Meibomian glands segmentation in infrared images with limited annotation.

AIM: To investigate a pioneering framework for the segmentation of meibomian glands (MGs), using limited annotations to reduce the workload on ophthalmologists and enhance the efficiency of clinical diagnosis. METHODS: Totally 203 infrared meibomian images from 138 patients with dry eye disease, accompanied by corresponding annotations, were gathered for the study. A rectified scribble-supervised gland segmentation (RSSGS) model, incorporating temporal ensemble prediction, uncertainty estimation, and a transformation equivariance constraint, was introduced to address constraints imposed by limited supervision information inherent in scribble annotations. The viability and efficacy of the proposed model were assessed based on accuracy, intersection over union (IoU), and dice coefficient. RESULTS: Using manual labels as the gold standard, RSSGS demonstrated outcomes with an accuracy of 93.54%, a dice coefficient of 78.02%, and an IoU of 64.18%. Notably, these performance metrics exceed the current weakly supervised state-of-the-art methods by 0.76%, 2.06%, and 2.69%, respectively. Furthermore, despite achieving a substantial 80% reduction in annotation costs, it only lags behind fully annotated methods by 0.72%, 1.51%, and 2.04%. CONCLUSION: An innovative automatic segmentation model is developed for MGs in infrared eyelid images, using scribble annotation for training. This model maintains an exceptionally high level of segmentation accuracy while substantially reducing training costs. It holds substantial utility for calculating clinical parameters, thereby greatly enhancing the diagnostic efficiency of ophthalmologists in evaluating meibomian gland dysfunction.

Two-dimensional speckle-tracking echocardiography in left ventricular systolic function in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate whether two-dimensional speckle-tracking echocardiography (2DSTE) can be considered a criterion for early left ventricular (LV) systolic impairment in patients with systemic lupus erythematosus (SLE) and to further explore the association with each other. METHODS: We included 38 patients with SLE and assessed the degree of disease activity according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 scoring criteria, together with 38 healthy controls who were matched by sex and age. Routine LV systolic function evaluation parameters were obtained by echocardiography as well as 2DSTE measurement of LV strain parameters to obtain global longitudinal strain (GLS) values, respectively. RESULTS: (I) On routine LV function parameters such as ejection fractions (EF) and left ventricular end-diastolic internal diameter (LVIDd), the SLE group and the control group did not reflect differences. In contrast, on the LV strain parameter obtained from 2DSTE measurements, the GLS values in all cardiac planes were lower in the SLE group than in the control group and showed statistically significant differences. (II) Correlation analysis showed that there was a correlation between SLEDAI and GLS, especially a meaningful correlation with GLS Avg and GLS A4C, with correlation coefficients of 0.35 and 0.47, respectively. CONCLUSIONS: The use of 2DSTE can detect early impaired LV systolic function in SLE patients, and GLS is progressively gaining attention as an indicator of subclinical myocardial injury and LV function in SLE patients. The correlation that exists between GLS and SLEDAI might contribute to a better assessment of cardiac involvement in SLE patients. Key Points • Cardiac involvement has become one of the major factors in the poor prognosis of SLE patients, which directly affects the mortality of SLE patients. Traditional echocardiography is difficult to detect early left ventricular function impairment, thus affecting clinicians' judgment and diagnosis. • 2DSTE can recognize subclinical myocardial injury in SLE patients at an early stage, and its derived strain parameters may be used as an indicator to evaluate myocardial involvement and reflect disease activity in SLE patients.

Alterations in peripheral T- and B-cell subsets in patients with systemic sclerosis.

OBJECTIVES: To determine the alteration of peripheral T and B cell subsets in patients with systemic sclerosis (SSc) and to evaluate their correlation with the progression of SSc. METHODS: We recruited 47 SSc patients and 45 healthy controls (HCs) in this study. Demographic and clinical data were then collected. Flow cytometry was used to detect the proportions of 44 different T and B cell subsets in circulating blood. RESULTS: The proportion of total B cells (p = .043) decreased in SSc patients, together with similar frequencies of total T cells, CD4+ T cells, and CD8+ T cells in both groups. Several subsets of T and B cells differed significantly between these two groups. Follicular helper T cells-1 (Tfh1) (p < .001), helper T cells-1 (Th1) (p = .001), regulatory T cells (Treg) (p = .004), effector memory CD8+ T cells (p = .041), and cytotoxic T cells-17 (Tc17) (p = .01) were decreased in SSc patients. Follicular helper T cells-2 (Tfh2) (p = .001) and, helper T cells-2 (Th2) (p = .001) levels increased in the SSc group. Regulatory B cells (Breg) (p = .015) were lower in the SSc group, together with marginal zone (MZ) B cells (p < .001), memory B cells (p = .001), and non-switched B cells (p = .005). The modified Rodnan skin score (mRSS) correlated with helper T cells-17 (Th17) (r = -.410, p = .004), Tfh1 (r = -.321, p = .028), peripheral helper T cells (Tph) (r = -.364, p = .012) and plasma cells (r = -.312, p = .033). CONCLUSIONS: The alterations in T and B cells implied immune dysfunction, which may play an essential role in systemic sclerosis.

Serum levels of CXCL5 are decreased and correlate with circulating platelet counts in systemic lupus erythematosus.

OBJECTIVE: To identify disease-specific serum chemokine profiles and potential anti-inflammatory chemokines in three rheumatic diseases. METHODS: The discovery cohort included 18 patients with rheumatoid arthritis (RA), 20 patients with primary Sjögren's syndrome (pSS), 24 patients with systemic lupus erythematosus (SLE) and 28 healthy subjects. Findings from the discovery cohort were validated in two replication cohorts, consisting of 23 patients with SLE matched with 23 healthy subjects and 62 patients with SLE, 16 patients with ANCA-associated vasculitis (AAV), and 32 healthy controls, respectively. Serum levels of chemokines were determined using multiplex assay or ELISA. RESULTS: In the discovery cohort, serum levels of multiple chemokines were increased in one or more diseases in comparison to healthy subjects, including CCL2, CCL20, CXCL9, CXCL10, and CXCL11 in SLE, CCL2, CCL4, and CXCL11 in pSS, and CCL2, CCL4, and CXCL9 in RA. Notably, serum levels of CCL3 (p = .0003) and CXCL5 (p = .0003) were decreased in SLE. The SLE-specific decrease in CXCL5 serum levels was confirmed in the two replication cohorts, with p = .0034 and p = .0006, respectively. Moreover, a positive correlation between serum levels of CXCL5 and circulating platelet counts (R = .71, p = .00018) in SLE observed in the discovery cohort was confirmed in both replication cohorts (R = .52, p = .011 and R = .49, p = .00005, respectively). CONCLUSION: In the present study, we demonstrate that serum levels of CXCL5 are decreased in patients with SLE and positively correlated with circulating platelet count. These findings suggest that platelet-associated CXCL5 is presumably involved in the development of SLE.

Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells.

Osteosarcoma is a prevalent kind of primary bone malignancy. Trifluoperazine, as an antipsychotic drug, has anti-tumor activity against a variety of cancers. Nevertheless, the impact of trifluoperazine on osteosarcoma is unclear. Our investigation aimed to explore the mechanism of trifluoperazine's effect on osteosarcoma. We found that trifluoperazine inhibited 143B and U2-OS osteosarcoma cell proliferation in a method based on the dose. Furthermore, it was shown that trifluoperazine induced the accumulation of reactive oxygen species (ROS) to cause mitochondrial damage and induced mitophagy in osteosarcoma cells. Finally, combined with RNA-seq results, we first demonstrated the AMPK/mTOR/ULK1 signaling pathway as a potential mechanism of trifluoperazine-mediated mitophagy in osteosarcoma cells and can be suppressed by AMPK inhibitor Compound C.

Advances in pathogenesis and treatment of ocular involvement in Behcet's disease.

Behcet's disease (BD) is a chronic multi-systemic disease characterized by relapsing-remitting oral ulcers, genital ulcers, ocular inflammatory involvements, and numerous other systemic features. Ocular involvements are quite common in BD and may cause severe tissue damage and potentially blindness. Even though the pathogenesis of BD remains ambiguous, growing evidences have shown that genetic factors, environmental triggers and immunological abnormalities play significant roles in its development and progression. Novel biotherapies targeting IFN-γ, TNF-α and interleukins have been used in recent years. In this review, we mainly pay attention to the ocular involvement of BD, and discuss the current understanding of mechanisms and advances in therapeutic approaches, especially novel biologics. Finally, we discuss the management in patients with pregnancy.

Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in a mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogentior niche as is a strategy to treat OI.

Effects of orthokeratology lenses on tear film and tarsal glands and control of unilateral myopia in children.

Introduction: To investigate the effects of an orthokeratology lens on the tear film and tarsal glands and myopia control in children with unilateral myopia using an intelligent analysis model. Methods: We retrospectively reviewed the medical records from November 2020 to November 2022 of 68 pediatric patients with unilateral myopia in Fujian Provincial Hospital who had been wearing an orthokeratology lens for more than 1 year. The 68 myopic eyes were included in the treatment group, while the 68 healthy, untreated contralateral eyes were included in the control group. Tear film break-up times (TBUTs) were compared between the two groups at various intervals, and an intelligent analysis model was used to compare the deformation coefficients of 10 meibomian glands in the central area and the different positions of the glands in the two groups after 12 months of treatment. Changes in axial length and equivalent spherical power were also compared between the groups before and after 12 months of treatment. Results: In the treatment group, TBUTs differed significantly between 1 and 12 months after treatment, although no significant differences from baseline were observed at 3 or 6 months. No significant differences in TBUTs were observed at any time point in the control group. After 12 months of treatment, significant between-group differences were observed for glands 2, 3, 4, 5, 6, 7, 8, and 10 (numbered from the temporal to nasal regions). The treatment group also exhibited significant differences in deformation coefficients at different detection positions in the central region, with glands 5 and 6 exhibiting the highest deformation coefficients. Increases in axial length and equivalent spherical power were significantly greater in the control group than in the treatment group after 12 months of treatment. Discussion: Wearing orthokeratology lenses at night can effectively control myopia progression in children with unilateral myopia. However, long-term use of these lenses may lead to meibomian gland deformation and impact tear film function, and the extent of deformation may vary at different positions in the central region.

Titanium surfaces with biomimetic topography and copper incorporation to modulate behaviors of stem cells and oral bacteria.

Purpose: Insufficient osseointegration and implant-associated infection are major factors in the failure of Ti-based implants, thus spurring scientists to develop multifunctional coatings that are better suited for clinical requirements. Here, a new biomimetic micro/nanoscale topography coating combined with antibacterial copper was simultaneously designed for Ti-based implant surfaces by adopting a hybrid approach combining plasma electrolytic oxidation and hydrothermal treatment. Results: The biological interactions between this biofunctionalized material interface and stem cells promoted cellular adhesion and spreading during initial attachment and supported cellular proliferation for favorable biocompatibility. Bone marrow mesenchymal stem cells (BMMSCs) on the coating displayed enhanced cellular mineral deposition ability, higher alkaline phosphatase activity, and upregulated expression of osteogenic-related markers without the addition of osteoinductive chemical factors, which improved osseointegration. More interestingly, this new coating reduced the viability of oral pathogens (Fusobacterium nucleatum and Porphyromonas gingivalis)-the primary causes of implant-associated infections as indicated by damage of cellular structures and decreased population. This is the first study investigating the antibacterial property of dental implants modified by a hybrid approach against oral pathogens to better mimic the oral environment. Conclusion: These findings suggest that biofunctionalization of the implant coating by surface modification methods and the incorporation of antibacterial copper (Cu) offer superior osteogenesis capability and effective antibacterial activity, respectively. These strategies have great value in orthopedic and dental implant applications.

Health Care-Seeking Behaviors, Disease Progression, Medications, Knowledge of, and Attitudes Toward Systemic Lupus Erythematosus in China: Cross-sectional Survey Study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving multiple organs throughout the body. The health care-seeking behaviors, disease progression of SLE, and patients' knowledge of and attitudes toward SLE have not been characterized in China. OBJECTIVE: The aim of this study was to depict the health care-seeking behaviors, disease progression, and medications in patients with SLE and to examine the factors associated with their disease flares, knowledge, and attitudes toward SLE in China. METHODS: We conducted a cross-sectional survey in 27 provinces in China. Descriptive statistical methods were used to depict the demographic characteristics, health care-seeking behaviors, medications, and health status. Multivariable logistic regression models were used to identify the factors associated with disease flares, medication changes, and attitudes toward SLE. An ordinal regression model was used to examine the factors associated with the knowledge of the treatment guidelines. RESULTS: We recruited 1509 patients with SLE, and 715 had lupus nephritis (LN). Approximately 39.96% (603/1509) of the patients with SLE were primarily diagnosed with LN, and 12.4% (112/906) developed LN (mean time 5.2 years) from non-LN. Patients whose registered permanent residences or workplaces in other cities from the same province and adjacent provinces seeking health care accounted for 66.9% (569/850) and 48.8% (479/981) of the patients with SLE in the provincial capital cities, respectively. Mycophenolate mofetil was the most commonly used immunosuppressive drug in patients without LN (185/794, 23.3%) and patients with LN (307/715, 42.9%). Femoral head necrosis (71/228, 31.1%) and hypertension (99/229, 43.2%) were the most common adverse event (AE) and chronic disease during treatment, respectively. Change of hospitals for medical consultation (odds ratio [OR] 1.90, 95% CI 1.24-2.90) and development of 1 chronic disease (OR 3.60, 95% CI 2.04-6.24) and AE (OR 2.06, 95% CI 1.46-2.92) and more were associated with disease flares. A pregnancy plan (OR 1.58, 95% CI 1.18-2.13) was associated with changes in medication. Only 242 (16.03%) patients with SLE were familiar with the treatment guidelines, and patients with LN tended to be more familiar with the disease (OR 2.20, 95% CI 1.81-2.68). After receiving treatment, 891 (59.04%) patients changed their attitudes toward SLE from fear to acceptance, and patients with college education or higher (OR 2.09, 95% CI 1.10-4.04) were associated with a positive attitude toward SLE. CONCLUSIONS: A large proportion of patients seeking health care in the provincial capital cities of China migrated from other cities. Persistent monitoring of potential AEs and chronic diseases during SLE treatment and managing patients who changed hospitals for medical consultation are essential for controlling disease flares. Patients had insufficient knowledge about SLE treatment guidelines and would benefit from health education to maintain a positive attitude toward SLE.

Recent Progress of Wearable Triboelectric Nanogenerator-Based Sensor for Pulse Wave Monitoring.

Today, cardiovascular diseases threaten human health worldwide. In clinical practice, it has been concluded that analyzing the pulse waveform can provide clinically valuable information for the diagnosis of cardiovascular diseases. Accordingly, continuous and accurate monitoring of the pulse wave is essential for the prevention and detection of cardiovascular diseases. Wearable triboelectric nanogenerators (TENGs) are emerging as a pulse wave monitoring biotechnology due to their compelling characteristics, including being self-powered, light-weight, and wear-resistant, as well as featuring user-friendliness and superior sensitivity. Herein, a comprehensive review is conducted on the progress of wearable TENGs for pulse wave monitoring. Firstly, the four modes of operation of TENG are briefly described. Secondly, TENGs for pulse wave monitoring are classified into two categories, namely wearable flexible film-based TENG sensors and textile-based TENG sensors. Next, the materials, fabrication methods, working mechanisms, and experimental performance of various TENG-based sensors are summarized. It concludes by comparing the characteristics of the two types of TENGs and discussing the potential development and challenges of TENG-based sensors in the diagnosis of cardiovascular diseases and personalized healthcare.

Magnetic Force-Assisted Nonlinear Three-Dimensional Wideband Energy Harvester Using Magnetostrictive/Piezoelectric Composite Transducers.

This paper presents a nonlinear magnetoelectric energy harvester which has the potential to harvest vibrational energy over a wide bandwidth in arbitrary motion directions. Three springs with equal intersection angles are adopted to absorb the multi-directional vibration energy. Magnetic interaction between the magnets and ME transducers allows the nonlinear motion with enhanced harvesting frequency range. Very good agreement is observed between the numerical and experimental open-circuit voltage output frequency response curves. The experimental results show that the harvester can harvest vibrational energy in an arbitrary direction, exhibiting a further bandwidth of 5.2 Hz. This study provides a new solution to effectively use the magnetoelectric energy harvester for multi-directional and bandwidth vibrational energy scavenging in the surrounding environment.

Pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus: A review.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease with a complex pathogenesis. Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of SLE that involves the nervous system and produces neurological or psychiatric symptoms. After decades of research, it is now believed that the diverse clinical manifestations of NPSLE are associated with intricate mechanisms, and that genetic factors, blood-brain barrier dysfunction, vascular lesions, multiple autoimmune antibodies, cytokines, and neuronal cell death may all contribute to the development of NPSLE. The complexity and diversity of NPSLE manifestations and the clinical overlap with other related neurological or psychiatric disorders make its accurate diagnosis difficult and time-consuming. Therefore, in this review, we describe the known pathogenesis and potential causative factors of NPSLE and briefly outline its treatment that may help in the diagnosis and treatment of NPSLE.

A clinical practice guideline for the screening and assessment of enthesitis in patients with spondyloarthritis.

Objective: The aim of this review is to provide guidance on the selection of approaches to the screening and assessment of enthesitis in patients with spondyloarthritis (SpA). Methods: Twenty-four questions regarding the approaches to the screening and assessment of enthesitis and the implementation details were devised, followed by a systemic literature review. The Grading of Recommendations Assessment, Development, and Evaluation methodology was employed in the development of this guideline, with modifications to evaluate non-interventional approaches under comprehensive consideration of costs, accessibility, and evidence strength. A consensus from the voting panel was required for the inclusion of the final recommendations and the strength of each recommendation. Results: Seventeen recommendations (including five strong recommendations) were included in this guideline. The voting panel expressed unequivocal support for the necessity of screening and assessment of enthesitis in patients with SpA. It was agreed unanimously that symptom evaluation and physical examination should serve as the initial steps to the recognition of enthesitis, whereas Maastricht Ankylosing Spondylitis Enthesitis Score is a reliable tool in both clinical trials and daily medical practice. Ultrasound examination is another reliable tool, with power Doppler ultrasound as an informative addition. Notwithstanding its high resolution, MRI is limited by the costs and relatively low accessibility, whereas radiographs had low sensitivity and therefore should be rendered obsolete in the assessment of enthesitis. PET/CT was strongly opposed in the detection of enthesitis. Conclusion: This guideline provides clinicians with information regarding the screening and assessment of enthesitis in patients with SpA. However, this guideline does not intend on dictating choices, and the ultimate decisions should be made in light of the actual circumstances of the facilities.

Renal response and its predictive factors of lupus nephritis: a 2-year real-world study of 56 hospital-based patients.

OBJECTIVES: Our aim was to evaluate the renal response rate of patients with lupus nephritis (LN) undergoing standard treatment during a 2-year follow-up and to investigate its predictive factors. METHODS: A prospective cohort study that enrolled 56 clinically diagnosed LN patients with urinary protein positivity was carried out. All patients underwent standard treatment. All patients were followed up at 6-month intervals for 2 years. Data on renal response and clinical characteristics were collected and analyzed. RESULTS: Among 56 patients, 27 (48.2%) and 13 (23.2%) patients achieved complete renal response (CR) and partial renal response (PR) at 6 months after induction therapy, respectively, and 42 (75.0%) and 4 (7.1%) patients developed CR and PR at 2 years. Among patients who achieved PR at 6 months, 90.0% achieved CR at 24 months, while only 37.5% of the patients who were unresponsive at 6 months achieved CR. In the multivariable Cox proportional-hazards model, female (OR 6.51, 95% CI 1.23-34.52, p = 0.028), disease duration (OR 0.84, 95% CI 0.73-0.98, p = 0.021), achieving PR within 6 months (OR 8.09, 95% CI 2.06-31.73, p = 0.003), and urine protein/creatinine ratio (UPCR) (OR 0.998, 95% CI 0.996-1.000, p = 0.025) were found to be predictive factors of CR. CONCLUSION: A total of 48.2% of patients achieved CR at 6 months of induction therapy, and the response rates gradually increased to 60.7%, 64.3%, and 75.0% at 12, 18, and 24 months. Besides, female, disease duration, partial response within 6 months, and UPCR were predictive factors for a complete renal response. Key Points • We evaluate the renal response rates in Chinese patients with lupus nephritis in the real world for 2 years. • A total of 48.2% and 75.0% of patients achieved a complete response after standard treatment for 6 months and 2 years. • Female, disease duration, partial response within 6 months, and UPCR are predictors of complete renal response.

Prevalence and Associated Factors of Electrocardiogram Abnormalities in Patients With Systemic Lupus Erythematosus: A Machine Learning Study.

OBJECTIVE: Electrocardiogram (EKG) abnormalities are predictive of subsequent cardiovascular events. Cardiac involvement is common in systemic lupus erythematosus (SLE). We aimed to determine the prevalence of EKG abnormalities in SLE patients and to examine the factors associated with EKG abnormalities with machine learning approaches. METHODS: Consecutive SLE patients' records were retrieved from the database of the hospital for the cross-sectional study. Abnormal EKGs with clinical significance were grouped by the presence of tachyarrhythmias, atrioventricular block, nonspecific ST segment changes, T wave abnormalities, ventricular hypertrophy, axis deviation, bundle branch block, and QT interval prolongation. Associated factors of the most common EKG abnormalities were assessed by comparing logistic regression and 4 other machine learning approaches. RESULTS: In the present study, 299 patients were enrolled, with 128 showing clinically significant abnormalities on EKG. T wave changes (52.3%), nonspecific ST segment-T wave (ST-T) changes (26.6%), and prolonged QT interval (8.6%) were the most prevalent abnormalities among patients with abnormal findings on EKG. Random forests models had the best performance in the discovery of associated factors. Age, disease duration, antinuclear antibody titer, disease activity (as measured by the Systemic Lupus Erythematosus Disease Activity Index 2000) were associated with nonspecific ST-T changes, prolonged QT interval, and T wave changes. Hypertension, positivity for anti-SSA antibodies, and secondary Sjögren's syndrome were influential factors for nonspecific ST-T changes, prolonged QT interval, and T wave changes, specifically. CONCLUSION: ST-T and T wave changes were the most common abnormalities seen on EKGs of SLE patients. Our finding suggests that age, longer disease duration, higher disease activity, hypertension, anti-SSA antibody positivity, and secondary Sjögren's syndrome are important and influential factors in these EKG abnormalities.

Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with differences in prevalence and severity among ancestral groups. This study was undertaken to identify novel genetic components, either shared by or distinct between Asian and European populations. METHODS: Both trans-ancestral and ancestry-specific meta-analyses of genome-wide association studies (GWAS) for SLE were performed, involving 30,604 participants of European, Chinese, or Thai origin. Using public epigenomic data and expression quantitative trait loci, fine-mapping analyses were conducted to identify putative causal variants and genes for the newly identified loci. Performance of polygenic risk scores for the Thai cohort was evaluated by comparing different training data. RESULTS: A 1-bp deletion upstream of IFNLR1 was found to be associated with SLE, with the risk allele correlated with increased expression of IFNLR1. This gene encodes interferon-λ (IFNλ) receptor 1, providing evidence of a role of type III IFN signaling in SLE. An intronic variant in SLC29A3 was found to be associated with SLE in Asians only. The putative risk variant may modulate SLC29A3 expression in a monocyte-specific manner. SLC29A3 encodes a lysosomal nucleoside transporter, and subsequent analyses suggested that reduced lysosomal function and phagocytosis might be the mechanism underlying this association. Ancestry-shared loci in or near TAOK3, CHD9, CAMK1D, ATXN1, and TARBP1 and Asian-specific loci close to PEX2, FCHSD2, and TMEM116 also reached the genome-wide significant association with SLE. In addition, trans-ancestral meta-analysis was shown to be valuable in risk prediction for individuals without ancestry-matched data. CONCLUSION: In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.

Moderate-intensity exercise alleviates pyroptosis by promoting autophagy in osteoarthritis via the P2X7/AMPK/mTOR axis.

Instability and excessive use of the knee joint can cause osteoarthritis (OA). Reasonable exercise can enhance the stability of the knee joint and prevent and relieve the occurrence and development of OA. As a key switch for inflammation, P2X purinoceptor 7 (P2X7) has attracted much attention in studies of OA. Exercise can regulate P2X7 expression and activation. However, the role of P2X7 in exercise-based prevention and treatment of OA is unknown. We previously showed that moderate-intensity exercise can significantly alleviate OA symptoms. Accordingly, in this study, we evaluated the effects of exercise on P2X7 expression and activation in chondrocytes. Micro-computed tomography, hematoxylin, and eosin staining, Toluidine Blue O staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling experiments showed that P2X7 expression was lower in the moderate-intensity exercise group than in the inflammation and low- and high-intensity exercise groups. Additionally, chondrocyte death, cartilage destruction, and the degree and severity of pyroptosis were significantly reduced, whereas autophagy levels were significantly increased in the moderate-intensity exercise group. Cell Counting Kit-8 assay, lactate dehydrogenase release, flow cytometry, enzyme-linked immunosorbent assay, cell fluorescence, western blot, reverse transcription-quantitative polymerase chain reaction, and transmission electron microscopy experiments showed that moderate activation of P2X7 promoted autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway and promoted autolysosome targeting for degradation of the inflammasome component NLRP3, thereby inhibiting pyroptosis. Additionally, the use of AMPK and mTOR activators and inhibitors indicated that the AMPK-mTOR signaling pathway, as the downstream of P2X7, played a key role in delaying the occurrence and development of OA. We propose that moderate-intensity exercise promoted chondrocyte autophagy through the P2X7/AMPK/mTOR signal axis to alleviate pyroptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA.