Inflammatory bowel disease and osteoporosis: Common genetic effects, pleiotropy, and causality.

INTRODUCTION: Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP. MATERIALS AND METHODS: Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD. RESULTS: LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD. CONCLUSIONS: Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP.

TBN as Organic Redox Cocatalyst for Oxidative Tiffeneau-Demjanov-Type Rearrangement Using O2 as Sole Oxidant.

The Tiffeneau-Demjanov-type rearrangement is a ring-expansion reaction involving the cationic rearrangement of cyclic alcohols. The carbocation intermediates can be generated in situ via various means, including Wacker oxidation. In near recent reports on the reinvestiagtions by Wahl et al. (Sietmann, J.; Tenberge, M.; Wahl, J. M. Wacker Oxidation of Methylenecyclobutanes: Scope and Selectivity in an Unusual Setting. Angew. Chem., Int. Ed. 2023, 62, e202215381) and Zhu et al. (Feng, Q.; Wang, Q.; Zhu, J.-P. Oxidative Rearrangement of 1,1-Disubstituted Alkenes to Ketones. Science 2023, 379, 1363-1368), stoichiometric oxidants were involved. In this work, we report the Tiffeneau-Demjanov-type rearrangement can be smoothly promoted by the Pd-TBN cocatalyzed aerobic Wacker oxidation using molecular oxygen as the sole oxidant. tert-Butanol is essential for achieving high yields. Since the first report by Grigg et al. in 1977 (Boontanonda, P.; Grigg, R. J. Palladium (II)-Catalysed Ring Expansion of Methylenecyclobutanes and Related Systems. J. Chem. Soc. Chem. Commun. 1977, 17, 583-584), the five-decade journey of Pd-catalyzed Tiffeneau-Demjanov-type rearrangement returns to the aerobic again.

Muscle-origin creatinine-cystatin C ratio is an osteoporosis marker in individuals with normal renal function: evidence from observational and Mendelian randomization analysis.

Background: Creatinine-cystatin C ratio (CCR) has been demonstrated as an objective marker of sarcopenia in clinical conditions but has not been evaluated as an osteoporosis marker in individuals with normal renal function. Methods: We selected 271,831 participants with normal renal function from UK Biobank cohort. Multivariable linear/logistic regression and Cox proportional hazards model were used to investigate the phenotypic relationship between CCR and osteoporosis in total subjects and gender-stratified subjects. Based on the genome-wide association study (GWAS) data, linkage disequilibrium regression (LDSC) and Mendelian randomization (MR) analysis were performed to reveal the shared genetic correlations and infer the causal effects, respectively. Results: Amongst total subjects and gender-stratified subjects, serum CCR was positively associated with eBMD after adjusting for potential risk factors (all P<0.05). The multivariable logistic regression model showed that the decrease in CCR was associated with a higher risk of osteoporosis/fracture in all models (all P<0.05). In the multivariable Cox regression analysis with adjustment for potential confounders, reduced CCR is associated with the incidence of osteoporosis and fracture in both total subjects and gender-stratified subjects (all P<0.05). A significant non-linear dose-response was observed between CCR and osteoporosis/fracture risk (P non-linearity < 0.05). LDSC found no significant shared genetic effects by them, but PLACO identified 42 pleiotropic SNPs shared by CCR and fracture (P<5×10-8). MR analyses indicated the causal effect from CCR to osteoporosis/fracture. Conclusions: Reduced CCR predicted increased risks of osteoporosis/fracture, and significant causal effects support their associations. These findings indicated that the muscle-origin serum CCR was a potential biomarker to assess the risks of osteoporosis and fracture.

Genetic effects and causal association analyses of 14 common conditions/diseases in multimorbidity patterns.

BACKGROUND: Multimorbidity has become an important health challenge in the aging population. Accumulated evidence has shown that multimorbidity has complex association patterns, but the further mechanisms underlying the association patterns are largely unknown. METHODS: Summary statistics of 14 conditions/diseases were available from the genome-wide association study (GWAS). Linkage disequilibrium score regression analysis (LDSC) was applied to estimate the genetic correlations. Pleiotropic SNPs between two genetically correlated traits were detected using pleiotropic analysis under the composite null hypothesis (PLACO). PLACO-identified SNPs were mapped to genes by Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA), and gene set enrichment analysis and tissue differential expression were performed for the pleiotropic genes. Two-sample Mendelian randomization analyses assessed the bidirectional causality between conditions/diseases. RESULTS: LDSC analyses revealed the genetic correlations for 20 pairs based on different two-disease combinations of 14 conditions/diseases, and genetic correlations for 10 pairs were significant after Bonferroni adjustment (P<0.05/91 = 5.49E-04). Significant pleiotropic SNPs were detected for 11 pairs of correlated conditions/diseases. The corresponding pleiotropic genes were differentially expressed in the brain, nerves, heart, and blood vessels and enriched in gluconeogenesis and drug metabolism, biotransformation, and neurons. Comprehensive causal analyses showed strong causality between hypertension, stroke, and high cholesterol, which drive the development of multiple diseases. CONCLUSIONS: This study highlighted the complex mechanisms underlying the association patterns that include the shared genetic components and causal effects among the 14 conditions/diseases. These findings have important implications for guiding the early diagnosis, management, and treatment of comorbidities.

Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

Accelerated biological aging as a potential risk factor for rheumatoid arthritis.

OBJECTS: Previous studies have suggested a potential correlation between rheumatoid arthritis (RA) and biological aging, but the intricate connections and mechanisms remain elusive. METHODS: In our study, we focused on two specific measures of biological age (PhenoAge and BioAge), which are derived from clinical biomarkers. The residuals of these measures, when compared to chronological age, are defined as biological age accelerations (BAAs). Utilizing the extensive UK Biobank dataset along with various genetic datasets, we conducted a thorough assessment of the relationship between BAAs and RA at both the individual and aggregate levels. RESULTS: Our observational studies revealed positive correlations between the two BAAs and the risk of developing both RA and seropositive RA. Furthermore, the genetic risk score (GRS) for PhenoAgeAccel was associated with an increased risk of RA and seropositive RA. Linkage disequilibrium score regression (LDSC) analysis further supported these findings, revealing a positive genetic correlation between PhenoAgeAccel and RA. PLACO analysis identified 38 lead pleiotropic single nucleotide polymorphisms linked to 301 genes, providing valuable insights into the potential mechanisms connecting PhenoAgeAccel and RA. CONCLUSION: In summary, our study has successfully revealed a positive correlation between accelerated biological aging, as measured by BAAs, and the susceptibility to RA.

Unraveling the relationship between high-sensitivity C-reactive protein and frailty: evidence from longitudinal cohort study and genetic analysis.

BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

RIPK1 inhibitor ameliorates pulmonary injury by modulating the function of neutrophils and vascular endothelial cells.

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

The metabolism-related lncRNA signature predicts the prognosis of breast cancer patients.

Long non-coding RNAs (lncRNAs) involved in metabolism are recognized as significant factors in breast cancer (BC) progression. We constructed a novel prognostic signature for BC using metabolism-related lncRNAs and investigated their underlying mechanisms. The training and validation cohorts were established from BC patients acquired from two public sources: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The prognostic signature of metabolism-related lncRNAs was constructed using the least absolute shrinkage and selection operator (LASSO) cox regression analysis. We developed and validated a new prognostic risk model for BC using the signature of metabolism-related lncRNAs (SIRLNT, SIAH2-AS1, MIR205HG, USP30-AS1, MIR200CHG, TFAP2A-AS1, AP005131.2, AL031316.1, C6orf99). The risk score obtained from this signature was proven to be an independent prognostic factor for BC patients, resulting in a poor overall survival (OS) for individuals in the high-risk group. The area under the curve (AUC) for OS at three and five years were 0.67 and 0.65 in the TCGA cohort, and 0.697 and 0.68 in the GEO validation cohort, respectively. The prognostic signature demonstrated a robust association with the immunological state of BC patients. Conventional chemotherapeutics, such as docetaxel and paclitaxel, showed greater efficacy in BC patients classified as high-risk. A nomogram with a c-index of 0.764 was developed to forecast the survival time of BC patients, considering their risk score and age. The silencing of C6orf99 markedly decreased the proliferation, migration, and invasion capacities in MCF-7 cells. Our study identified a signature of metabolism-related lncRNAs that predicts outcomes in BC patients and could assist in tailoring personalized prevention and treatment plans.

PKM2 is a Novel Osteoporosis-Associated Protein in Chinese.

Purpose:Osteoporosis is characterized by low bone mineral density (BMD) and high risk of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. This study was to identify PBM-expressed proteins significant for osteoporosis in Chinese Han elderly population (>65 years), and focused on two phenotypes of osteoporosis: low BMD and OF. METHODS: Label-free quantitative proteomics was employed to profile PBM proteome and to identify differentially expressed proteins (DEPs) between OF (N=27) vs. non-fractured (NF, N=24) subjects and between low BMD (N=12) vs. high BMD (N=12) subjects in women. Western blotting (WB) was conducted to validate differential expression, and ELISA to evaluate translational value for secretory protein of interest. RESULTS: We discovered 59 DEPs with fold change (FC)>1.3 (P<1×10-5), and validated the significant up-regulation of pyruvate kinase isozyme 2 (PKM2) with osteoporosis (P<0.001). PKM2 protein upregulation with OF was replicated with PBM in men (P=0.04). Plasma PKM2 protein level was significantly elevated with OF in an independent sample (N=100, FC=1.68, P=0.01). Pursuant functional assays showed that extracellular PKM2 protein supplement not only promoted monocyte trans-endothelial migration, growth, and osteoclast differentiation (marker gene expression), but also inhibited osteoblast growth, differentiation (ALP gene expression), and activity. CONCLUSION: The above findings suggest that PKM2 protein is a novel osteoporosis-associated functional protein in Chinese Han elderly population. It may serve as a risk biomarker and drug target for osteoporosis.

High sensitivity C-reactive protein and prediabetes progression and regression in middle-aged and older adults: A prospective cohort study.

BACKGROUND: This study aimed to investigate the effect of systemic inflammation, assessed by high sensitivity C-reactive protein (hs-CRP) levels, on prediabetes progression and regression in middle-aged and older adults based on the China Health and Retirement Longitudinal Study (CHARLS). METHODS: Participants with prediabetes from CHARLS were followed up 4 years later with blood samples collected for measuring fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The level of hs-CRP was assessed at baseline and categorized into tertiles (low, middle, and high groups). Prediabetes at baseline and follow-up was defined primarily according to the American Diabetes Association (ADA) criteria. Logistic regression models were used to estimate the odds ratios (ORs) and confidence intervals (CIs). We also performed stratified analyses according to age, gender, BMI, the presence of hypertension, and the disease history of heart disease and dyslipidemia and sensitivity analyses excluding a subset of participants with incomplete data. RESULTS: Of the 2,874 prediabetes included at baseline, 834 participants remained as having prediabetes, 146 progressed to diabetes, and 1,894 regressed to normoglycemia based on ADA criteria with a 4 year follow-up. After multivariate logistics regression analysis, prediabetes with middle (0.67-1.62 mg/L) and high (>1.62 mg/L) hs-CRP levels had an increased incidence of progressing to diabetes compared with prediabetes with low hs-CRP levels (<0.67 mg/L; OR = 1.846, 95%CI: 1.129-3.018; and OR = 1.632, 95%CI: 0.985-2.703, respectively), and the incidence of regressing to normoglycemia decreased (OR = 0.793, 95%CI: 0.645-0.975; and OR = 0.769, 95%CI: 0.623-0.978, respectively). Stratified analyses and sensitivity analyses showed consistent results. CONCLUSIONS: Low levels of hs-CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes.

Telomere Length Is a Driving Hallmark for Aging-Related Biochemical Hallmarks: Evidence From the Shared Genetic Effect and Causal Inference.

Telomere shortening is an important sign and driving factor of aging, but its association mechanisms and causal effects with other aging-related biochemical hallmarks are largely unknown. This study first performed comprehensive genetic analyses (eg, shared genetic analysis, pleiotropic analysis, and gene enrichment analysis) to detect the underlying molecular mechanisms for the associations between telomere length (TL) and aging-related biochemical hallmarks. Then, further bidirectional Mendelian randomization (MR) analyses investigated the causal effects between TL and other biochemical hallmarks. The genetic correlations were negative between TL and growth differentiation factor-15 (GDF15) (p = .024), C-reactive protein (p = .007), hemoglobin A1c (p = .007), and red blood cell (RBC) (p = .022), but positive between TL and insulin-like growth factor 1 (IGF-1) (p = .002) and white blood cell counts (p = .007). The increased TL has causal effects on the low levels of GDF15 (p = 3.73E-06), sex hormone binding globulin (p = 6.30E-06), testosterone (p = 5.56E-07), fasting insulin (p = 2.67E-05), and RBC (p = 1.54E-05), but the higher levels of IGF-1 (p = 3.24E-07). In conclusion, the observed phenotypic correlations between TL and aging-related biochemical hallmarks may arise from a combination of shared genetic components and causal effects. Telomere length is regarded as a driving hallmark for aging-related biochemical hallmarks.

A constitutive serine protease inhibitor suppresses herbivore performance in tea (Camellia sinensis).

Protease inhibitors promote herbivore resistance in diverse plant species. Although many inducible protease inhibitors have been identified, there are limited reports available on the biological relevance and molecular basis of constitutive protease inhibitors in herbivore resistance. Here, we identified a serine protease inhibitor, CsSERPIN1, from the tea plant (Camellia sinensis). Expression of CsSERPIN1 was not strongly affected by the assessed biotic and abiotic stresses. In vitro and in vivo experiments showed that CsSERPIN1 strongly inhibited the activities of digestive protease activities of trypsin and chymotrypsin. Transient or heterologous expression of CsSERPIN1 significantly reduced herbivory by two destructive herbivores, the tea geometrid and fall armyworm, in tea and Arabidopsis plants, respectively. The expression of CsSERPIN1 in Arabidopsis did not negatively influence the growth of the plants under the measured parameters. Our findings suggest that CsSERPIN1 can inactivate gut digestive proteases and suppress the growth and development of herbivores, making it a promising candidate for pest prevention in agriculture.

Natural phytoalexins inspired the discovery of new biphenyls as potent antifungal agents for treatment of invasive fungal infections.

With the aim of discovering novel and effective antifungal agents derived from natural sources, a series of new biphenyls based on natural biphenyl phytoalexins were designed, synthesized and evaluated for their antifungal activities against four invasive fungi. By modifying the two benzene rings of noraucuparin, a well-known biphenyl phytoantitoxin, some promising compounds with remarkable antifungal activity were discovered. Notably, compounds 23a, 23e and 23h exhibited potent activities and a broad antifungal spectrum with low MICs of 0.25-16 µg/mL, which were 8-256-fold more potent than that of the lead compound noraucuparin. Particularly, they displayed comparable potency to the positive control amphotericin B against Cryptococcus neoformans. Some interesting structure-activity relationships have also been discussed. Preliminary mechanism studies revealed that compound 23h might achieve its rapid fungicidal activity by disrupting the fungal cell membrane. Moreover, compound 23h exhibited significant inhibition against some virulence factors of Cryptococcus neoformans, low toxicity to normal human cells, as well as favorable pharmacokinetic and drug-like properties. The above results evidenced that the development of new antifungal candidates derived from natural phytoalexins was a bright and promising strategy.

[Omalizumab Treats Aspirin-Induced Asthma Complicated With Nasosinusitis and Otitis Media:Report of One Case].

Omalizumab,as a biological agent targeting IgE,is a recombinant humanized monoclonal antibody and the first targeted drug approved for treating moderate-to-severe bronchial asthma.By reviewing one case of aspirin-induced asthma complicated with nasosinusitis and otitis media,we discussed the value of omalizumab in the treatment of asthma and its complications,aiming to provide a reference for clinical practice.

Serum cholinesterase as a new nutritional indicator for predicting weaning failure in patients.

Aim: The objective of this study is to examine the correlation between patient serum cholinesterase (SCHE) concentration and weaning failure in the context of invasive mechanical ventilation (IMV), as well as to identify predictors of ventilator weaning failure. Additionally, this study investigates the potential relationship between SCHE and nutritional risk for developing more effective weaning strategies. Method: A retrospective observational study was conducted. The sample was collected from 227 patients with IMV over 48 h who underwent SBT before weaning. Relevant experimental samples and data collection were analyzed at the time of patient admission and before the initiation of the SBT. The correlation between SCHE and weaning failure was determined by multifactorial logistic regression and propensity matching scores. Results: Weaning was successful in 127 patients and failed in 100 patients. Depending on the difficulty of weaning, 55 of these patients had difficulty in weaning and 45 had long-term weaning. In the crude cohort, experimental data collected on the day of SBT showed that SCHE concentrations were higher in patients with successful weaning than in those with failed weaning (4,514 u/l vs. 3,190 u/l p < 0.01). The critical value for predicting weaning failure was SCHE 3,228 u/l (p < 0.01). Ventilator weaning failure was predicted by multifactorial logistic regression analysis of SCHE, heart rate, and PaO2 before SBT, with SCHE predicting ventilator weaning failure (AUC 0.714; 95% CI 0.647-0.782) better than heart rate (AUC 0.618; 95% CI 0.545-0.690), PaO2 (AUC 0.59; 95% CI 0.515-0.664). After propensity-matched scores, SCHE remained an independent predictor of weaning failure (p = 0.05). And the SCHE concentration was strongly correlated with the patient's weaning difficulties (p < 0.01). The Nutrition Risk in Critically Ill (NUTRIC) score was also significantly correlated with SCHE according to Spearman's correlation analysis (p < 0.01). Conclusion: Our study revealed that the patients who experienced weaning failure exhibited lower SCHE values compared to those who successfully underwent weaning. Before spontaneous breathing trial (SBT), SCHE, heart rate, and PaO2 were identified as independent predictors of weaning failure. Following propensity score matching (PSM), SCHE and heart rate remained independent predictors. Patients with SCHE levels below 3,228 u/l should undergo careful evaluation before weaning. Our findings suggest that malnutrition may be a contributing factor to weaning failure in patients.

The Casual Association Inference for the Chain of Falls Risk Factors-Falls-Falls Outcomes: A Mendelian Randomization Study.

Previous associations have been observed not only between risk factors and falls but also between falls and their clinical outcomes based on some cross-sectional designs, but their causal associations were still largely unclear. We performed Mendelian randomization (MR), multivariate Mendelian randomization (MVMR), and mediation analyses to explore the effects of falls. Our study data are mainly based on White European individuals (40-69 years) downloaded from the UK Biobank. MR analyses showed that osteoporosis (p = 0.006), BMI (p = 0.003), sleeplessness (p < 0.001), rheumatoid arthritis (p = 0.001), waist circumference (p < 0.001), and hip circumference (p < 0.001) have causal effects on falls. In addition, for every one standard deviation increase in fall risk, the risk of fracture increased by 1.148 (p < 0.001), the risk of stroke increased by 2.908 (p = 0.003), and a 1.016-fold risk increase in epilepsy (p = 0.009). The MVMR found that sleeplessness is an important risk factor for falls. Finally, our mediation analyses estimated the mediation effects of falls on the hip circumference and fracture (p < 0.001), waist circumference and epilepsy (p < 0.001), and sleeplessness and fracture (p = 0.005). Our study inferred the causal effects between risk factors and falls, falls, and outcomes, and also constructed three causal chains from risk factors → falls → falls outcomes.

A mechanism study of DUSP1 in inhibiting malignant progression of endometrial carcinoma by regulating ERK/AP-1 axis and dephosphorylation of EPHA2.

Background: Endometrial carcinoma is one of the most common female malignancies worldwide. Based on our preliminary investigation, DUSP1 was identified as a potential biomarker for endometrial carcinoma prognosis, but its function and mechanism remained unclear. Methods: In this study, genes highly correlated with DUSP1 in endometrial cancer were found through correlation analysis, and the promoter sequence of DUSP1 was analyzed by PROMO program. Next-generation phosphorylation mass spectrometry was used to explore new downstream target proteins and pathways of DUSP1 in endometrial carcinoma. The mRNA and protein expression levels were detected by real-time quantitative PCR, immunohistochemistry and Western blotting. The cell survival and proliferation were analyzed by CCK8 assay, cell apoptosis was analyzed by Annexin-V-APC and PI dual staining assay, and the cell invasion was analyzed by Transwell method. Results: (1) There was a high correlation between the expression of DUSP1 and the genes involved in AP-1 complex and its co-expression network. (2) Promoter sequence analysis predicted that the members of AP-1 complex might be the upstream transcriptional regulators of DUSP1. (3) Transfection experiments proved DUSP1 can inhibit tumor growth and invasion, and promote apoptosis by regulating ERK pathway. (4) The results of phosphorylation mass spectrometry showed that overexpression of DUSP1 mainly dephosphorylated EPHA2 in endometrial carcinoma, and co-immunoprecipitation verified the protein interaction between DUSP1 and EPHA2. (5) Overexpression or knockdown of EPHA2 significantly changed the phosphorylation level of EPHA2. (6) The expression of EPHA2 protein was high in patients with more aggressive endometrial cancer. (7) Using EPHA2 inhibitor could significantly slow down the growth rate of tumor cells. Conclusion: (1) There exists a mutual regulation relationship between DUSP1 and AP-1 co-expression network in endometrial carcinoma. (2) It is reported for the first time that DUSP1 phosphatase acts on the ser899 site of EphA2 in endometrial carcinoma. (3) DUSP1 can inhibit tumor growth and invasion, and promote apoptosis by regulating MAPK pathway through directly dephosphorylating ERK, or by dephosphorylating EPHA2.

Air pollution, genetic factors and the risk of osteoporosis: A prospective study in the UK biobank.

Purpose: To reveal relationship between air pollution exposure and osteoporosis (OP) risk. Methods: Based on large-scale data from the UK Biobank, we evaluated the relationship between OP risk and several air pollutants. Then air pollution scores (APS) were constructed to assess the combined effects of multiple air pollutants on OP risk. Finally, we constructed a genetic risk score (GRS) based on a large genome-wide association study of femoral neck bone mineral density and assessed whether single or combined exposure to air pollutants modifies the effect of genetic risk on OP and fracture risk. Results: PM2.5, NO2, NOx, and APS were significantly associated with an increased risk of OP/fracture. OP and fracture risk raised with increasing concentrations of air pollutants: compared to the lowest APS quintile group, subjects in the highest quintile group had a hazard ratio (HR) (95% CI) estimated at 1.140 (1.072-1.213) for OP and 1.080 (1.026-1.136) for fracture. Moreover, participants with low GRS and the highest air pollutant concentration had the highest risk of OP, the HRs (95% CI) of OP were 1.706 (1.483-1.964), 1.658 (1.434-1.916), 1.696 (1.478-1.947), 1.740 (1.506-2.001) and 1.659 (1.442-1.908), respectively, for PM2.5, PM10, PM2.5-10, NO2, and NOx. Similar results were also observed for fractures. Finally, we assessed the joint effect of APS and GRS on the risk of OP. Participants with higher APS and lower GRS had a higher risk of developing OP. Similar results were observed in the joint effect of GRS and APS on fracture. Conclusions: We found that exposure to air pollution, individually or jointly, could improve the risk of developing OP and fractures, and increased the risk by interacting with genetic factors.

Establishment of reference intervals for bone turnover markers in healthy Chinese older adults.

BACKGROUND: Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. AIM: To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. SUBJECTS AND METHODS: A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; ß cross-linked C-terminal telopeptide of type I collagen, ß-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. RESULTS: The reference intervals of P1NP, ß-CTX and P1NP/ß-CTX were 15.8-119.9 ng/mL, 0.041-0.675 ng/mL and 49.9-1261.5 for females and 13.6-111.4 ng/mL, 0.038-0.627 ng/mL and 41.0-1269.1 for males, respectively. In the multiple linear regression analysis, only ß-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p < .05). CONCLUSION: This study established age- and sex-specific reference intervals for BTMs in a large sample of healthy Chinese participants ≥ 50 and < 80 years of age and explored the correlations between BTMs and BMD, which provides an effective reference for the assessment of bone turnover in the clinical practice of osteoporosis.