverse reactions of vaccine. Therefore tailored information should be provided by clinician and public health doctors for targeted groups through effective methods to improve public understanding of vaccination. [ABSTRACT FROM AUTHOR]

Results of a five-year research project and several industrial collaborations have produced tools that model the individual effects and complex dynamic interactions between an IT system's application workload and resource contention at multiple levels in the execution environment. An evaluation shows significant resource efficiency gains without sacrificing the performance specified in service-level agreements. [ABSTRACT FROM AUTHOR]

Aims The lung is a major organ targeted by irradiation (R) in cancer radiotherapy of the thoracic region. Irradiation induced lung injury (RILI) is a common major obstacle in thoracic cancer radiotherapy. Tetrahydropalmatine (THP) has been shown to have a protective effect against oxidative stress. This study was designed to investigate the potential radioprotective effect of THP against RILI and to elucidate the underlying mechanisms. Materials and methods Sprague–Dawley rats were treated with THP and R. THP was delivered 1 h before R. Using TUNEL staining to explore the effectiveness of THP displayed on R induced pulmonary cells apoptosis. Lung histopathologic findings, bronchoalveolar lavage fluid (BALF) levels of total cell counts, protein and inflammatory cytokines, fibrotic factors (hydroxyproline content), apoptotic mediators (caspase-3 and cytochrome c) and malondialdehyde (MDA) were also evaluated after R. Key findings THP significantly ameliorates the deleterious effects of R. Further studies showed that THP decreased lung injury by inhibiting the pulmonary cells apoptosis; reduced lung inflammation by decreasing BALF cells recruitment and lowering BALF protein levels; reduced pulmonary fibrosis by decreasing collagen content of lung tissues. THP also ameliorated oxidative modification of rat lungs as evidenced by levels of lipid peroxidation. BALF cytokine analysis, moreover, pointed to a mitigation of the chronic inflammatory profile of irradiated lungs as a result of the protective effect of THP treatment. Significance THP can effectively attenuate RILI through anti-apoptosis, anti-fibrosis and anti-inflammation mechanisms. [ABSTRACT FROM AUTHOR]

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl4-induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives was effectively improved. All compounds demonstrated the effect of different degrees in improving the liver enzyme ( ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead. [ABSTRACT FROM AUTHOR]

Twelve novel dicoumarol glucagon-likepeptide 1 (GLP-1) conjugateswere designed, synthesized, and tested for biological activity. Allderivatives retained receptor activation efficacy, and exhibited improvedalbumin affinity and in vitro stabilityin rat plasma. The in vivo elimination half-lives of 13cand 13l(22.07 and 18.78 h, respectively) were muchlonger than those of the GLP-1 receptor agonists exendin-4 (2.82 h)and liraglutide (12.53 h). The prolonged in vivo antidiabetic effectsof 13cand 13lon db/db mice were confirmedby the hypoglycemic efficacy test and the multiple intraperitonealglucose tolerance test. Importantly, a once daily administration of 13cto db/db mice for 7 weeks provided long-term beneficialeffects by lowering glycated hemoglobin (HbA1c) levels to 5.05%, whichwas lower than with liraglutide treatment (5.41%). These results suggestthat 13cis a promising long-lasting GLP-1 mimetic thatmay be suitable for clinical use following further research. [ABSTRACT FROM AUTHOR]

• This study designed a new method to automatically extract lake body. • This study compared the new method with the five other methods. • The new method showed the highest accuracy and stability, especially during the lake ice period. Lakes play an important role in terrestrial ecosystems and have a significant impact on human production and life. Remote sensing techniques have been widely used to monitor changes in lakes. Several studies have been conducted pertaining to extraction of lake bodies using optical remote sensing images; however, owing to the influence of ice and snow in the lake and other parameters such as noise, the accuracy and stability of lake extraction still need to be improved. This study designed a new method by combing K-means clustering and the flood fill method (KCFFM) to improve the accuracy and stability of extraction results from complex backgrounds. Using Landsat 8 Operational Land Imager (OLI) data for five lakes in Central Asia, the accuracy and stability of KCFFM in summer and winter were evaluated and compared with those of five other methods. KCFFM showed the highest accuracy and stability among all the methods, especially during the lake ice period. For KCFFM, the Kappa coefficient was greater than 0.97 and 0.92 and the overall accuracy was greater than 99% and 98% in summer and winter, respectively. The area error rate of KCFFM was less than 3%, except for Lake Alakol (less than 10%). In addition, KCFFM significantly decreased the area error rate compared to other methods (1% to 15% in summer and 10% to 50% in winter). The proposed method optimized the time continuity, accuracy, and stability of lake body extraction. Thus, KCFFM can provide valuable basic data for monitoring lake water bodies. [ABSTRACT FROM AUTHOR]

Aim: To explore whether the General Movement Optimality Score (GMOS) could help to identify asymmetric movement in infants with neonatal arterial ischemic stroke (NAIS) in the early stage.Method: Twenty-seven infants with NAIS (16 males, 11 females) were enrolled. The general movement video was recorded approximately one month after birth. The GMOS focused separately on the neck and trunk and the upper and lower extremities. The differences between the ipsilesional and contralesional limbs were analyzed.Results: Eight infants who developed cerebral palsy (CP) had middle cerebral artery (MCA) infarction involving the main branch. By GMOS evaluation, the scores of the contralesional upper and/or lower limbs were lower than those of the ipsilesional side (p < 0.05). In the contralesional limbs, the CP group had a lower GMOS than the non-CP group. Distal rotatory components of the contralesional upper limbs and tremulous movement of the lower limbs showed significant differences.Interpretation: The GMOS could help to quantitatively find and assess the asymmetric movement of global and contralesional limbs. Distal rotatory movement of the upper limbs could be an early sign of abnormal motor function in infants with NAIS. [ABSTRACT FROM AUTHOR]

Aim: To detect early brain structural and clinical functional markers of brain injury and development based on a magnetic resonance imaging (MRI) scoring system and a general movement assessment (GMA) for preterm infants later diagnosed with cerebral palsy (CP).Study Design: Retrospective cohort study. General movements (GMs) were scored according to a semiquantitative scoring system: the GMs optimality score (GMOS) at preterm and term ages and the Motor Optimality Score (MOS) at the corrected age of 3 months after birth. Brain magnetic resonance imaging (MRI) at term-equivalent age was scored using an MRI scoring system. We analyzed the relationship between the early degree of cerebral white matter (WM) abnormality and the GMOS and the MOS for infants born <32 weeks gestational age later diagnosed with CP in a comparison group of neurotypical controls.Subjects: Sixteen preterm infants were included in this study who underwent MRI and GMs assessment. 8 out of the 16 preterm infants were later diagnosed with CP, while the other 8 infants with normal motor development (N) were placed into the control group. Their median gestational age was 30w6d and 27w6d for each group respectively.Results: The cerebral WM MRI scores were significantly higher in the CP group than in the control group (p < 0.01). The GMOS and MOS were significantly higher in the control group than in the CP group (p < 0.05). The MOS showed a strong correlation to the cerebral WM MRI score (r = -0.88) and the subscale of cerebral WM items (the cystic degeneration and the focal signal abnormalities) of the MRI score (r = -0.94) in the CP group. The MOS also showed a correlation with corrected biparietal diameter (cBPD) in the preterm infant group with CP (r = 0.75). Results of linear regression analyses between term MRI and GMs measures in preterm infants with CP are presented. Cerebral WM scores were associated with the MOS (β = -0.63; 95%CI = -0.97, -0.29; p < 0.01). Cerebral WM injury, including the subscale of cystic degeneration and focal signal abnormalities was closely associated with the MOS (β = -0.83; 95%CI = -1.13, -0.54; p < 0.001).Conclusion: Cerebral WM scores show a strong association with a decreased motor performance on the MOS in preterm infants later diagnosed with CP. Severe white matter injury and significantly decreased MOS scores may provide useful early markers and strong evidence to early predict the risk of later development of cerebral palsy in preterm infants. [ABSTRACT FROM AUTHOR]

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-a or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM. [ABSTRACT FROM AUTHOR]

Abstract: Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure–activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1μM. [Copyright &y& Elsevier]

Infectious diseases have become one of the most threatening global challenge with high morbidity and mortality, bringing great difficulties to clinical diagnosis and treatment. New strategy for high-specific and sensitive bacteria detection are urgently needed in facing the crisis of worldwide antibiotic resistance. Herein, a novel method through the integration of dual aptamer technology and CRISPR-Cas12a assisted rolling circle amplification (RCA) was present to obtain both accurate identification and high-sensitive detection of Methicillin-Resistant Staphylococcus Aureus (MRSA). The specificity inherited from the dual functionalized aptamers initiated bioconjugation to specifically recognize the protein targets on the surface of bacteria. Besides the target activity, the functionalized aptamer could also convert the protein recognition to nucleic acids signals. Through the integration of attached RCA and CRISPR-Cas12a assisted trans- cleavage, dual amplification of the nucleic acid signal was obtained. Based on this, we have extended the application of CRISPR-Cas12a from the nucleic acid detection to bacteria detection. As a result, the proposed method was demonstrated to be with significantly improved sensitivity towards MRSA detection. We believe that the novel integrated strategy would diversify the existing pool of bacterial detection and inspire the development of promising drug candidates in the future. • Extended the application of CRISPR-Cas12a from the nucleic acid detection to bacteria detection. • The proposed method was demonstrated to be with significantly improved sensitivity towards MRSA detection. • Dual signal amplification through the integration of rolling circle amplification (RCA) and CRISPR-Cas12a assisted trans- cleavage. [ABSTRACT FROM AUTHOR]

Short-time water demand forecasting is essential for optimal control in a water distribution system (WDS). Current methods (e.g., time-series models and conventional artificial neural networks) have limited power in practice due to the nonlinear nature of changes in water demand. In particular, 15-min time-step forecasting may not be accurate when using conventional models. To tackle this problem, this paper investigates the potential of deep learning in short-term water demand forecasting, developing a gated recurrent unit network (GRUN) model to forecast water demand 15 min and 24 h into the future with a 15-min time step. The performance of GRUN was compared with a conventional artificial neural network (ANN) model and seasonal autoregressive integrated moving average (SARIMA) model. A correction module was used to reduce the cumulative error. The results show that the deep learning method improves the performance of water demand prediction. The correction module enhances the performance of ANN and GRUN models. In general, deep neural network models like GRUN outperform the ANN and SARIMA models for both 15-min and 24-h forecasts. These findings can provide more flexible and effective solutions for water demand forecasting. [ABSTRACT FROM AUTHOR]

Both power and performance are important concerns for enterprise data centers. While various management strategies have been developed to effectively reduce server power consumption by transitioning hardware components to lower power states, they cannot be directly applied to today's data centers that rely on virtualization technologies. Virtual machines running on the same physical server are correlated because the state transition of any hardware component will affect the application performance of all the virtual machines. As a result, reducing power solely based on the performance level of one virtual machine may cause another to violate its performance specification. This paper proposes PARTIC, a two-layer control architecture designed based on well-established control theory. The primary control loop adopts a multi-input multi-output control approach to maintain load balancing among all virtual machines so that they can have approximately the same performance level relative to their allowed peak values. The secondary performance control loop then manipulates CPU frequency for power efficiency based on the uniform performance level achieved by the primary loop. Empirical results demonstrate that PARTIC can effectively reduce server power consumption while achieving required application-level performance for virtualized enterprise servers. [ABSTRACT FROM AUTHOR]