Substrate-Tuned Domino Annulation for Selective Synthesis of Poly-substituted Benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-Azaheterocyclic Substituted 2-Arylquinolines.

A domino annulation/oxidation of heterocyclic ketene aminals (HKAs) and 2-aminochalcones has been developed for the selective synthesis of poly-substituted benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-azaheterocyclic substituted 2-arylquinolines. These reactions proceed well under mild conditions without any additives. Plausible mechanisms for such a polycyclic ring system assembly were also proposed. Moreover, benzo[f]imidazo[2,1-a][2,7]naphthyridine 3g displayed a fluorescence effect, demonstrating the potential applications in organic optical materials.

Burden of caregivers who care for oldest-old parents with disability: A cross-sectional study.

OBJECTIVE: To describe the characteristics of oldest-old Chinese with disability and their adult-child caregivers, and the extent to which these characteristics were associated with caregiver burden. METHODS: The study was based on 168 pairs of disabled oldest-old adults and their adult-child caregivers, derived from the Chinese Longitudinal Healthy Longevity Survey. Descriptive analyses of care recipients' and caregivers' characteristics were conducted respectively, in reference to caregiver burden. Statistically significant characteristics identified in these bivariate analyses were then jointly evaluated in multiple linear regression models with caregiver burden as the outcome. RESULTS: Care recipients positive emotion status [(ß = -0.227 (-0.412, -0.042)], multiple chronic disease [(ß = 0.513 (0.081, 0.945)], and caregivers spent more caregiving time [(ß = 0.225 (0.061, 0.389)] were main factors associated with caregiver burden. CONCLUSION: Adult-children caregivers perceived heavier burden if care recipients had low positive emotions, had multiple chronic diseases, and caregivers spent more time caregiving.

Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study.

OBJECTIVES AND METHODS: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them. RESULTS: Lower eBMD were observed in patients with PsA than in controls in both model0 (ß-coefficient=-0.014, p=0.0006) and model1 (ß-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (ß-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture. CONCLUSIONS: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.

Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone mass loss by modulating TRAF6-mediated signaling.

Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by overactivated osteoclastic bone resorption. Targeting TNF receptor-associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast-related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF-κB (RANK) ligand-induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose-dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine in vitro. Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency-induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c-Jun N-terminal kinase (JNK)/p38, NF-κB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker-related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6-mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast-related disorders, including osteoporosis.-Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone mass loss by modulating TRAF6-mediated signaling.

Effect of CD14 polymorphisms on the risk of cardiovascular disease: evidence from a meta-analysis.

BACKGROUND: CD14 polymorphisms are associated with an increased risk of cardiovascular events. So far, many studies have been conducted, whereas the results were not always consistent. MATERIALS AND METHODS: Twenty-six articles involving thirty-seven datasets were recruited to evaluate the association between rs2569190 (9413 patients and 7337 controls), C-159T (4813 patients and 2852 controls) polymorphisms and cardiovascular diseases in a meta-analysis. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals. RESULTS: The strongest association was observed between rs2569190 and CVD in overall population (T vs. C, OR = 1.169, 95% CI: 1.087-1.257, p = 2.44 × 10- 5). Analysis after stratification by ethnicity indicated that rs2569190 was related to CVD in East Asian population (T vs. C, OR = 1.370, 95% CI; 1.226-1.531, p = 2.86 × 10- 8) and a potential relationship in European (T vs. C, OR = 1.100, 95% CI: 1.019-1.189, p = 0.015). In the stratification of endpoints, the associations were found in CHD subgroup (T vs. C, OR = 1.357, 95% CI: 1.157-1.592, p = 2.47 × 10- 7) and in AMI subgroup (T vs. C, OR = 1.152, 95% CI: 1.036-1.281, p = 0.009). However, we did not find any association between C-159T polymorphism with cardiovascular disease under any model. CONCLUSIONS: The SNP rs2569190 significantly contribute to susceptibility and development of cardiovascular disease, particularly in the East Asian population and in the subtype CHD group, in addition, a potential association was observed in the AMI group, T allele acts as a risk factor for cardiovascular disease.

Mechanical Properties and Porosity of Acrylic Cement Bone Loaded with Alendronate Powder.

Aseptic loosening is the most common complication of joint replacement. Previous studies showed that acrylic bone cement loaded with a commercially-available alendronate powder (APAC) had good promise against wear debris-mediated osteolysis for prevention of aseptic loosening. The purpose of the present study was to investigate the effect of adding alendronate powder to an acrylic bone cement on quasi-static mechanical properties (namely, compressive strength, compressive modulus, tensile strength, and flexural strength), fatigue life, porosity, and microstructure of the cement. The results showed that adding up to 1 wt./wt.% alendronate powder exerted no detrimental effect on any of the quasi-static mechanical properties. However, the fatigue life of APAC decreased by between ~17% and ~27 % and its porosity increased by between ~ 5-7 times compared with corresponding values for the control cement (no alendronate powder added). Fatigue life was negatively and significantly correlated with porosity. Considering that fatigue life of the cement plays a significant role in joint replacement survival, clinical use of APAC cannot be recommended.

Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk.

Background: There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk. Aims: To explore the relationship between major depressive disorder (MDD) and fracture risk. Methods: We conducted a nested case-control analysis (32 670 patients with fracture and 397 017 individuals without fracture) and a matched cohort analysis (16 496 patients with MDD and 435 492 individuals without MDD) in the same prospective UK Biobank data set. Further, we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools. We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci. We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study. Results: We found that MDD was associated with a 14% increase in fracture risk (hazard ratio (HR) 1.14, 95% CI 1.14 to 1.15, p<0.001) in the nested case-control analysis, while fracture was associated with a 72% increase in MDD risk (HR 1.72, 95% CI 1.64 to 1.79, p<0.001) in the matched cohort analysis, suggesting a longitudinal and bidirectional relationship. Further, genetic summary data suggested a genetic overlap between MDD and fracture. Specifically, we identified four shared genomic loci, with the top signal (rs7554101) near SGIP1. The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling. We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa. In addition, we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD. Conclusions: The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis. The shared genetic components (such as SGIP1) between the diseases suggest that modulating the endocannabinoid system could be a potential therapeutic strategy for both MDD and bone loss.

Synthesis and structure-activity optimization of 7-azaindoles containing aza-ß-amino acids targeting the influenza PB2 subunit.

The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-ß3- or ß2,3 -amino acids were synthesized possessing a good binding affinity of PB2. The aza-ß-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated. Then a lead HAA-09 was validated, and the attached aza-ß3-amino acid moiety with acyclic tertiary carbon side chain well occupied in the key hydrophobic cavity of PB2_cap binding domain. Importantly, HAA-09 displays potent polymerase inhibition capacity, low cytotoxicity (selectivity index up to 2915) as well as robust anti-viral activity against A/WSN/33 (H1N1) virus and oseltamivir-resistant H275Y variant. Moreover, HAA-09 exhibited druggability with high plasma stability (t1/2 ≥ 12 h) and no obvious hERG inhibition (IC50 > 10 µM). Also, HAA-09 demonstrated a favorable safety profile when orally administrated in healthy mice at a high dose of 40 mg/kg QD for consecutive 3 days. Besides, in vivo therapeutic efficacy (85.7% survival observed at the day 15 post infection) was demonstrated when HAA-09 was administrated orally at 12.5 mg/kg BID starting 48 h post infection for 9 days. These data support that exploring the interactions between side chains on aza-ß3- or ß2,3 -amino acid moieties and hydrophobic pocket of PB2_cap binding domain is a potential medicinal chemistry strategy for developing potent PB2 inhibitors.

Validation of Moorong Self-Efficacy Scale among Chinese stroke survivors.

PURPOSE: To examine the psychometric properties of a Chinese version of the Moorong Self-Efficacy Scale (MSES-C) among stroke survivors. METHODS: A cross-sectional descriptive study was conducted with 160 stroke survivors recruited from the three neurology departments in China. Reliability, concurrent validity, and construct validity of the scale were determined. RESULTS: The MSES-C whole scale showed good internal consistency with a Cronbach's α of 0.953. There was a moderate to a strong positive correlation between the MSES-C and Chinese version of the General Self-Efficacy Scale (r = 0.695, p < 0.000), a strong positive correlation between the MSES-C and Chinese version of the stroke specific self-efficacy scale (r = 0.801, p < 0.000), positive correlations between the MSES-C and Chinese versions of the Modified Barthel Index (r = 0.695, p < 0.000), and a negative correlation between the MSES-C and National Institutes of Health Stroke Scale (r = -0.511, p < 0.000). Known-group validity was also supported. CONCLUSIONS: The MSES-C is a reliable and valid instrument for assessing self-efficacy in Chinese stroke survivors.Implications for RehabilitationThe Chinese version of the Moorong Self-Efficacy Scale demonstrated good internal consistency and showed satisfactory concurrent and construct validity among stroke survivors.The Moorong Self-Efficacy Scale can be used to assess stroke recovery among the Chinese population in clinical and research settings.

Association of spouse's health status with the onset of depressive symptoms in partner: Evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND: This study aimed to evaluate the associations between the multidimensional health status of one spouse and the onset of depressive symptoms in partner, and whether the associations differed by gender and residence. METHODS: We analyzed data from 2401 females and their husbands (scenario 1), and 2830 males and their wives (scenario 2) who participated in the 2011/2012 and 2015 waves of China Health and Retirement Longitudinal Study. Depressive symptoms were assessed using the 10-item Centre for Epidemiological Studies Depression Scale. Multidimensional health indicators included mobility disability, activities of daily living disability, frailty, global cognition, depressive symptoms, comorbidity, and self-reported health. Principal component analysis was used to construct a composite health indicator reflecting overall health status that was then categorized into three groups (poor, moderate, and excellent). Logistic regression models were performed. RESULTS: We observed strong associations of spouse's health status with the onset of depressive symptoms in partner. For instance, females whose husbands had poor overall health status reported more depressive symptoms than those having husbands with excellent overall health after four years (OR: 1.75; 95 % CI: 1.35, 2.26). These associations were statistically significant in rural females and urban males, but surprisingly disappeared in rural males and urban females. LIMITATIONS: No exact timing of depressive symptoms onset. CONCLUSIONS: In Chinese middle-aged and older adults, spouse's health status is associated with depressive symptoms in partner and the associations vary by gender and residence. The findings underscore the importance of considering partner's health status to manage one spouse's mental health.

Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit.

Influenza is an acute respiratory infectious disease caused by influenza virus, leading to huge morbidity and mortality in humans worldwide. Despite the availability of antivirals in the clinic, the emergence of resistant strains calls for antivirals with novel mechanisms of action. The PB2 subunit of the influenza A virus polymerase is a promising target because of its vital role in the 'cap-snatching' mechanism. In this review, we summarize the technologies and medicinal chemistry strategies for hit identification, hit-to-lead and lead-to-candidate optimization, and current challenges in PB2 inhibitor development, as well as offering insights for the fight against drug resistance.

Plasma superoxide dismutase activity in relation to disability in activities of daily living and objective physical functioning among Chinese older adults.

BACKGROUND: This study aimed to examine the associations of plasma superoxide dismutase (SOD) activity, an indicator of oxidative stress, with disability in activities of daily living (ADL) and objective physical functioning among Chinese older adults. METHODS: We used cross-sectional data of 2223 older adults (≥65 years, including 1505 adults≥80 years) from the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study. Plasma SOD activity was assessed by the T-SOD assay kit based on the hydroxylamine method. Outcomes included ADL disability and disability in three objective physical tasks (standing up from a chair, picking up a book from the floor, and turning around 360°). Logistic regression models were used to examine the associations of plasma SOD activity with outcomes. RESULTS: After controlling for age and sex, compared with participants in the lowest quartile group of SOD activity, those in the highest quartile group had 31% lower odds of ADL disability (odds ratio [OR]: 0.69; 95%CI: 0.48, 0.98); 60% lower odds of disability in standing up from a chair (OR: 0.40; 95%CI: 0.25, 0.63); and 57% lower odds of disability in picking up a book from a floor (OR: 0.43; 95%CI: 0.28, 0.65). The results did not change substantially after controlling for additional covariates. We did not observe statistically significant age and sex differences. CONCLUSIONS: Overall, plasma SOD activity was associated with subjectively and objectively measured disability in Chinese older adults, highlighting the potential of SOD activity to serve as a biomarker of physical functioning.

Associations of Serum Albumin With Disability in Activities of Daily Living, Mobility and Objective Physical Functioning Regardless of Vitamin D: Cross-Sectional Findings From the Chinese Longitudinal Healthy Longevity Survey.

Objective: To examine the associations of serum albumin, a nutrition indicator, with disability in activities of daily living (ADL), mobility, and objective physical functioning among Chinese older adults. Materials and Methods: Cross-sectional data of 2233 older adults (≥65 years) who participated in the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study was used. Serum albumin was measured by immunoturbidimetric assay. Physical functioning included subjectively (ADL and mobility) and objectively measured disability (standing up from a chair, picking up a book from the floor, and turning around 360°). Multivariable logistic regression models were performed. Results: After adjusting for age and sex, compared with participants in the lowest quartile group of serum albumin, those in the highest quartile group had 45% lower odds of disability in ADL (odds ratio [OR]: 0.55; 95% confidence interval [CI]: 0.38, 0.80); 48% lower odds of disability in mobility (OR: 0.52; 95% CI: 0.38, 0.71); 46% lower odds of disability in standing up from a chair (OR: 0.54; 95% CI: 0.34, 0.85); and 37% lower odds of disability in picking up a book from the floor (OR: 0.63; 95% CI: 0.40, 0.97). We did not observe a statistically significant interaction effect between serum albumin and vitamin D on disability in physical functioning. Conclusion: Serum albumin level was associated with physical functioning among Chinese older adults, regardless of vitamin D level. The findings indicate that appropriate management of poor nutritional status, in particular low serum albumin levels, may contribute to maintaining physical functioning in older adults.

Serum 25-hydroxyvitamin D in relation to disability in activities of daily living, mobility, and objective physical functioning among Chinese older adults.

OBJECTIVES: Vitamin D deficiency is common among older adults, but its association with physical function is not fully understood. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D and disability in activities of daily living (ADL), mobility, and objective physical functioning among Chinese older adults. METHODS: We used cross-sectional data of 2225 older adults (≥65 years) who participated in the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study. Serum levels of 25-hydroxyvitamin D were measured by enzyme immunoassay. Outcomes included ADL disability, mobility disability, and disability in three objective physical examinations (standing-up from a chair, picking-up a book from the floor, and turning-around 360°). RESULTS: The multiple regression models suggested that participants in the serum 25-hydroxyvitamin D deficiency group had higher odds of ADL disability (OR: 4.08; 95% confidence interval (CI): 2.81, 5.92), mobility disability (OR: 1.59; 95% CI: 1.05, 2.41), and disability in standing-up from a chair (OR: 2.43; 95% CI: 1.60, 3.69), picking-up a book from the floor (OR: 3.09; 95% CI: 2.07, 4.60), and turning-around 360° (OR: 3.09; 95% CI: 2.07, 4.60). Subgroup analyses revealed that some of the above associations (particularly those with mobility disability and disability in turning-around 360°) were only statistically significant among the oldest-old. CONCLUSIONS: Among the oldest-old in China, serum 25-hydroxyvitamin D deficiency was associated with disability in ADL, mobility, and objective physical functioning, highlighting the importance of managing the serum 25-hydroxyvitamin D level to promote healthy aging.

A panel of eight mRNA signatures improves prognosis prediction of osteosarcoma patients.

ABSTRACT: Genetic alterations are vital to the progression of osteosarcoma carcinoma. The present study investigated a panel of gene signatures that could evaluate prognosis in osteosarcoma based on data from the Therapeutically Applicable Research To Generate Effective Treatments initiative. Osteosarcoma messenger RNA (mRNA) profiles and clinical data were downloaded from the therapeutically applicable research to generate effective treatments database. Patients with osteosarcoma were divided into two groups based on findings at diagnosis: with and without metastasis. Differentially expressed mRNAs were compared and analyzed between groups. Univariate and multivariate Cox regression analyses identified a set of eight mRNAs with the ability to classify patients into high-risk and low-risk groups with significantly different overall survival times. Further analysis indicated that the eight-mRNA signature was an independent prognostic factor after adjusting for other clinical factors. Receiver operating characteristic curve analysis demonstrated a good performance of the eight-mRNA signature. Further, the biological processes and signaling pathways of the eight-mRNA signature were reviewed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes resources. Finally, the results of the TCGA analysis were verified by other cohorts from Gene Expression Omnibus database. The identification of an eight-mRNA signature not only provides a prognostic biomarker of osteosarcoma but also offers the potential of novel therapeutic targets for its treatment.

Oral Bisphosphonate Therapy for Osteogenesis Imperfecta: A Systematic Review and Meta-Analysis of Six Randomized Placebo-Controlled Trials.

OBJECTIVE: To assess the effectiveness and safety of oral bisphosphonates in increasing bone mineral density (BMD), reducing fractures, and improving clinical function in patients with osteogenesis imperfecta (OI). METHODS: Studies were eligible for inclusion if they were randomized controlled trials of directly comparing oral bisphosphonate therapy with placebo-group in OI patients. Data synthesis regarding to bone mineral density as measured by dual-energy X-ray absorptiometry (DEXA), decreased fracture incidence, change in biochemical markers of bone and mineral metabolism, bone histology, growth, bone pain, quality of life, and others were assessed, and meta-analysis done when possible. RESULTS: From 98 potential references and six randomized controlled studies a total of 263 participants receiving oral bisphosphonates and 143 placebo treatments contributed data to meta-analysis. Pooled meta-analysis of three studies suggested that there was significant difference between bisphosphonate treated group and placebo in number of patients with at least one fracture (mean difference 0.53, 95% confidence interval 0.32-0.89, P = 0.02). Pooled meta-analysis of two studies suggested that significant difference was noted between bisphosphonate treated group and placebo in mean percentage change in spine BMD (T-score) (mean difference 28.43, 95% confidence interval 7.09-49.77, P = 0.009). The similar effect was shown in the term of mean change (Z-score) in spine BMD. CONCLUSIONS: Significant improvement in lumbar areal BMD in patients affected with OI has been shown when treated with oral bisphosphonates, even though only a small population was enrolled. We cannot draw a definite conclusion that the increase in BMD can be translated into fracture reduction and clinical functional improvement. The optimal method, dose, type, initiation, and duration of oral bisphosphonates therapy still remains unclear. Well-designed, adequately-powered, placebo-controlled RCTs investigating the effects of oral bisphosphonates on fractures reduction and improvement in quality of life in both children and adults are studied here.

Reversibly Transforming a Highly Swollen Polyelectrolyte Hydrogel to an Extremely Tough One and its Application as a Tubular Grasper.

Poly(2-acrylamido-2-methyl-1-propanesulfonic acid) and its copolymer hydrogels are typical polyelectrolyte gels with extremely high swelling capacity that are widely used in industry. It's common to consider these hydrogels as weak materials that are difficult to toughen. Reported here is a facile strategy to transform swollen and weak poly(acrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic acid) [P(AAm-co-AMPS)] hydrogels to tough ones by forming strong sulfonate-Zr4+ metal-coordination complexes. The resultant hydrogels with moderate water content possess high stiffness, strength, and fracture energy, which can be tuned over 3-4 orders of magnitude by controlling the composition and metal-to-ligand ratio. Owing to the dynamic nature of the coordination bonds, these hydrogels show rate- and temperature-dependent mechanical performances, as well as good self-recovery properties. This strategy is universal, as manifested by the drastically improved mechanical properties of hydrogels of various natural and synthetic sulfonate-containing polymers. The toughened hydrogels can be converted to the original swollen ones by breaking up the metal-coordination complexes in alkaline solutions. The reversible brittle-tough transition and concomitant dramatic volume change of polyelectrolyte hydrogels afford diverse applications, as demonstrated by the design of a tubular grasper with holding force a thousand times its own weight for objects with different geometries. It is envisioned that these hydrogels enable versatile applications in the biomedical and engineering fields.

Identification of PIEZO1 polymorphisms for human bone mineral density.

Bone mineral density (BMD) is a key indicator for diagnosis and treatment for osteoporosis; the reduction of BMD could increase the risk of osteoporotic fracture. It was very recently found that Piezo1 mediated mechanically evoked responses in bone and further participated in bone formation in mice. Here, we performed cross phenotype meta-analysis for human BMD at lumbar spine (LS), femoral neck (FN), distal radius/forearm (FA) and heel and screened out 14 top SNPs for PIEZO1, these SNPs were overlapped with putative enhancers, DNase-I hypersensitive sites and active promoter flanking regions. We found that the signal of the best SNP rs62048221 was mainly from heel ultrasound estimated BMD (-0.02 SD per T allele, P = 8.50E-09), where calcaneus supported most of the mechanical force of body when standing, walking and doing physical exercises. Each copy of the effect allele T of SNP rs62048221 was associated with a decrease of 0.0035 g/cm2 BMD (P = 4.6E-27, SE = 0.0003) in UK Biobank data within 477,760 samples. SNP rs62048221 was located at the enhancer region (HEDD enhancer ID 2331049) of gene PIEZO1, site-directed ChIP assays in human mesenchymal stem cells (hMSCs) showed significant enrichment of H3K4me1 and H3K27ac in this region, luciferase assays showed that rs62048221 could significantly affect the activity of the enhancer where it resides. Our results first suggested that SNP rs62048221 might mediate the PIEZO1 expression level via modulating the activity of cis-regulatory elements and then further affect the BMD.

[Biomechanical strength of bone cement impregnated with diphosphonate].

OBJECTIVE: To investigate the biomechanical strength of diphosphonate impregnated bone cement (DIBC). METHODS: DIBC specimens were manufactured and randomly assigned to the control groups and the DIBC groups. According to the corresponding ASTM/ISO standards, the static biomechanical strength and the fatigue limit were tested systematically. The particle size distribution of diphosphonate powder was analyzed with the laser light scattering method. The fatigue test results, given as number of cycles-to-failure, were analyzed using the linearized format of the two-parameter Weibull function. RESULTS: With the drug load increased, there was a slight increase in static biomechanical strength and a moderate decrease in fatigue limit, both with statistical significance. When immersed in PBS before the tests, the DIBC specimens presented an overall significant decrease of static biomechanical strength and fatigue limit. The profile of drug particle sizes presented a normal distribution. CONCLUSIONS: The adopted diphosphonate is a much homogeneous powder which contains particles with a low range of sizes. The impregnation of diphosphonate exerted no or less negative effect on the biomechanical strength of the acrylic bone cement, of which the static strength of DIBC is maintained high above the ASTM/ISO standards.