Research progress in RIPK3 and its inhibitors / 中国药理学通报

Receptor-interacting serine/threonine-protein kinase 3(RIPK3),a member of the RIP kinase family,plays an important role in cell death,especially in necroptosis. In addition,RIPK3 is also involved in apoptosis and pyroptosis,suggesting that RIPK3 may be the intersection of multiple cell death and it possesses the potential to be a target for precise regulation of cell death. According to the kinase binding mode,current RIPK3 inhibitors can be classified into type ,type Ⅱ and other types. This review summarizes the research progress in the role of RIPK3 in cell death and its inhibitors,which is of great significance in seeking drugs for the treatment of injury-related diseases.

Advances in the Diagnosis and Treatment of Cushing′s Syndrome / 罕见病研究

Cushing′s syndrome (CS), an endocrine disorder resulting from excessive glucocorticoid secretion by the adrenal cortex, poses significant challenges to both diagnosis and treatment. The diagnostic process involves comprehensive evaluation, combining laboratory tests and imaging studies for screening, qualification, and localization. Surgical intervention remains the primary treatment approach, although pharmacological therapy also plays a crucial role. With an increasing understanding of the pathogenesis of CS, more potential targets for orphan drug development have been discovered. This article summarizes the current status of diagnosis and treatment for CS and provides an outlook on future research directions.

Construction and validation of a nomogram model to predict abnormal female factors in in vitro fertilization / 中国组织工程研究

BACKGROUND:Reducing the rate of abnormal fertilization is an effective approach to improving the efficacy of in vitro fertilization and reducing patients'financial strain.However,the current research on abnormal fertilization has focused on exploring the types of prokaryotic nuclei and their generation mechanisms,as well as analyzing embryos formed by abnormal fertilization,chromosomal ploidy and utilization value.There is a lack of clinical prediction models for abnormal fertilization based on retrospective studies. OBJECTIVE:To construct a nomogram model to predict abnormal female factors in in vitro fertilization. METHODS:A total of 5 075 patients undergoing treatment for conventional in vitro fertilization at Nanxishan Hospital of Guangxi Zhuang Autonomous Region from March 2017 to March 2022 were retrospectively analyzed.The male confounders were calibrated on a 1:1 propensity score with a match tolerance of 0.02,and 1 672 cases were successfully matched.According to the Vienna Consensus,patients with≥60%normal fertilization capacity were included in the normal fertilization group(n=836)and those with<60%normal fertilization capacity were included in the abnormal fertilization group(n=836).The model and validation groups were obtained by random sampling at a ratio of 7:3.Factors related to the occurrence of abnormal fertilization following conventional in vitro fertilization in the model group were screened using univariate analysis and the best matching factors were selected using the Least Absolute Shrinkage and Selection Operator(LASSO)and included in a multifactorial forward stepwise Logistic regression to identify their independent influencing factors and plot a nomogram.Finally,the prediction model was validated for discrimination,accuracy and clinical application efficacy using receiver operating characteristic curves,calibration curves,clinical decision curves and clinical impact curves. RESULTS AND CONCLUSION:The univariate analysis indicated the factors influencing the occurrence of abnormal fertilization were age,controlled ovarian hyperstimulation protocol,number of assisted pregnancies,years of infertility,infertility factors,anti-mullerian hormone,sinus follicle count,basal luteinizing hormone,luteinizing hormone concentration on the human chorionic gonadotropin day,and estradiol level on human chorionic gonadotropin injection day(P<0.05).LASSO regression further identified the best matching factors,including age,microstimulation protocol,number of assisted pregnancies,years of infertility,anti-mullerian hormone,luteinizing hormone level on human chorionic gonadotropin injection day,and estradiol level on human chorionic gonadotropin injection day(P<0.05).Multifactorial forward stepwise Logistic regression results showed that age,microstimulation protocol,number of assisted conceptions,years of infertility,anti-mullerian hormone,and estradiol level on human chorionic gonadotropin injection day were independent influencing factors for the occurrence of abnormal fertilization following conventional in vitro fertilization.The receiver operating characteristic curves showed an area under the curve of 0.761(0.746,0.777)for the model group and 0.767(0.733,0.801)for the validation group,indicating that the model has good discrimination.The mean absolute error of the calibration curve was 0.044,and the Hosmer-Lemeshow test indicated that there was no significant difference between the predicted probability of abnormal fertilization and the actual probability of abnormal fertilization(P>0.05),indicating the prediction model has good consistency and accuracy.The clinical decision curves and clinical impact curves showed that the model and validation groups had the maximum net clinical benefit at valve probability values of 0.00-0.52 and 0.00-0.48,respectively,and there was a good clinical application efficacy in this valve probability range.To conclude,the nomogram model has good discrimination and accuracy as well as clinical application efficacy for predicting the occurrence of abnormal fertilization in women undergoing conventional in vitro fertilization based on age,microstimulation protocol,number of assisted conceptions,years of infertility,anti-mullerian hormone,and estradiol level on human chorionic gonadotropin injection day.

Health-related quality of life of men with primary osteoporosis and its changes after bisphosphonates treatment.

INTRODUCTION: Osteoporosis leads to more serious consequences in men than in women, but less is known about its impacts on health-related quality of life (HRQoL) of men, and whether the anti-osteoporosis treatment can improve HRQoL of men with osteopenia/osteoprosis. METHODS: We enrolled men with primary osteoporosis and age-matched healthy controls. We collected medical history, serum levels of carboxyl-terminal type I collagen telopeptide, procollagen type I propeptides, and bone mineral density of patients. All patients and controls completed the short-form 36 (SF-36) questionnaires. Changes in HRQoL of osteopenia/osteoporosis men were prospectively evaluated after alendronate or zoledronic acid treatment. RESULTS: A total of 100 men with primary osteoporosis or osteopenia and 100 healthy men were included. The patients were divided into three subgroups: osteopenia (n = 35), osteoporosis (n = 39) and severe osteoporosis (n = 26). Men with osteoporosis or severe osteoporosis had impaired HRQoL in domains of physical health compared to healthy controls. HRQoL scores in physical health related domains of patients with severe osteoporosis were significantly lower compared to healthy controls, and were the poorest among the three subgroups of patients. Fragility fracture history was correlated with lower SF-36 scores about physical health. In 34 men with newly diagnosed osteoporosis receiving bisphosphonates treatment, HRQoL scores were significantly improved in domains of physical health after treatments. CONCLUSIONS: The HRQoL is significantly impaired in men with osteoporosis, and the more severe the osteoporosis, the poorer the HRQoL. Fragility fracture is an important influencing factor of deteriorated HRQoL. Bisphosphonates treatment is beneficial to improve HRQoL of osteopenia/osteoporosis men.

Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis.

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.

AMPK activator decelerates osteoarthritis development by inhibition of ß-catenin signaling in chondrocytes.

Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of ß-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of ß-catenin signaling have not been determined. Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 5'-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in ß-cateninS552 phosphorylation and ß-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results: We found that metformin inhibited ß-cateninS552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited ß-catenin nuclear translocation and ß-catenin reporter activity. In addition, metformin also attenuated the expression of ß-catenin downstream target genes. We also demonstrated that metformin inhibited ß-cateninS552 phosphorylation in articular cartilage in mice. Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of ß-catenin signaling in chondrocytes. The translational potential of this article: This study demonstrated the interaction between AMPK and ß-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.

Prevalence and trends of anemia among pregnant women in eight provinces of China from 2016 to 2020 / 中华预防医学杂志

This study analyzed the anemia status and change trend of 219 835 pregnant women in eight provinces from 2016 to 2020 in the Maternal and Newborn Health Monitoring Program(MNHMP). The results showed that from 2016 to 2020, the anemia rate of pregnant women in eight provinces was 41.27%, and the rates of mild, moderate and severe anemia were 28.56%, 12.59% and 0.12% respectively; the anemia rates in eastern, central and western regions were 41.87%, 36.09% and 44.63% respectively, and the anemia rates in urban and rural areas were 39.87% and 42.23%. From 2016 to 2020, the anemia rate of pregnant women decreased from 44.93% to 38.22%, with an average annual decline of 3.86% (95%CI:-5.84%, -1.85%). The anemia rate among pregnant women of the eastern region (AAPC=-6.16%, 95%CI:-9.79%, -2.38%) fell faster than that among pregnant women of the central region (AAPC=0.71%, 95%CI:-6.59%, 8.57%) and western region (AAPC=-1.53%, 95%CI:-5.19%, 2.28%). From 2016 to 2020, the moderate anemia rate in pregnant women decreased from 14.98% to 10.74%, with an average annual decline of 8.72% (95%CI:-12.90%, -4.34%), with a statistically significant difference (P<0.05); AAPC for mild and severe anemia in pregnant women was 1.56% (95%CI: 3.44%, 0.36%) and 18.86% (95%CI: 39.88%, 9.52%), respectively, without statistically significant difference (P>0.05).

Association between cognitive impairment and main metals among oldest old aged 80 years and over in China / 中华预防医学杂志

Objective: To identify the main metals involved in cognitive impairment in the Chinese oldest old, and explore the association between these metal exposures and cognitive impairment. Methods: A cross-sectional study was conducted on 1 568 participants aged 80 years and older from Healthy Aging and Biomarkers Cohort Study (2017 to 2018). Fasting venous blood was collected to measure the levels of nine metals (selenium, lead, cadmium, arsenic, antimony, chromium, manganese, mercury, and nickel). The cognitive function of these participants was evaluated by using the Chinese version of the Mini-Mental State Examination (CMMSE). The random forest (RF) was applied to independently identify the main metals that affected cognitive impairment. The multivariate logistic regression model and restricted cubic splines (RCS) model were used to further verify the association of the main metals with cognitive impairment. Results: The age of 1 568 study subjects was (91.8±7.6) years old, including 912 females (58.2%) and 465 individuals (29.7%) with cognitive function impairment. Based on the RF model (the out-of-bag error rate was 22.9%), the importance ranking of variables was conducted and the feature screening of five times ten-fold cross-validation was carried out. It was found that selenium was the metal that affected cognitive function impairment, and the other eight metals were not included in the model. After adjusting for covariates, the multivariate logistic regression model showed that with every increase of 10 μg/L of blood selenium levels, the risk of cognitive impairment decreased (OR=0.921, 95%CI: 0.889-0.954). Compared with the lowest quartile(Q1) of blood selenium, the ORs (95%CI) of Q3 and Q4 blood selenium were 0.452 (0.304-0.669) and 0.419 (0.281-0.622) respectively. The RCS showed a linear dose-response relationship between blood selenium and cognitive impairment (Pnonlinear>0.05). Conclusion: Blood selenium is negatively associated with cognitive impairment in the Chinese oldest old.

Evaluation of ankle joint protection effect of parachute ankle brace on paratrooper landing / 中华劳动卫生职业病杂志

Objective: To study the protective effect of parachute ankle brace on ankle joint during simulated parachuting landing. Methods: In August 2021, 30 male paratroopers were selected as the test subjects by simple random sampling method. They jumped from the 1.5 m and 2.0 m height platforms respectively with and without parachute ankle brace, and landed on the sandy ground in a semi-squat parachute landing position. The experiment was divided into 1.5 m experimental group and control group and 2.0 m experimental group and control group. Angle sensor and surface electromyograph were used to measure and analyze the coronal tilt range of the ankle joint and the percentage of maximal voluntary contraction (MVE%) of the muscles around the ankle joint, respectively, to evaluate the protective effect of the parachute ankle brace. Results: At the same height, the tilt range of coronal plane of ankle in experimental group was significantly reduced compared with control group, and the difference was statistically significant (P<0.05). Under the same protection state, the tilt range of the coronal plane of the ankle in the 1.5 m group was significantly reduced compared with that in the 2.0 m group, and the difference was statistically significant (P<0.05). The coronal plane inclination range of the ankle in 2 m experimental group was significantly lower than that in 1.5 m control group, and the difference was statistically significant (P<0.05). Compared with 1.5 m control group, MVE% of right tibialis anterior muscle and bilateral lateral gastrocnemius decreased in 1.5 m experimental group, while MVE% of bilateral peroneus longus increased, with statistical significance (P<0.05). Compared with 2.0 m control group, the MVE% of bilateral tibialis anterior muscle and right lateral gastrocnemius decreased in 2.0 m experimental group, while the MVE% of bilateral peroneus longus increased, with statistical significance (P<0.05). The MVE% of bilateral tibialis anterior muscle, bilateral lateral gastrocnemius muscle and right peroneus longus muscle in 1.5 m experimental group decreased compared with 2.0 m experimental group, and the differences were statistically significant (P<0.05). Compared with 2.0 m control group, the MVE% of bilateral tibialis anterior muscle, right lateral gastrocnemius muscle and right peroneus longus muscle in 1.5 m control group decreased, and the differences were statistically significant (P<0.05) . Conclusion: Wearing parachute ankle brace can effectively limit the coronal plane inclination range of ankle joint, improve the stability of ankle joint and reduce the load on the muscles around ankle joint by landing. Reducing the height of the jumping platform can reduce the coronal plane incline range of the ankle and the muscle load around the ankle during landing.

Comorbidity of myopia and obesity and the moderating role of lifestyle among primary and secondary school students in Inner Mongolia Autonomous Region in 2021 / 中国学校卫生

Objective@#To describe the current status of the prevalence of co-morbid myopia and obesity among 7-18 years students in the Inner Mongolia Autonomous Region in 2021 and to analyze the moderating effect of lifestyle in this association ，so as to provide scientific basis for the establishment of the mechanism of Co-morbidity，Shared Etiology，and Shared Prevention of common diseases in children and adolescents.@*Methods@#A total of 139 630 primary and secondary school students aged 7-18 years from Inner Mongolia Autonomous Region were selected by stratified random cluster sampling method in September,2021. Myopia was determined using distance visual acuity examination and refractive error examination, and obesity was determined according to the BMI classification criteria for overweight, obesity screening of Chinese school age children and adolescents. Used a questionnaire, healthy lifestyles were determined according to the American Heart Association s Healthy Lifestyle Score by totaling the six scores for smoking, alcohol consumption, diet, exercise, screen time, and sleep duration.The χ 2 test was used to compare the association between group differences in the co-morbidity rate of myopia and obesity. The multivariable Logistic regression model was used to explore the influencing factors of the co-morbidity of myopia and obesity, and the stratified analysis was used to analyze the moderating effect of lifestyles on the prevalence of the co-morbidity.@*Results@#The prevalence of myopia and obesity co-morbidity among students aged 7-18 years old in the Inner Mongolia Autonmous Region in 2021 was 13.7%, higher among boys than girls ( 15.5 % vs. 11.8%), higher among those aged 10-12 years old than 7-9,13-15,and 16-18 years old (14.7%,13.7%, 13.3%, 12.0%), higher among other ethnic minorities than Han Chinese and Mongolians (15.3%, 14.0%, 12.5%), higher in urban areas than that in suburban areas(15.3%, 13.0%), and middle economic level tracts were higher than poor and good tracts (14.8%, 12.9 %, 12.6%) ( χ 2=392.37，115.73，62.80，119.02，121.60, P <0.05). Multivariable Logistic regression modeling showed that unhealthy lifestyles ( OR=1.24, 95%CI=1.19-1.29 ) and middle level of lifestyle score ( OR=1.15, 95%CI=1.10-1.19 ) students had higher prevalence of co-morbidity, and the results were statistically significant among both boys and girls, the age groups of 10- 12, 13-15, and 16-18 years old, as well as the Han and Mongolian ethnic groups (all P <0.05).@*Conclusion@#In 2021, the current situation of myopia and obesity co-morbidity and unhealthy lifestyles among primary and secondary school students in the Inner Mongolia Autonomous Region are not optimistic.

Application of standardized patient teaching based on Calgary-Cambridge communication model in nurse patient communication training for junior college interns / 中国实用护理杂志

Objective:To explore the effect of applying standardized patient teaching based on Calgary-Cambridge communication model in nurse patient communication training for junior college interns, and to enrich the teaching methods of nurse patient communication training in domestic medical institutions.Methods:This study was a quasi-experimental study. In July 2022, 78 students were selected from 335 junior college interns in the First Affiliated Hospital of Shandong First Medical University by random coding method, and were randomly divided into the experimental group (39 students) and the control group (39 students) by lot. The control group received routine training. The experimental group received standardized patient teaching based on Calgary Cambridge communication model: teaching the key points of communication, guiding demonstration based on Calgary Cambridge communication model, and guiding reflection and exploration. The nurse patient communication ability, nurse patient communication practice skills, communication self-efficacy, and teaching satisfaction of the two groups of interns were compared between the two groups after 8 weeks of training.Results:After training, the total score of nurse patient communication ability evaluation in the experimental group was (91.41 ± 5.35) points, higher than that in the control group (88.08 ± 7.40) points, there was significant difference ( t=2.24, P<0.05); after training, the communication self-efficacy score of the experimental group was (30.21 ± 4.28) points, higher than that of the control group (27.94 ± 5.09) points, there was significant difference ( t=2.09, P<0.05); the total score of communication practice skills in the experimental group was (173.59 ± 18.48) points, higher than that in the control group (158.44 ± 15.57) points, there was significant difference ( t=3.82, P<0.05); the total score of communication teaching and training satisfaction in the experimental group was (16.77 ± 2.94) points, higher than that in the control group (15.22 ± 1.90) points, and there was significant difference ( t=2.68, P<0.05). Conclusions:The standardized patient teaching based on Calgary Cambridge communication model can effectively improve the practical skills of nurse patient communication of junior college interns, and promote the improvement of their nurse patient communication self-efficacy, which is conducive to the improvement of nurse patient communication ability junior college intern.

Practice of video-assisted teaching ward rounds for typical cases of ophthalmology / 基础医学与临床

Objective To investigate the efficacy of video-assisted teaching ward rounds for typical cases of oph-thalmology in clinical practice for medical undergraduates.Methods A total of 45 students from clinical medicine in Peking Union Medical College were enrolled.They were randomly divided into the experimental group(23 students)and control group(22 students).Primary angle closure glaucoma(PACG)was selected as the learning content,the experimental group was trained by video-assisted teaching ward rounds,while the control group was trained by internship in outpatient clinic.All students joined the test of typical case PACG and a ques-tionnaire survey was implemented for the experimental group.Results The average score of experimental group was higher than control group[(84.30±4.53)vs.(78.05±5.76),t＝4.05,P＜0.001].For video-assisted teaching ward rounds,in experimental group,86.9%(20/23)students believed it was more practical,95.6%(22/23)students thought it was very helpful and 91.3%(21/23)students considered it was conductive to im-prove interest of learning and clinical thinking ability.Conclusions Video-assisted teaching ward rounds improves students'understanding memory of ophthalmic typical cases,which is a potential supplement teaching method in clinical practice training of ophthalmology for medical undergraduates.

Application value of magnetic resonance imaging intravoxel incoherent motion diffusion-weighted imaging and texture analysis in differential diagnosis and staging of nasopharyngeal carcinoma / 肿瘤研究与临床

Objective:To investigate the application value of magnetic resonance imaging (MRI) intravoxel incoherent motion (IVIM)-diffusion-weighted imaging (DWI) metrics and texture analysis in the differential diagnosis and staging of nasopharyngeal carcinoma.Methods:The clinical data of 125 nasopharyngeal carcinoma patients (the research group) in Tangshan People's Hospital from October 2019 to October 2021 and 76 patients with nasopharyngeal hyperplasia during the same period (the control group) were retrospectively analyzed. All patients underwent MRI T2WI and IVIM-DWI sequence scanning, and then the plain T2WI images, DWI, and IVIM-DWI quantitative parameter pseudo-color maps including pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were obtained. The texture analysis metrics like apparent diffusion coefficient (ADC), D, D* and f were recorded. IVIM-DWI and texture analysis metrics were compared among patients in both groups and patients in different clinical stages; and the receiver operating characteristic (ROC) curve was plotted to evaluate the efficacy of IVIM sequence parameters and texture analysis metrics in the differential diagnosis and staging of nasopharyngeal carcinoma.Results:Compared with the control group, a marked reduction in D value [(0.80±0.13)×10 -3 mm 2/s vs. (1.19±0.27)×10 -3 mm 2/s], f value [(11.3±2.2)% vs. (15.6±3.3)%], mean ADC value [(0.92±0.17)×10 -3 mm 2/s vs. (1.16±0.19)×10 -3 mm 2/s] and variance (2 189±862 vs. 3 563±925) (all P < 0.05); a notable increase in skewness (0.50±0.17 vs. 0.31±0.12), kurtosis (0.56±0.13 vs. -0.21±0.06) and entropy (10.5±2.3 vs. 7.1±2.1) (all P < 0.05). The area under the curve (AUC) of IVIM sequence parameters and texture analysis metrics in the differential diagnosis of nasopharyngeal carcinoma was 0.763 and 0.803, respectively; the AUC, sensitivity and specificity of the combination of IVIM sequence parameters and texture analysis metrics for the differential diagnosis of nasopharyngeal carcinoma was 0.868, 89.6% and 86.8%, respectively. Compared with patients in stage Ⅰ-Ⅱ nasopharyngeal carcinoma, patients in stage Ⅲ-Ⅳ reported the lower D value [(0.75±0.13)×10 -3 mm 2/s vs. (0.89±0.16)×10 -3 mm 2/s], f value [(10.8±2.8)% vs. (12.1±3.0)%] (all P < 0.05), and the lower mean ADC value [(0.90±0.14)×10 -3 mm 2/s vs. (0.96±0.16)×10 -3 mm 2/s], and variance (2 063±831 vs. 2 431±846) (all P < 0.05), skewness (0.56±0.15 vs. 0.39±0.16), kurtosis (0.62±0.15 vs. 0.44±0.13) and entropy (11.0±2.1 vs. 9.1±2.4) (all P < 0.05). The AUC of IVIM sequence parameters and texture analysis metrics in differentiating nasopharyngeal carcinoma with different stages was 0.863 and 0.796, respectively; the AUC, sensitivity and specificity of the combination of IVIM sequence parameters and texture analysis metrics in differentiating nasopharyngeal carcinoma with different stages was 0.894, 85.4% and 90.7%, respectively. Conclusions:MRI texture analysis and IVIM quantitative analysis are of high value in the differential diagnosis and staging of nasopharyngeal carcinoma; and the texture analysis achieves higher sensitivity and specificity in the differential diagnosis and staging of nasopharyngeal carcinoma compared with IVIM quantitative analysis; the combined application of both has the highest overall efficacy.

Roles of focal adhesion proteins in skeleton and diseases

The skeletal system, which contains bones, joints, tendons, ligaments and other elements, plays a wide variety of roles in body shaping, support and movement, protection of internal organs, production of blood cells and regulation of calcium and phosphate metabolism. The prevalence of skeletal diseases and disorders, such as osteoporosis and bone fracture, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, increases with age, causing pain and loss of mobility and creating a huge social and economic burden globally. Focal adhesions (FAs) are macromolecular assemblies that are composed of the extracellular matrix (ECM), integrins, intracellular cytoskeleton and other proteins, including kindlin, talin, vinculin, paxillin, pinch, Src, focal adhesion kinase (FAK) and integrin-linked protein kinase (ILK) and other proteins. FA acts as a mechanical linkage connecting the ECM and cytoskeleton and plays a key role in mediating cell-environment communications and modulates important processes, such as cell attachment, spreading, migration, differentiation and mechanotransduction, in different cells in skeletal system by impacting distinct outside-in and inside-out signaling pathways. This review aims to integrate the up-to-date knowledge of the roles of FA proteins in the health and disease of skeletal system and focuses on the specific molecular mechanisms and underlying therapeutic targets for skeletal diseases.

The roles of sclerostin and irisin on bone and muscle of orchiectomized rats.

BACKGROUND: The reduction in androgen level gives rise to a decrease in bone mineral density (BMD) and muscle strength, but the exact mechanisms are unclear. We investigated the roles of novel cytokines of sclerostin and irisin on bone and muscle of orchiectomized rats. METHODS: Twenty 3-month-old male rats were randomized to receive sham or orchiectomy (ORX) operation. Rats were euthanized after 8 weeks of surgery, and serum levels of sclerostin and irisin were measured by enzyme-linked immunosorbent assay at baseline and execution. Grip strength was measured by a grip strength tester at baseline and before execution. BMD and bone microarchitecture were measured by microcomputed tomography. The samples of bone and muscle were harvested at execution. Bone biomechanics were measured by three-point bending tests and vertebral body indentation tests. Bone and muscle histological features were analyzed by hematoxylin and eosin stain, Von Kossa's stain and tartrate resistant acid phosphatase stain. Simple linear regression analyses were used to analyze the relationships between serum levels of sclerostin, irisin and grip strength and BMD of ORX rats. RESULTS: Serum sclerostin level increased from 279 ± 44 pg/mL to 586 ± 57 pg/mL since baseline to 8 weeks after ORX (P = 0.002), which was significantly higher than that in sham rats (406 ± 20 pg/mL at execution) (P = 0.012). Serum irisin level decreased from 4.12 ± 0.20 ng/mL to 3.55 ± 0.29 ng/mL since baseline to 8 weeks of ORX (P = 0.048), which was significantly lower than sham rats (4.84 ± 0.37 pg/mL at execution) (P = 0.013). Trabecular BMD, parameters of bone microarchitecture, bone strength, grip strength and the myofibers size of soleus muscles were significantly lower in ORX rats than in sham group. Grip strength was positively correlated with femoral trabecular BMD (r = 0.713, P < 0.001) and bone volume/total volume (r = 0.712, P < 0.001) in all rats. The serum sclerostin level was negatively correlated to femoral trabecular BMD (r = -0.508, P = 0.022) and grip strength (r = -0.492, P = 0.028). Serum irisin level was positively correlated with femoral trabecular BMD (r = 0.597, P = 0.005), but no obvious correlation was found between irisin level and muscle strength in all rats. CONCLUSIONS: Reduced BMD, impaired bone microarchitecture, weak strength of bone and muscle, and thin myofibers were induced by androgen deficiency of ORX rats. Serum sclerostin and irisin levels were significantly changed after ORX, which might be closely correlated with the occurrence of osteoporosis and sarcopenia in ORX rats.

Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) can be differentiated into osteoblasts and adipocytes. During these processes, super enhancers (SEs) play important roles. Here, we performed comprehensive characterization of the SEs changes associated with adipogenic and osteogenic differentiation of hMSCs, and revealed that SEs changed more dramatically compared with typical enhancers. We identified a set of lineage-selective SEs, whose target genes were enriched with cell type-specific functions. Functional experiments in lineage-selective SEs demonstrated their specific roles in directed differentiation of hMSCs. We also found that some key transcription factors regulated by lineage-selective SEs could form core regulatory circuitry (CRC) to regulate each other's expression and control the hMSCs fate determination. In addition, we found that GWAS SNPs of osteoporosis and obesity were significantly enriched in osteoblasts-selective SEs or adipocytes-selective SEs, respectively. Taken together, our studies unveiled important roles of lineage-selective SEs in hMSCs differentiation into osteoblasts and adipocytes.

The role of osteocalcin in regulation of glycolipid metabolism and muscle function in children with osteogenesis imperfecta.

Objective: Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We investigate the relationship between serum OC levels and glycolipid metabolism and muscle function in children with osteogenesis imperfecta (OI). Methods: A total of 225 children with OI and 80 healthy controls matched in age and gender were included in this single center study. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated analyzers. Serum levels of fasting insulin (FINS) were measured using an automated electrochemiluminescence system. Serum levels of OC and undercarboxylated osteocalcin (ucOC) were measured by enzyme-linked immunosorbent assay. Grip strength and timed-up-and-go (TUG) test were measured. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Results: OI patients had significantly higher body mass index (BMI), FBG, and HOMA-IR, but lower HDL-C levels, lower grip strength and longer TUG than control group (all P<0.05). Serum OC, ucOC levels, and ucOC/OC in OI type III patients were significantly lower than those in OI patients with type I and IV. Serum levels of OC, ucOC, and ucOC/OC were negatively correlated to BMI, FBG, insulin levels, and HOMA-IR (all P<0.05). The ratio of ucOC/OC was positively correlated to grip strength (r=0.512, P=0.036), lean mass percentage (%LM) of the total body and limbs, and negatively correlated to fat mass percentage (%FM) of the total body, %FM and fat mass index (FMI) of the trunk (all P<0.05). Conclusions: Obesity, glucolipid metabolic abnormalities, and reduced grip strength were common in children with OI. Circulating osteocalcin and ucOC may play an important role in the regulation of glucose metabolism, as well as the muscle function of children with OI.

Lineage-specific rearrangement of chromatin loops and epigenomic features during adipocytes and osteoblasts commitment.

Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. The processes are driven by the rewiring of chromatin architectures and transcriptomic/epigenomic changes. Here, we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for chromatin loops detection. We also generated matched RNA-seq, ChIP-seq and ATAC-seq data for integrative analysis. After comprehensively comparing adipogenesis and osteogenesis, we quantitatively identified lineage-specific loops and screened out lineage-specific enhancers and open chromatin. We reveal that lineage-specific loops can activate gene expression and facilitate cell commitment through combining enhancers and accessible chromatin in a lineage-specific manner. We finally proposed loop-mediated regulatory networks and identified the controlling factors for adipocytes and osteoblasts determination. Functional experiments validated the lineage-specific regulation networks towards IRS2 and RUNX2 that are associated with adipogenesis and osteogenesis, respectively. These results are expected to help better understand the chromatin conformation determinants of hMSCs fate commitment.

Thickness dependent thermal performance of a poly(3,4-ethylenedioxythiophene) thin film synthesized via an electrochemical approach.

Polymer-based thermal interface materials (TIMs) have attracted wide attention in the field of thermal management because of their outstanding properties including light weight, low cost, corrosion resistance and easy processing. However, the low thermal conductivity (∼0.2 W m-1 K-1) of the intrinsic polymer matrix largely degrades the overall thermal performance of polymer-based TIMs even those containing highly thermal conductive fillers. Hence, enhancing the intrinsic thermal conductivity of the polymer matrix is one of the most critical problems needed to be solved. This paper studies the thermal conductivity of poly(3,4-ethylenedioxythiophene) (PEDOT) films fabricated via cyclic voltammetry. By controlling the number of cycles in the electrochemical synthesis, different thickness of PEDOT films could be obtained. A time-domain thermoreflectance (TDTR) system was employed to evaluate the thermal performance of such as-prepared PEDOT films. We have demonstrated that a PEDOT film with thickness of 40 nm achieves the highest out-of-plane thermal conductivity of ∼0.60 W m-1 K-1, which is almost three folds the thermal conductivity of commercially available pristine PEDOT:PSS film with similar thickness. The X-ray diffraction spectrum reveals that the PEDOT thin film with high crystallinity at the initial stage of electrochemical synthesis leads to enhanced thermal transportation. The findings in this work not only offer an opportunity to fabricate polymer materials exhibiting enhanced thermal conductivity, but also allow one to adjust the thermal performance of conducting polymers in practical applications.

Giant Thermal Transport Tuning at a Metal/Ferroelectric Interface.

Interfacial thermal transport plays a prominent role in the thermal management of nanoscale objects and is of fundamental importance for basic research and nanodevices. At metal/insulator interfaces, a configuration commonly found in electronic devices, heat transport strongly depends upon the effective energy transfer from thermalized electrons in the metal to the phonons in the insulator. However, the mechanism of interfacial electron-phonon coupling and thermal transport at metal/insulator interfaces is not well understood. Here, the observation of a substantial enhancement of the interfacial thermal resistance and the important role of surface charges at the metal/ferroelectric interface in an Al/BiFeO3 membrane are reported. By applying uniaxial strain, the interfacial thermal resistance can be varied substantially (up to an order of magnitude), which is attributed to the renormalized interfacial electron-phonon coupling caused by the charge redistribution at the interface due to the polarization rotation. These results imply that surface charges at a metal/insulator interface can substantially enhance the interfacial electron-phonon-mediated thermal coupling, providing a new route to optimize the thermal transport performance in next-generation nanodevices, power electronics, and thermal logic devices.