Quercetin alleviates Mycoplasma gallisepticum-induced inflammatory damage and oxidative stress through inhibition of TLR2/MyD88/NF-κB pathway in vivo and in vitro.

Chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum (MG) in chickens leads to enormous economic damage to the poultry industry yearly. The active components and mechanism of action of the traditional herbal remedy Ephedra houttuynia powder (EHP), which had been approved for clinical treatment against MG infection in China, remain unknown. In this study, the active components of EHP against MG were screened using a network pharmacological method, additionally, we studied the mechanism of action of the screened results (quercetin (QUE)). The findings demonstrated that QUE was an essential element of EHP against MG infection, effectively attenuating MG-induced oxidative stress and activation of the TLR2/MyD88/NF-κB pathway. Following QUE therapy, IL-1, IL-6, and TNF-α content and expression were downregulated, whereas IL-4 and IL-10 expression were upregulated, eventually suppressing the inflammatory response both in vitro and in vivo. Together, this study presents a strong rationale for using QUE as a therapeutic strategy to inhibit MG infection-induced inflammatory damage and oxidative stress.

Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis.

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial-mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.

Proteomic analysis of ITPR2 as a new therapeutic target for curcumin protection against AFB1-induced pyroptosis.

Aflatoxin B1 (AFB1) is extremely carcinogenic and can cause liver cancer in humans and animals with continued ingestion. As a natural compound, curcumin (Cur) exhibits excellent anti-inflammatory, and anti-cancer properties with few side effects. In this study, a total of 60 male mice (6-week-olds, 15 per group). After one week of acclimatization feeding, the mice were divided into control group (Con), AFB1 group, curcumin group (Cur), and AF+Cur group. The mice were gavaged with curcumin (Cur, 100 mg/kg) and/or AFB1 (0.75 mg/kg). To identify a new therapeutic target for AFB1-induced pyroptosis, we performed proteomic profiling for curcumin alleviating liver injury caused by AFB1 to further validate the targets through volcano plot analysis, Venn analysis, heatmap analysis, correlation, cluster analysis, GO and KEGG enrichment. AFB1 exposure resulted in the loss of hepatocyte membrane, swelling of the endoplasmic reticulum, and a significant increase in transaminase (ALT and AST) contents, while curcumin greatly improved these changes. We found that differentially expressed proteins are enriched in the endoplasmic reticulum membrane and identified ITPR2 as a target of curcumin that alleviates AFB1-induced liver injury by proteomics. Furthermore, ITPR2 expression was detected by immunofluorescence, and qRT-PCR for mRNA expression of genes downstream of ITPR2 (calpain1, calpain2, caspase-12, caspase-3). ITPR2-activated endoplasmic reticulum stress-related proteins (calpain1, calpaini2, bcl-2, BAX, cl-caspase-12, cl-caspase-3), apoptosis (PARP) and pyroptosis (DFNA5) related proteins were examined by western blotting. The analysis showed that it effectively prevents AFB1-induced pyroptosis by lowering endoplasmic reticulum stress via interfering with ITPR2 and its downstream proteins (calpain1, calpain2, bcl-2, Bax) and inhibiting caspase-12/caspase-3 pathway. Conclusively, this study applied proteomic profiling to elucidate ITPR2 as a new target, which might give a new perspective on the mechanism of curcumin alleviating AFB1-induced pyroptosis.

Thigh MRI in antisynthetase syndrome, and comparisons with dermatomyositis and immune-mediated necrotizing myopathy.

OBJECTIVES: To evaluate MRI changes to define muscle-lesion specific patterns in patients with antisynthetase syndrome (ASS), and compare them with those in other common idiopathic inflammatory myopathy subtypes. METHODS: Qualitative and semi-quantitative thigh MRI evaluations were conducted in patients with ASS, DM and immune-mediated necrotizing myopathy (IMNM). RESULTS: This study included 51 patients with ASS, 56 with DM and 61 with IMNM. Thigh MRI revealed muscle oedema (62.7%), myofascial oedema (90.2%), subcutaneous-tissue oedema (60.8%) and fatty infiltration of muscles (68.6%) in patients with ASS. Compared with IMNM, ASS and DM were associated with more frequent adductor-muscle relative sparing (40.6% vs 3.6%, P<0.001, and 25.6% vs 3.6%, P<0.001) and subcutaneous-tissue oedema (60.8% vs 23.0%, P<0.001, and 57.1% vs 23.0%, P<0.001). Although ASS and DM exhibited similar oedema patterns, there were certain subtle differences between them. The ASS group was less frequently symmetric (60.6% vs 88.4%, P=0.005, and 60.6% vs 80.0%, P=0.048), but more frequently showed myofascial oedema of the tensor fasciae latae (80.4% vs 48.2%, P<0.001, and 80.4% vs 31.1%, P<0.001) than either the DM or IMNM groups. The receiver operating characteristic curve analysis showed an optimal combination of thigh MRI findings had an area under the curve with 0.893 for diagnosing ASS. CONCLUSION: Thigh MRI in ASS exhibited frequent myofascial oedema. ASS oedema patterns resembled those of DM more than those of IMNM. Bilateral asymmetry, adductor-muscle relative sparing and remarkable myofascial oedema of tensor fasciae latae were the most characteristic ASS imaging findings.

Snoring and napping independently increased the serum uric acid levels and hyperuricemia risk: The Henan Rural Cohort Study.

BACKGROUND AND AIMS: Evidence on the association of snoring, daily sleep duration (daytime napping and night sleep duration) with hyperuricemia (HUA) was limited, especially in the resources-poor areas. This study aimed to investigate the independent effect of snoring frequency and daily sleep duration on HUA prevalence in rural Chinese adults. METHODS AND RESULTS: 29,643 participants aged 18-79 years were included in the final cross-sectional analysis from the Henan Rural Cohort Study. Multivariate logistic regression and linear regression models with HUA and serum uric acid (SUA) levels as dependent variables were conducted, respectively. Of the 29,643 included adults, 3498 suffered from HUA. Compared to never snoring, the adjusted odds ratio (OR) and 95% confidence interval (CI) of HUA for rare snoring, occasional snoring, and habitual snoring were 1.35 (1.17, 1.56), 1.30 (1.14, 1.47), and 1.59 (1.47, 1.73), respectively (P for trend <0.001). Compared with no napping, participants who had daytime napping of 61-90 and > 91 min were associated with a 29% and 30% increase in the prevalence of HUA, respectively (P for trend <0.001). But in night sleep duration groups, no significant associations were observed. The positive associations between snoring and HUA were attenuated in people aged ≥65 and people with type 2 diabetes mellitus (both P for interaction <0.05). CONCLUSION: Habitual snoring or longer daytime napping was independently associated with increased HUA prevalence and SUA levels in rural Chinese adults, which indicates the significance of early intervention and treatment of snoring and longer daytime napping to prevent hyperuricemia.

Genetic factors increase the identification efficiency of predictive models for dyslipidaemia: a prospective cohort study.

BACKGROUND: Few studies have developed risk models for dyslipidaemia, especially for rural populations. Furthermore, the performance of genetic factors in predicting dyslipidaemia has not been explored. The purpose of this study is to develop and evaluate prediction models with and without genetic factors for dyslipidaemia in rural populations. METHODS: A total of 3596 individuals from the Henan Rural Cohort Study were included in this study. According to the ratio of 7:3, all individuals were divided into a training set and a testing set. The conventional models and conventional+GRS (genetic risk score) models were developed with Cox regression, artificial neural network (ANN), random forest (RF), and gradient boosting machine (GBM) classifiers in the training set. The area under the receiver operating characteristic curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were used to assess the discrimination ability of the models, and the calibration curve was used to show calibration ability in the testing set. RESULTS: Compared to the lowest quartile of GRS, the hazard ratio (HR) (95% confidence interval (CI)) of individuals in the highest quartile of GRS was 1.23(1.07, 1.41) in the total population. Age, family history of diabetes, physical activity, body mass index (BMI), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were used to develop the conventional models, and the AUCs of the Cox, ANN, RF, and GBM classifiers were 0.702(0.673, 0.729), 0.736(0.708, 0.762), 0.787 (0.762, 0.811), and 0.816(0.792, 0.839), respectively. After adding GRS, the AUCs increased by 0.005, 0.018, 0.023, and 0.015 with the Cox, ANN, RF, and GBM classifiers, respectively. The corresponding NRI and IDI were 25.6, 7.8, 14.1, and 18.1% and 2.3, 1.0, 2.5, and 1.8%, respectively. CONCLUSION: Genetic factors could improve the predictive ability of the dyslipidaemia risk model, suggesting that genetic information could be provided as a potential predictor to screen for clinical dyslipidaemia. TRIAL REGISTRATION: The Henan Rural Cohort Study has been registered at the Chinese Clinical Trial Register. (Trial registration: ChiCTR-OOC-15006699 . Registered 6 July 2015 - Retrospectively registered).

Numerical investigation on the transmission and dispersion of aerosols in a 7-stories building drainage system.

In previous reports, the positive SARS-CoV-2 nucleic acid was detected in the fecal samples from confirmed pneumonia patients, suggesting a high probability of the fecal-oral transmission. To date, however, the role played by the drainage system of a high-rise building in the virus transmission is not clear and especially studies on the dynamics mechanism behind is scarce. From this point of view, the present work carries out a computational fluid dynamics (CFD) modeling to investigate the effects of the water seal effectiveness of the floor drain, the negative/positive pressures (P 1 , P 2 ) in the bathroom, temperature differential (ΔT), outside wind velocity (v), the piping fittings and the negative pressure at the cowl (P 3 ) on the transmission of the virus-laden aerosol particles in a drainage system of a typical 7-storeys residential building. The CFD models are first validated by the previous experiments in literature. Numerical results imply that the drainage system might play an essential role to the virus transmission. Then, results indicate that, the leakage risk of the aerosol particles via the floor drain with inefficient water-seal (UFD) mainly exists at the upper floors above the neutral pressure level (NPL). Besides, the negative and positive pressures at the bathroom can enhance and reduce the exposure risk of aerosol particles from the corresponding UFD, respectively. The ΔT increasing does not modify the location of the NPL. Moreover, the exposure risk of aerosol particles can be effectively avoided by the well water-sealed floor drains and/or the presence of a proper negative pressure at the cowl on the top floor. Finally, based on the CFD results, several protection suggestions on the drainage system and human activities are provided.

Association of long-term exposure to ambient air pollutants with prolonged sleep latency: The Henan Rural Cohort Study.

BACKGROUND: Prolonged sleep latency is associated with far-reaching public health consequences. Although evidence about the effect of air pollution on sleep problem has been shown, the effect on sleep latency remained unknown. The study aimed to analyze the association between long-term exposure to air pollution and prolonged sleep latency in rural China. METHODS: In all, 27935 participants were included in the study from Henan Rural Cohort Study. A satellite-based spatiotemporal model was used to evaluate the 3-year average concentration of air pollutants at the home address of participants before the baseline survey. Air pollutants included NO2 (nitrogen dioxide), PM1 (particulate matter with aerodynamic diameters ≤1 µm), PM2.5 (particulate matter with aerodynamic diameters ≤ 2.5 µm), and PM10 (particulate matter with aerodynamic diametes ≤ 10 µm). A logistic regression model was conducted to assess the odds ratio (OR) and 95% confidence interval (95% CI) between air pollutants and prolonged sleep latency. RESULTS: There were 5825 (20.85%) participants with prolonged sleep latency. The average concentration of NO2, PM1, PM2.5, and PM10 were 38.22 (2.54) µg/m3, 56.29 (1.75) µg/m3, 72.30 (1.87) µg/m3, and 130.01 (4.58) µg/m3. The odds ratio (95%CI) of prolonged sleep latency with an IQR increase of NO2, PM1, PM2.5, and PM10 were 1.59 (1.33-1.90), 1.23 (1.13-1.33), 1.28 (1.13-1.45) and 1.43 (1.22-1.67). The stratified analysis showed the effect of air pollutants was stronger among those with stroke. CONCLUSION: Long-term exposure to NO2, PM1, PM2.5 and PM10 were associated with prolonged sleep latency. The adverse impact of air pollution should be considered when treating sleep problems.

Associations of SRD5A1 gene variants and testosterone with dysglycemia: Henan Rural Cohort study.

BACKGROUND AND AIM: Multiple studies support a complex relationship between testosterone and type 2 diabetes mellitus (T2DM) and the transformation of testosterone is affected by several reductases. Thus, we aimed to explore the associations of steroid-5α-reductase type 1 (SRD5A1) gene polymorphism with impaired fasting glucose (IFG) and T2DM and the interactive effects of testosterone and genotypes on glycometabolism. METHODS AND RESULTS: A case-control study including 2365 participants was performed. Genomic DNA was extracted from the whole blood and genotyped for the SRD5A1 single nucleotide polymorphisms (SNP) rs1691053. Multivariable logistic regression and linear regression were performed to estimate the associations of SRD5A1 rs1691053 alleles and genotypes with glycometabolism. Generalized linear models were used to investigate the modulatory effects of serum testosterone on glycometabolism indexes in males. After multivariable adjustment, the odds ratio (OR) of homozygous CC genotypes in male carriers was 2.62 (95%CI: 1.11-6.18) for IFG. Furthermore, significant associations of SRD5A1 rs1691053 polymorphisms with adverse indices of glycometabolism were observed in males. Interestingly, the opposite associations in females were observed. The interactive associations of SNP and testosterone were found and mutations were more likely to lead unfavorable metabolic phenotypes. CONCLUSION: These results showed that SRD5A1 rs1691053 gene polymorphism was independently associated with glycometabolism. The interaction between a genetic polymorphism from SRD5A1 and testosterone involved glycometabolism was identified in males. Although this preliminary data should be replicated with other rigorous researches, it highlighted the importance of the SNP-testosterone interaction over the present of glycometabolism.

Dose-response association of sleep quality with anxiety symptoms in Chinese rural population: the Henan rural cohort.

BACKGROUND: The epidemiological evidence on the association of sleep quality on anxiety symptoms has been inconclusive. This study aimed to explore the association between sleep quality and anxiety symptoms in rural Chinese population and investigate whether age, lifestyles, and chronic diseases modified this association. METHODS: A total of 27,911 participants aged 18-79 years from the Henan Rural Cohort Study were included in the study. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) scale. Poor sleep quality was defined as PSQI ≥6. Anxiety symptoms were evaluated with the two-item generalized anxiety disorder scale (GAD-2). Individual with score ≥ 3 was viewed as having anxiety symptoms. Logistic regression and restricted cubic spline were conducted to examine the association of sleep quality with anxiety symptoms. RESULTS: Altogether, 6087 (21.80%) participants were poor sleepers and 1557 (5.58%) had anxiety symptoms. The odds of anxiety were increased with increment of PSQI score after fitting restricted cubic splines. The poor sleep quality was associated with a higher possibility of anxiety symptoms [odd ratio (OR): 4.60, 95% confidence interval (CI): 3.70-5.72] in men, and (OR: 3.56, 95% CI: 3.10-4.09) in women for multivariable analysis. Further, stratified analyses showed that the effect of sleep quality on anxiety symptoms could be modified by age, marital status, smoking status, drinking status, hypertension, and type 2 diabetes mellitus. CONCLUSIONS: A dose-response association between PSQI score and anxiety symptoms was found. In addition, the relationship between poor sleep quality and greater anxiety symptoms was observed in this rural population, especially in participants aged ≥60 years and those with unhealthy habits or had a chronic disease. TRIAL REGISTRATION: The trial was prospectively registered on July 6, 2015 and available online at ClinicalTrials.gov ID: ChiCTR-OOC-15006699 .

Adiposity reduces the risk of osteoporosis in Chinese rural population: the Henan rural cohort study.

BACKGROUND: Adiposity plays a crucial role in the risk of osteoporosis. However, the impact of body fat distribution on the skeleton is contentious. The study was designed to explore the association of various adiposity indices with estimated bone mineral density (BMD) and the risk of osteoporosis based on body mass index (BMI), body fat percentage (BFP), waist circumference (WC), waist to hip ratio (WHR), waist to height ratio (WHtR), and visceral fat index (VFI). METHODS: A total of 8475 subjects derived from the Henan Rural Cohort Study were analyzed. The estimated BMD of study participants were measured by calcaneal quantitative ultrasound (QUS). Linear regression and binary logistic regression were performed to estimate the association of adiposity and the outcomes. RESULTS: The mean age of the study participants was 55.23 ± 11.09 years and 59.61% were women. The crude and age-standardized prevalence of high osteoporosis risk was 16.24 and 11.82%. Per unit increment in adiposity indices was associated with 0.005-0.021 g/cm2 increase in estimated BMD. The adjusted odds ratios (95% confidence interval) for high osteoporosis risk in per 1 SD increase of WC, WHR, WHtR, BMI, BFP, and VFI were 0.820 (0.748, 0.898), 0.872 (0.811, 0.938), 0.825 (0.765, 0.891), 0.798 (0.726, 0.878), 0.882 (0.800, 0.972), and 0.807 (0.732, 0.889), respectively. Stratified analyses indicated greater effects on individuals aged 55 years or older. CONCLUSIONS: The adiposity indices have an inverse association with the risk of osteoporosis among Chinese rural population, especially in the elderly.

Association of serum testosterone with different classes of glucose metabolism and the mediation effect of obesity: The Henan Rural Cohort Study.

AIMS: We aimed to investigate the association of serum testosterone with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM) and calculate the proportion explained by obesity status on the relationship. MATERIALS AND METHODS: A case-control study including 2775 participants was performed. Serum testosterone was quantified by liquid chromatography-tandem mass spectrometry. Conditional logistic regression and multivariable linear regression were performed to estimate the relationships between testosterone and different glucose status. Waist circumference (WC) was used as a mediator to estimate the mediation effect. RESULTS: After adjusting for multiple variables, serum testosterone levels were negatively associated with T2DM in males (per 1 unit natural log-transformed, odd ratio (OR) = 0.73, 95% confidence interval (CI): 0.56, 0.96; Tertile 3 vs Tertile 1, OR = 0.46, 95% CI:0.29, 0.72) while were positively in females (per 1 unit natural log-transformed, OR = 1.56, 95% CI:1.32, 1.84; Tertile 3 vs Tertile 1, OR = 3.55, 95% CI: 2.22, 5.66). In males, a higher testosterone tended to be associated with a lower fasting plasma glucose level and a weaker HOMA2-IR but a stronger HOMA2-ß. Opposite findings were observed in females. Furthermore, WC played a full and partial mediating role in the relationship between testosterone and IFG and T2DM both in males and females. CONCLUSION: Serum testosterone levels had opposite effects on IFG and T2DM in males and females. With higher serum testosterone levels, the dysglycemia progression was decreased among males while increased among females. In addition, WC played a full and partial mediating role in the relationship between testosterone and IFG and T2DM.

Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury.

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data.

BACKGROUND: We aimed to analyse genome-wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. METHODS: One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle-derived genome-wide RNA-sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single-sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA-Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, and single-nucleus RNA-sequencing (snRNA-seq) were performed in the remaining patients to validate the most correlated gene signature. RESULTS: Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA-Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs  = 0.744, P < 0.001; MRI rs  = 0.718, P < 0.001). Muscle qRT-PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs  = 0.883, P < 0.001) and histological fibrofatty replacement (rs  = 0.804, P < 0.001) and disease duration (rs  = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs  = -0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA-seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro-adipogenic progenitors, satellite cells, and myoblasts. CONCLUSIONS: We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.

XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis.

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.

Clinicopathological and circulating cell-free DNA profile in myositis associated with anti-mitochondrial antibody.

OBJECTIVE: Anti-mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell-free mitochondrial DNA (ccf-mtDNA), and circulating cell-free nuclear DNA (ccf-nDNA) in AMA-associated IIMs. METHODS: Medical records of 37 IIMs patients with AMAs were reviewed. Circulating cell-free mtDNA and ccf-nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty-eight immune-mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti-synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed. RESULTS: Limb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf-mtDNA levels in AMA-associated IIMs were significantly higher than those in HCs (p < 0.001), but no significant differences between AMA-associated IIMs and IMNM, DM, or ASS. Serum ccf-nDNA levels in AMA-associated IIMs were significantly higher than those in HCs (p = 0.02), and significantly lower than those in DM (p = 0.02). Serum ccf-nDNA levels correlated negatively with MMT8 total scores (rs = -0.458, p = 0.037) and positively with mRS scores (rs = 0.486, p = 0.025). Serum ccf-nDNA levels were significantly higher in the non-remission group (p < 0.01). INTERPRETATION: AMA-associated IIMs exhibit distinct clinicopathological features. Serum ccf-nDNA may serve as a potential marker for disease severity and prognosis in AMA-associated IIMs.

Attractive deep morphology-aware active contour network for vertebral body contour extraction with extensions to heterogeneous and semi-supervised scenarios.

Automatic vertebral body contour extraction (AVBCE) from heterogeneous spinal MRI is indispensable for the comprehensive diagnosis and treatment of spinal diseases. However, AVBCE is challenging due to data heterogeneity, image characteristics complexity, and vertebral body morphology variations, which may cause morphology errors in semantic segmentation. Deep active contour-based (deep ACM-based) methods provide a promising complement for tackling morphology errors by directly parameterizing the contour coordinates. Extending the target contours' capture range and providing morphology-aware parameter maps are crucial for deep ACM-based methods. For this purpose, we propose a novel Attractive Deep Morphology-aware actIve contouR nEtwork (ADMIRE) that embeds an elaborated contour attraction term (CAT) and a comprehensive contour quality (CCQ) loss into the deep ACM-based framework. The CAT adaptively extends the target contours' capture range by designing an all-to-all force field to enable the target contours' energy to contribute to farther locations. Furthermore, the CCQ loss is carefully designed to generate morphology-aware active contour parameters by simultaneously supervising the contour shape, tension, and smoothness. These designs, in cooperation with the deep ACM-based framework, enable robustness to data heterogeneity, image characteristics complexity, and target contour morphology variations. Furthermore, the deep ACM-based ADMIRE is able to cooperate well with semi-supervised strategies such as mean teacher, which enables its function in semi-supervised scenarios. ADMIRE is trained and evaluated on four challenging datasets, including three spinal datasets with more than 1000 heterogeneous images and more than 10000 vertebrae bodies, as well as a cardiac dataset with both normal and pathological cases. Results show ADMIRE achieves state-of-the-art performance on all datasets, which proves ADMIRE's accuracy, robustness, and generalization ability.

Variation of Female Pronucleus Reveals Oocyte or Embryo Chromosomal Copy Number Variations.

The characteristics of the human pronuclei (PNs), which exist 16-22 h after fertilization, appear to serve as good indicators to evaluate the quality of human oocyte and embryo, and may reflect the status of female and male chromosome composition. Here, a quantitative PN measurement method that is generated by applying expert experience combined with deep learning from large annotated datasets is reported. After mathematic reconstruction of PNs, significant differences are obtained in chromosome-normal rate and chromosomal small errors such as copy number variants by comparing the size of the reconstructive female PN. After integrating the whole procedure of PN dynamics and adjusting for errors that occur during PN identification, the results are robust. Notably, all positive prediction results are obtained from the female propositus population. Thus, the size of female PNs may mirror the internal quality of the chromosomal integrity of the oocyte. Embryos that develop from zygotes with larger female PNs may have a reduced risk of copy number variations.

Clinical, pathological, and genetic characterization in a large Chinese cohort with female dystrophinopathy.

We aimed to investigate the clinical, pathological, and genetic characteristics of Chinese female dystrophinopathy and to identify possible correlations among them. One hundred forty genetically and/or pathologically confirmed female DMD variant carriers were enrolled, including 104 asymptomatic carriers and 36 symptomatic carriers. Twenty of 36 symptomatic and 16 of 104 asymptomatic carriers were sporadic with no family history. Muscle pathological analysis was performed in 53 carriers and X chromosome inactivation (XCI) analysis in 19 carriers. In asymptomatic carriers, the median age was 35.0 (range 2.0-58.0) years, and the serum creatine kinase (CK) level was 131 (range 60-15,745) IU/L. The median age, age of onset, and CK level of symptomatic carriers were 15.5 (range 1.8-62.0) years, 6.3 (range 1.0-54.0) years, and 6,659 (range 337-58,340) IU/L, respectively. Four female carriers with X-autosome translocation presented with a Duchenne muscular dystrophy (DMD) phenotype. Skewed XCI was present in 70.0% of symptomatic carriers. Compared to Becker muscular dystrophy (BMD)-like carriers, DMD-like carriers were more likely to have an early onset age, rapidly progressive muscle weakness, delayed walking, elevated CK levels, severe reduction of dystrophin, and skewed XCI. Our study reports the largest series of symptomatic female DMD carriers and suggests that delayed walking, elevated CK levels, severe reduction of dystrophin, X-autosome translocation, and skewed XCI pattern are associated with a severe phenotype in female dystrophinopathy.

Novel variants, muscle imaging, and myopathological changes in Chinese patients with VCP-related multisystem proteinopathy.

OBJECTIVE: The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin-containing protein (VCP) gene. METHODS: Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next-generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. RESULTS: Seven variants in VCP were identified, and two were novel. All the patients presented with adult-onset muscle weakness. The appearance of "isolated island sign" or "contra-isolated island sign" was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62-positive protein aggregates were observed in all the patients. CONCLUSION: Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb-girdle distribution. The characteristic pattern of fatty infiltration, especially the "isolated island" and "contra-isolated island" on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.