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Abstract Background Positive self-perception of aging (SPA) is a well-known predictor of longevity, while how and to what extent SPA is linked with all-cause mortality among older adults is still unclear. This study aims to elucidate the relationship between positive SPA and all-cause mortality and its potential mediators among Chinese older adults. Methods This is a 20-year dynamic cohort study conducted among 22,957 older adults aged ≥ 65 years old from a nationally representative sample. Positive SPA was measured using a validated 7-item scale. Potential mediators including health behaviors and social participation were collected using a self-reported questionnaire. Cox proportional hazards regression models were conducted to examine the association between positive SPA and all-cause mortality. A mediation analysis was conducted to determine whether health behaviors and social participation mediated the association between SPA and all-cause mortality. Results Throughout follow-up (median [interquartile range], 46 [21–84] months), all-cause mortality was 87.4%. Compared with older adults with the lowest quartile positive SPA, hazard ratio(HR) of all-cause mortality among older adults with the second, third, and fourth quartile of positive SPA was 0.96(95%CI:0.93-1.00), 0.93(95%CI:0.90–0.99), and 0.92(95%CI:0.87–0.96) respectively after controlling for all potential mediators and covariates. The mediation analysis showed that regular daily vegetable intake, physical activity, and high social participation explained 41.1-48.5% of the variance in the association between positive SPA and all-cause mortality. Conclusions In this cohort study, we found that high positive SPA was associated with decreased all-cause mortality directly, and indirectly through healthy lifestyle behaviors and social participation. These findings suggest that interventions targeted at promoting or maintaining positive SPA may contribute to healthy ageing among older adults in China.

Abstract Background Insulin resistance (IR) is involved in the pathophysiological processes of arrhythmias. Increasing evidence suggests triglyceride and glucose (TyG) index, metabolic score for insulin resistance (METS-IR), triglyceride glucose-body mass index (TyG-BMI), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio are simple and reliable surrogates for IR. Although they have been associated with atrial fibrillation (AF), evidence supporting this is limited. Here, this is the first study to investigate the association between TyG-BMI index and AF recurrence following radiofrequency catheter ablation (RFCA). The performance of the four non-insulin-based IR indexes in predicting AF recurrence after ablation was explored. Methods A total of 2242 AF patients who underwent a de novo RFCA between June 2018 to January 2022 at two hospitals in China were included in this retrospective study. The predictive values of IR indexes for AF recurrence after ablation were assessed. Results During 1-year follow-up, 31.7% of patients experienced AF recurrence. The multivariable analysis revealed that TyG index, METS-IR, and TyG-BMI index were independent risk factors for AF recurrence. Restricted cubic spline analysis revealed a connection between METS-IR, TyG-BMI index, and AF recurrence (P

Osteochondroma is one of the most common benign bone tumors, mainly involving the bone ends of long bones, and involving the spine is rare. It often involves the competing, followed by the thoracic and lumbar spine, and rarely involves the sacrum. We report the imaging findings of a solitary osteochondroma of the sacrum. The patient was a 37-year-old woman who presented clinically with progressive low back pain associated with left buttock pain and discomfort. CT and MRI showed that the lesion originated from the left lamina of S1 and grew anteriorly and superiorly, resulting in compressive resorption of the L5 vertebral bone, left foraminal stenosis and adjacent nerve root swelling. The patient underwent surgery and the mass was completely excised and recovered well postoperatively. Osteochondroma arising from the sacrum is rare and can lead to compressive resorption of adjacent bone, and imaging techniques are conducive to the localization and characterization of the lesion and provide useful information for clinical treatment.

Abstract Aim The association between composite dietary antioxidant index (CDAI) and diabetes remains unknown. Our study was to investigate the association of CDAI with diabetes. Methods A total of 11,956 participants were enrolled from the National Health and Nutrition Examination Surveys (NHANES). The CDAI was calculated from the intake of six dietary antioxidants. Multivariable logistic regressions were performed to explore the associations between CDAI and the prevalence of diabetes and glycemic index. Non-linear associations were explored using restricted cubic splines. Results In the multivariate logistic regression model, the odds ratio (95% confidence interval) of CDAI associating with obesity was 0.98 (0.97-1.00; p = 0.033). Compared with the lowest quartile, the highest quartile was related to 0.84-fold risk of diabetes (0.71–0.99; p = 0.035). However, CDAI was not independently associated with fasting glucose and hemoglobin A1c. Conclusion CDAI was negatively associated with diabetes and the relationship was independent of other traditional risk factors.

Abstract Background Conventional blood and stool tests are normally used for early screening of colorectal cancer (CRC) but the accuracy and efficiency remain to be improved. Recent findings suggest Fusobacterium nucleatum to be a biomarker for CRC. This study evaluated the role of F. nucleatum and developed CRC diagnostic models by combining F. nucleatum with fecal occult blood (FOB), transferrin (TRF), carcinoembryonic antigen (CEA), carbohydrate antigen 19‐9 (CA19‐9), gender, and age. Materials and Methods Candidates including 71 healthy individuals and 59 CRC patients were recruited. Abundance of F. nucleatum in stool or tissue samples was measured by quantitative real‐time PCR. CEA, CA19‐9, TRF, and FOB were measured in parallel. These biomarkers together with genders and ages were the seven parameters used to develop CRC diagnostic models. Ten different machine learning algorithms were tested to achieve the best performance. Results Fecal F. nucleatum abundance was found significantly higher in CRC group compared to healthy group (p = 0.0005). Among the CRC patients, F. nucleatum abundance in tumor tissue was significantly higher than that in paracancerous tissue (p = 0.0087). CRC diagnostic models using different parameters were generated based on Logistic Regression algorithm, which showed good performance. The area under the curve (AUC) score of fecal F. nucleatum as the single diagnostic biomarker was 0.68 while the accuracy was 0.56. The diagnostic performance was obviously improved with the highest AUC (0.93) and accuracy (0.87) achieved when using all the 7 clinical parameters. The combination F. nucleatum + FOB + gender + age had the second highest AUC (0.92) and accuracy (0.85). A more utilitarian model using F. nucleatum + FOB showed relatively high AUC at 0.86 and accuracy at 0.81. Conclusions F. nucleatum is valuable for CRC diagnosis. Combination of different clinical parameters could significantly improve CRC diagnostic performance. The combination F. nucleatum + FOB + gender + age may be an effective and noninvasive method for clinical application.

In this work the authors investigate the structure-sequence dependance. The ability to design and characterize proteins at interfaces between three common folds suggests that fold switching is an intrinsic feature of protein folding language and likely important in the evolution of protein structure and function.

BackgroundEpicardial adipose tissue (EAT) is related to atrial fibrillation. The association between EAT volume and premature ventricular complexes (PVCs) remains unclear. Our study aimed to investigate the effect of EAT volume on the risk of frequent PVCs and burden levels of PVCs.MethodsThis observational study retrospectively recruited consecutive patients who had consultation between 2019 and 2021 at the First Affiliated Hospital of Zhengzhou University. Frequent PVC patients (n = 402) and control patients (n = 402) undergoing non-contrast computed tomography (CT) were enrolled. We selected evaluation criteria for the conduct of a 1:1 propensity score matching (PSM) analysis. Multivariable logistic analysis was used to investigate factors related to frequent PVCs. Furthermore, the determinants of EAT volume and the burden levels of PVCs were evaluated.ResultsPatients with PVCs had a significantly larger EAT volume than control patients. EAT volume was significantly larger in male PVC patients with BMI ≥24 kg/m2, diabetes mellitus, and E/A ratio

Abstract Background Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS. Objectives This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults. Methods This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration. Results Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17–2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P

Ultrasonic pulse frequency tungsten inert gas welding technology was adopted to join Ti-22Al-25Nb alloy. There were some cracks in the Ti-22Al-25Nb alloy weld joint after post-weld heat treatment. The hardness and Young’s modulus of α2, O, and β/B2 phases in Ti-22Al-25Nb alloy were examined with an in situ nanoindentation technique. The phase transition stresses of three different phases in the weld joint of Ti-22Al-25Nb alloy were analyzed to explain why cracks occur in the weld joint of Ti-22Al-25Nb alloy during post-weld heat treatment. The results show that mean hardness is highest for the α2 phase, second-highest for the O phase, and lowest for the β/B2 phase; the mean Young’s modulus has the same trend in Ti-22Al-25Nb alloy. Phase transition stress results in cracks in the weld joint of Ti-22Al-25Nb alloy during post-weld heat treatment. By improving post-weld heat treatment, the ultimate strength of the Ti-22Al-25Nb alloy weld joints reaches 750 MPa, which is 72.5% that of the base material.

IntroductionFunctional ability (FA) and social participation (SP) are important indicators of healthy aging, both their trajectories are heterogeneous. It is little known about how the SP trajectories affects FA trajectories.MethodsFA was assessed by 20 items covering the ability of meeting basic needs and mobility. SP was assessed by frequency of participating in 10 social activities. Group-based trajectory modeling (GBTM) was used to identify the trajectories of FA and SP of the participants.ResultsTwo FA trajectories were identified: low baseline-decline tendency (16.1%) and high baseline-stable tendency (83.9%) trajectories. Two SP trajectories were also identified: low baseline-stable tendency (58.5%) and high baseline-increase tendency (41.5%) trajectories. After controlling for the potential covariates, participants among the high baseline-increase tendency SP trajectory group also had significantly higher odds ratios to be belonged in high baseline-stable tendency FA trajectory group (ORs = 2.64, 95%CI = 1.98–3.05).ConclusionsHigh-increasing social participation had a protective effect to maintain high baseline-stable tendency functional ability among older adults. These findings suggest social participation appears to have great benefits on promoting healthy aging in China.

AimAdvanced liver fibrosis is independently associated with new onset of atrial fibrillation (AF). Non-invasive liver fibrosis scores are considered an effective strategy for assessing liver fibrosis. This study aimed to investigate the association between advanced liver fibrosis and AF recurrence after ablation in patients with non-alcoholic fatty liver disease (NAFLD).Materials and methodsA total of 345 AF patients with NAFLD who underwent de novo ablation between 2019 and 2020 at two large hospitals in China were included in this study. AF recurrence was defined as the occurrence of atrial arrhythmia for more than 30 s by electrocardiogram or 24 h Holter monitoring after the first 3 months of ablation. Predictive values of non-alcoholic fatty liver disease fibrosis score (NFS) and Fibrosis-4 (FIB-4) scores for AF burden and recurrence after ablation were assessed.ResultsAt the 1 year follow-up after ablation, 38.8% of patients showed recurrence. Patients with recurrence who had higher FIB-4 and NFS scores were more likely to have persistent AF and a duration of AF ≥ 3 years. In Kaplan–Meier analysis, patients with intermediate and high NFS and FIB-4 risk categories had a higher risk of AF recurrence. Compared to patients with the low risk, intermediate and high NFS, and FIB-4 risk were independently associated with AF recurrence in multivariate Cox regression analysis (high risk: NFS, hazard ratio (HR): 3.11, 95% confidence interval (CI): 1.68∼5.76, p < 0.001; FIB-4, HR: 3.91, 95% CI: 2.19∼6.98, p < 0.001; intermediate risk: NFS, HR: 1.85, 95% CI: 1.10∼3.10, p = 0.020; FIB-4, HR: 2.08, 95% CI: 1.27∼3.41, p = 0.003).ConclusionNFS and FIB-4 scores for advanced liver fibrosis are associated with AF burden. Advanced liver fibrosis is independently associated with AF recurrence following ablation. Advanced liver fibrosis might be meaningful in risk classification for patients after AF ablation.

Background: Epicardial adipose tissue (EAT) thickness is an independent predictor for the recurrence of premature ventricular beats after ablation. However, it is unclear whether EAT volume is associated with the recurrence of idiopathic ventricular tachycardia (IVT) following ablation. This study sought to investigate the association between EAT volume and IVT recurrence following radiofrequency ablation for IVT patients. Methods: This retrospective study included 69 IVT patients undergoing computed tomography examination before ablation who underwent their first catheter ablation between 2017 and 2021. The predictive value of EAT volume for IVT recurrence following ablation was assessed. Results: During the follow-up period (median: 540 days; range: 253–929 days), 26.1% (18/69) of the patients experienced IVT recurrence. The cut-off point of EAT volume for predicting IVT recurrence was 160.30 mL, and the area under the curve (AUC) was 0.751 (95% confidence interval (CI): 0.615–0.887) by the receiver operating characteristic curve. Kaplan-Meier analysis showed that patients with larger EAT volumes had higher cumulative rates of IVT recurrence. Multivariable analysis also revealed that EAT volume (per 10 mL increase; hazard ratio (HR): 1.16, 95% CI: 1.03–1.32, p = 0.018) was independently associated with IVT recurrence. Furthermore, patients with an epicardial site of IVT had a significantly larger EAT volume than IVT patients with non-epicardial origins. Conclusions: A larger EAT volume may be associated with IVT recurrence after catheter ablation. EAT volume may be helpful for risk stratification in patients undergoing IVT ablation.

Chen et al. describe a rational design of subtilisin mutants that degrade active RAS by cleaving a conserved sequence in switch 2. They further modified the active site to be dependent on a cofactor to generate high target specificity. Proteases engineered to cleave this region degraded RAS in vitro and in cells with a promise of adaptability for other target proteins too.

PurposeResilience is a multidimensional concept determining healthy aging, however, there were limited studies examining the association between frailty and resilience in detail. In this study, we aimed to examine the association of frailty with three dimensions of resilience-strength, optimism, and tenacity among Chinese older adults.MethodsA cross-sectional study was conducted among 10,209 participants who were sampled by three-stage sampling method, from three cities in China from June 2020 to July 2021. The Chinese version of the Connor–Davidson Resilience Scale (CD-RISC) was used to measure resilience's 3 dimensions (strength, optimism and tenacity), which were converted into quartiles for the analysis. Frailty status was measured using the Chinese version of the FRAIL scale, categorized into robustness, pre-frailty and frailty. Multinomial logistic regression was used to examine associations between frailty status with strength, optimism and tenacity.ResultsThe overall proportions of robustness, pre-frailty, and frailty were 42.7, 48.7, and 8.6%, respectively. After controlling for sociodemographic characteristics, self-rated health, and health behaviors, compared with older adults with the lowest quartile of strength, older adults with the second quartile (odds ratio, OR = 0.67, 95% CI: 0.57–0.78), third quartile (OR = 0.60, 95% CI: 0.50–0.72), and fourth quartile (OR = 0.58, 95% CI: 0.46–0.73) of strength had lower ORs for pre-frailty, and who also had lower ORs (0.44, 95% CI: 0.33–0.58; 0.42, 95% CI: 0.30–0.59; 0.34, 95% CI: 0.20–0.56, respectively) for frailty. There were no homogeneous associations between optimism and tenacity with frailty status.ConclusionHigher strength was associated with lower chance of being pre-frail and frail among Chinese older adults. This finding implies that community-based training programs aiming to enhance psychological resilience, especially strength, may contribute to healthy aging. Future studies should examine the effects of resilience on frailty using longitudinal or experimental study designs in cross-cultural contexts.

PurposeFrailty is an emerging global public health burden. Most existing studies have focused on risk factors for frailty, focusing less on protective factors against frailty. This study aims to examine the association between the sense of coherence (SOC), the most common construct of salutogenesis and frailty status among community-dwelling old adults.MethodA cross-sectional study was conducted among 7,970 old adults aged ≥65 years in three cities in China from June 2019 to October 2020. Frailty was operationalised as the sum of self-reported fatigue, resistance, ambulation, illness, and loss of weight (FRAIL scale). The χ2 test was used to analyse the distribution difference of frailty in demographic, behavioural, and SOC levels. Confounder-adjusted multinomial logistic regression was used to examine the association between SOC and frailty.ResultsThe prevalence of pre-frailty and frailty was 43.1 and 8.0%, respectively. The results of the confounder-adjusted regression showed that older adults with moderate-level SOC (odds ratio, OR: 0.61, 95% CI: 0.54–0.69) and strong-level SOC (OR: 0.55, 0.48–0.64) had lower odds of being pre-frail compared to those with weak SOC. It also showed that older adults with moderate-level SOC (OR: 0.32, 95% CI: 0.27–0.40) and strong-level SOC (OR: 0.22, 95% CI: 0.16–0.29) had lower odds of being frail compared to those with weak SOC.ConclusionSOC may be a protective factor against frailty. Improving SOC may be a strategy to prevent frailty among Chinese community-dwelling older adults.

BackgroundThe World Health Organization proposed a multidimensional concept of healthy aging in 2015; there was limited evidence about how the concept was constructed and measured. The current study aims to develop a health aging scale (HAS) following the WHO framework and validate it using data from the China Health and Retirement Longitudinal Study (CHARLS).MethodsA total of 13,233 adults aged ≥ 45 years old from the CHARLS included in current study. Based on the WHO framework, 37 self-reported indicators were used to determine healthy aging. Exploratory factor analysis and second-order and bi-factor modeling, as well as psychometric coefficients, were used to examine the structure of healthy aging. To assess concurrent validity of the HAS, regression analyses were used to examine the associations of HAS and its subscales with sociodemographic characteristics, health conditions, healthcare utilization and life satisfaction in Wave 1. The predictive validity of HAS and subscales was assessed by their associations with mortality in Wave 2 follow-up using Cox regressions.ResultsThe general HAS and its five subscales were generated according to bi-factor modeling [CFI = 0.949; TLI = 0.942; SRMSR = 0.030; and RMSEA = 0.033 (95% CI, 0.032–0.034)] and psychometric coefficients (ω = 0.903; ωH = 0.692; ECV = 0.459). The general HAS presented solid evidence of concurrent validity with various sociodemographic characteristics, health conditions, healthcare utilization and life satisfaction; and predictive validity with mortality.ConclusionsThe population-based multidimensional healthy aging scale and its subscales can be used to monitor the trajectories of general healthy aging and its subdomains to support the development of healthy aging policies and interventions.

Objective. To analyze the role of PD-1/PD-L1 signaling pathway in regulating T cell activation and secretion of proinflammatory factors in atrial fibrillation. Methods. Forty-five patients with atrial fibrillation admitted to the cardiology department of our hospital from July 2019 to March 2021 were selected to be included in the atrial fibrillation group, and another 45 healthy volunteers were selected as the control group to compare the changes of T cell CD69 and human leukocyte antigen-DR (HLA-DR) expression in the peripheral blood of the two study groups; compare the changes of programmed death factor-1 on CD4+ and CD8+ lymphocytes in the peripheral blood of the two groups (PD-1) expression changes and PD-L1 and PD-L2 expression changes on peripheral blood myeloid dendritic cells (mDCs) cells; compare the changes of interleukin-2, interleukin-6, interleukin-10, and interleukin-17A (IL-2, IL-6, IL-10, and IL-17), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) concentrations on peripheral blood inflammatory factors in the two groups; and isolate the two groups of peripheral blood mDCs cells; α interferon upregulated PD-L1 expression in the cells and analyzed the effect of PD-L1 expression on the ability of mDCs to stimulate T cells to secrete cytokines.Results. The positive expression rates of CD69 and HLA-DR on peripheral blood CD3+ T lymphocytes were significantly higher in patients in the atrial fibrillation group than in the control group, and the differences were statistically significant (P0.05). The positive expression rate of PD-L1 on mDCs cells was significantly lower in patients in the atrial fibrillation group than in the control group (P0.05). The concentrations of IL-2, IL-6, IL-10, and IFN-γ in peripheral blood were significantly higher in patients in the atrial fibrillation group than in the control group (P0.05). In the atrial fibrillation group, the ability of mDCs to stimulate T cells to secrete IL-2 and IFN-γ was significantly higher, and the ability to secrete IL-10 was significantly lower compared with the control group (P0.05). Conclusion. PD-1/PD-L1 signaling pathway may play an immunomodulatory role in the pathogenesis of atrial fibrillation by promoting increased secretion of inflammatory factors through regulating T cell activation.

Self-similar fractals can be generated using subdivision and the subdivision curves/surfaces are actually attractors. Such a connection has been studied between fractals and an extended family of subdivision including stationary and non-stationary schemes. This paper aims to move one step further on such a connection and introduce multiple-function systems, which has a set of function systems and choose one for each step of iteration. These multiple-function systems can be obtained by deriving the iterated function systems based on the subdivision operators and applying some modifications, including deleting some transformations, to them. Such multiple-function systems can be arranged in a tree structure and can generate different attractors along different paths in the tree. Several examples are presented to illustrate the performance of these multiple-function systems.

Abstract Background Atrial fibrillation (AF), a supraventricular arrhythmia that impairs cardiac function, is a main source of morbidity and mortality. Serum‐derived extracellular vesicles (EVs) have been identified to carry potential biomarker or target for the diagnosis and treatment of AF. We intended to dissect out the role of lncRNA MIAT enriched in serum‐derived EVs in AF. Methods MIAT expression was quantified in EVs isolated from serum samples of AF patients. Mouse and cell models of AF were developed after angiotensin II (Ang II) induction. Relationship between MIAT, miR‐485‐5p, and CXCL10 was identified. Ectopic expression and depletion assays were implemented in Ang II‐treated mice or HL‐1 cells, or those co‐cultured with serum‐derived EVs to explore the roles of EV‐carried MIAT. Results MIAT was upregulated in EVs from serum samples of AF patients. Further analysis indicated that MIAT enriched in serum‐derived EVs promoted atrial fibrosis, inflammation and oxidative stress, and aggravated the atrial remodeling and resultant AF. Mechanistically, MIAT bound to miR‐485‐5p and weakened its inhibitory role on the target CXCL10, which was responsible for the role of serum‐derived EV containing MIAT in cellular fibrosis, oxidative stress and inflammation, and atrial remodeling in vivo. Conclusions In conclusion, serum‐derived EV containing MIAT facilitates atrial remodeling and exacerbates the AF by abolishing the miR‐485‐5p‐mediated CXCL10 inhibition. This finding aids in the deeper understanding about the pathophysiology of AF.

High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.

Summary: Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best-known tumor suppressors that promote homology recombination (HR) and arrest cell cycle. However, it remains ambiguous whether and how their E3 ligase activity regulates HR. Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. Depleting LARP7 suppresses the expression of CDK1 complex, arrests the cell at the G2/M DNA damage checkpoint, and reduces BRCA2 phosphorylation, which thereby facilitates RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast cancer patients leads to chemoradiotherapy resistance both in vitro and in vivo. Altogether, this study unveils a mechanism by which BRCA1/BARD1 control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin β4 (Tβ4) through stepwise hydrolysis, involving meprin-α and prolyl endopeptidase (PREP). It is well acknowledged that AcSDKP exerts beneficial effects on multiple cardiovascular and renal diseases. However, the functional role of AcSDKP in inflammatory bowel disease (IBD) remains poorly understood. Here, we aimed to assess the content of AcSDKP in patients with IBD and investigate the impact of AcSDKP on intestinal inflammation in IBD. We found that in the inflamed mucosal specimens of patients with ulcerative colitis, the expression levels of Tβ4 and meprin-α were decreased, while PREP was expressed at similar levels to non-inflamed mucosa. In vitro, AcSDKP inhibited the expression of proinflammatory factors in intestinal epithelial cells partially by reducing the activation of MEK-ERK signaling. In vivo studies showed that transgenic mice, with lower levels of AcSDKP, were more vulnerable to dextran sulfate sodium (DSS)-induced colitis and exhibited more severe intestinal inflammatory responses. On the other hand, exogenous AcSDKP infusion significantly attenuated the clinical symptoms and intestinal mucosal inflammation in DSS-induced mice. In conclusion, results from this study demonstrated the anti-inflammatory function of AcSDKP within the intestine and suggest that AcSDKP has a promising therapeutic potential for IBD treatment.

Background and aims: Defective autophagy has been proposed as an important event in a growing number of autoimmune and inflammatory diseases such as rheumatoid arthritis and lupus. However, the precise role of mechanistic target of rapamycin (mTOR)-dependent autophagy and its underlying regulatory mechanisms in the intestinal epithelium in response to inflammation and oxidative stress remain poorly understood. Methods: The levels of p-mTOR, LC3B, p62 and autophagy in mice and LPS-treated cells were examined by immunoblotting, immunohistochemistry, confocal microscopy and transmission electron microscopy (TEM). We evaluated the expression of IL-1β, IL-8, TNF-α, MDA, SOD and T-AOC by quantitative real time-polymerase chain reaction (qRT-PCR) and commercially available kits after silencing of mTOR and ATG5. In vivo modulation of mTOR and autophagy was achieved by using AZD8055, rapamycin and 3-methyladenine. Finally, to verify the involvement of TLR4 signalling and the NF-κB pathway in cells and active ulcerative colitis (UC) patients, immunofluorescence, qRT-PCR, immunoblotting and TEM were performed to determine TLR4 signalling relevance to autophagy and inflammation. Results: The mTOR-dependent autophagic flux impairment in a murine model of colitis, human intestinal epithelial cells and active UC patients is probably regulated by TLR4-MyD88-MAPK signalling and the NF-κB pathway. Silencing mTOR remarkably attenuated, whereas inhibiting ATG5 aggravated, LPS-induced inflammation and oxidative injury. Pharmacological administration of mTOR inhibitors and autophagy stimulators markedly ameliorated experimental colitis and oxidative stress in vivo. Conclusions: Our findings not only shed light on the regulatory mechanism of mTOR-dependent autophagy, but also provided potential therapeutic targets for intestinal inflammatory diseases such as refractory inflammatory bowel disease. Keywords: Autophagy, mTOR, Inflammation, Oxidative stress

Superconducting Bi _1.68 Pb _0.32 Sr _1.75 Ca _1.85 Cu _2.85 O _10+ _y (Bi-2223) powders were prepared by a conventional solid-state reaction using hand grinding and wet ball milling. The effects of the ball milling and sintering times on the phase evolution were examined by x-ray diffraction and magnetic susceptibility measurements. Single-phase Bi-2223 powders with a superconducting transition temperature of about 108 K were optimally prepared by wet ball milling for 20 h and sintering at 867 °C for 80 h. Finding these optimal preparation conditions were crucial for mass producing high-quality single-phase Bi-2223 precursor powders with a much lower cost of energy. Furthermore, we found that ball milling led to thinner grains than hand grinding.

Objective Prognostic prediction of colorectal cancer (CRC) remains challenging because of its heterogeneity. Aberrant expression of caudal-type homeobox transcription factor 2 (CDX2) is strongly correlated with the prognosis of CRC. Methods Tissue samples of patients with CRC who underwent surgery in Xinhua Hospital (Shanghai, China) from January 2010 to January 2013 were collected. CDX2 expression was semiquantitatively evaluated via immunohistochemistry. Results In total, 138 patients were enrolled in this study from a prospectively maintained institutional cancer database. The median follow-up duration was 57.5 months (interquartile range, 17.0–71.0 months). In the Cox proportional hazards model, low CDX2 expression combined with stage T4 CRC was significantly the worst prognostic factor for disease-free survival (hazard ratio = 7.020, 95% confidence interval = 3.922–12.564) and overall survival (hazard ratio = 5.176, 95% CI = 3.237–10.091). In the Kaplan–Meier survival analysis, patients with low CDX2 expression and stage T4 CRC showed significantly worse disease-free survival and overall survival than those with low CDX2 expression alone. Conclusion CDX2 expression combined with the T stage was more accurate for predicting the prognosis of CRC. Determining the prognosis of CRC using more than one variable is valuable in developing appropriate treatment and follow-up strategies.

In this paper, an integrable KP equation is studied using symmetry and conservation laws. First, on the basis of various cases of coefficients, we construct the infinitesimal generators. For the special case, we get the corresponding geometry vector fields, and then from known soliton solutions we derive new soliton solutions. In addition, the explicit power series solutions are derived. Lastly, nonlinear self-adjointness and conservation laws are constructed with symmetries.

We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (IBD). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile acid receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1β production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.

Background & Aims: It has recently been reported that thymosin beta-4 (Tβ4) has anti-fibrogenic effects in human hepatic stellate cells (HSCs) in vitro, but the mechanisms underlying these effects remain unclear. The aim of this study was to investigate the roles of Tβ4 in the proliferation, migration, and activation of HSCs. Methods: Enzyme-linked immunosorbent assays (ELISA), immunohistochemistry, and western blot assays were utilized to determine the expression levels of Tβ4 in serum, liver tissues, and LX-2 cells. Tβ4 was depleted in LX-2 cells using small interfering RNAs (siRNAs). Cell proliferation was analyzed using cell counting kit-8 (CCK-8) viability assays, and cell migration was investigated using wound-healing and transwell migration assays. Results: The expression of Tβ4 was significantly reduced during the progression of liver fibrosis. The depletion of Tβ4 significantly promoted the proliferation and migration of LX-2 cells via the activation of the PI3K/Akt signaling pathway. The pro-migratory and pro-proliferative effects of Tβ4 depletion in LX-2 cells can be counteracted by treatment with the Akt inhibitor MK-2206. In addition, Tβ4 depletion was also associated with the activation of HSCs via the enhanced expression of α-smooth muscle actin (α-SMA) and vimentin. Conclusions: Our results suggest that Tβ4 participates in liver fibrosis by inhibiting the migration, proliferation, and activation of HSCs and that Tβ4 may be an effective target in the treatment of liver fibrosis.

A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD, however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here we for the first time showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2 (S1PR2). Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contributes to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.

Vertebrate limbs originate from the lateral plate mesoderm (LPM) and the overlying ectoderm. While normal limb formation in defined regions has been well studied, the question of whether other positions retain limb-forming potential has not been fully investigated in mice. By ectopically activating β-catenin in the ectoderm with Msx2-cre, we observed that local tissue outgrowths were induced, which either progressed into limb-like structure within the inter-limb flank or formed extra tissues in other parts of the mouse embryo. In the presumptive abdominal region of severely affected embryos, ectopic limb formation was coupled with impaired abdominal ventral body wall (AVBW) closure, which indicates the existence of a potential counterbalance of limb formation and AVBW closure. At the molecular level, constitutive β-catenin activation was sufficient to trigger, but insufficient to maintain the ectopic expression of a putative limb-inducing factor, Fgf8, in the ectoderm. These findings provide new insight into the mechanism of limb formation and AVBW closure, and the crosstalk between the Wnt/β-catenin pathway and Fgf signal.

BACKGROUND: We have raised a panel of broad spectrum neutralizing monoclonal antibodies against the highly pathogenic H5N1 avian influenza virus, which neutralize the infectivity of, and afford protection against infection by, most of the major genetic groups of the virus evolved since 1997. Peptide mimics reactive with one of these broad spectrum H5N1 neutralizing antibodies, 8H5, were identified from random phage display libraries. METHOD: The amino acid residues of the most reactive 12mer peptide, p125 (DTPLTTAALRLV), were randomly substituted to improve its mimicry of the natural 8H5 epitope. RESULT: 133 reactive peptides with unique amino acid sequences were identified from 5 sub-libraries of p125. Four residues (2,4,5.9) of the parental peptide were preserved among all the derived peptides and probably essential for 8H5 binding. These are interspersed among four other residues (1,3,8,10), which exhibit restricted substitution and probably could contribute to binding, and another four (6,7,11,12) which could be randomly substituted and probably are not essential for binding. One peptide, V-1b, derived by substituting 5 of the latter residues is the most reactive and has a binding constant of 3.16×10(-9) M, which is 38 fold higher than the affinity of the parental p125. Immunoassay produced with this peptide is specifically reactive with 8H5 but not also the other related broad spectrum H5N1 avian influenza virus neutralizing antibodies. Serum samples from 29 chickens infected with H5N1 avian influenza virus gave a positive result by this assay and those from 12 uninfected animals gave a negative test result. CONCLUSION: The immunoassay produced with the 12 mer peptide,V1-b, is specific for the natural 8H5 epitope and can be used for detection of antibody against the broad spectrum neutralization site of H5N1 avian influenza virus.

Dietary fructose is widely used in beverages, processed foods, and Western diets as food additives, and is closely related to the increased prevalence of multiple diseases, including inflammatory bowel disease (IBD). However, the detailed mechanism by which high fructose disrupts intestinal homeostasis remains elusive. The present study showed that high-fructose corn syrup (HFCS) administration exacerbated intestinal inflammation and deteriorated barrier integrity. Several in vivo experimental models were utilized to verify the importance of gut microbiota and immune cells in HFCS-mediated dextran sulfate sodium (DSS)-induced colitis. In addition, untargeted metabolomics analysis revealed the imbalance between primary bile acids (PBAs) and secondary bile acids (SBAs) in feces. Hence, high fructose was speculated to modulate gut microbiota community and reduced the relative abundance of Clostridium and Clostridium scindens at genus and species level respectively, followed by a decrease in SBAs, especially isoalloLCA, thereby affecting Th17/Treg cells equilibrium and promoting intestinal inflammation. These findings provide novel insights into the crosstalk between gut flora, bile acids, and mucosal immunity, and highlight potential strategies for precise treatment of IBD. [ABSTRACT FROM AUTHOR]