Novel potential lncRNA biomarker in B cells indicates essential pathogenic pathway activation in patients with SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.

Association between sarcopenic obesity and mortality in patients on peritoneal dialysis: a prospective cohort study.

Background: Whether sarcopenic obesity had unfavorable effect on survival of peritoneal dialysis (PD) patients is unknown. We aimed to investigate the association between sarcopenic obesity and survival in PD patients. Methods: This was a prospective observational study. Eligible PD patients from November 2016 to December 2017 were enrolled and followed until August 31, 2023. Sarcopenia was defined following the recommendations of the Asian Working Group for Sarcopenia (AWGS) as low appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS). Obesity was defined using the percentage of body fat (PBF). Survival analysis was conducted using the Kaplan-Meier and log-rank test. The Cox regression and the cumulative incidence competing risk (CICR) analyzes were used to investigate the association between sarcopenic obesity and all-cause mortality. Results: A total of 223 patients were enrolled with 133 (59.6%) males, a median age of 57.5 (44.6, 65.7) years, a median dialysis vintage of 20.3 (6.4, 57.7) months and 48 (21.5%) who had comorbid diabetes mellitus. Among them, 46 (20.6%) patients were sarcopenic, and 25 (11.2%) patients were diagnosed with sarcopenic obesity. After followed up for 51.6 (25.6, 73.9) months, the Kaplan-Meier curve showed the sarcopenic obesity (log-rank = 13.527, p < 0.001) group had significant lower survival rate compared to the nonsarcopenic non-obesity group. For multivariate analysis, the CICR method showed patients with sarcopenic obesity had significantly higher mortality rate (HR: 2.190, 95% CI: 1.011-4.743, p = 0.047) compared to those with nonsarcopenic non-obesity. Conclusion: Sarcopenia is not uncommon in PD patients, with a considerable proportion having sarcopenic obesity. There is a significant association between sarcopenic obesity and an increased risk of mortality in PD patients.

The association of cervical sagittal alignment with anterior bone loss following single-level anterior cervical surgery.

Background: Anterior bone loss (ABL) is a common phenomenon after cervical disc replacement (CDR), which can also be observed after anterior cervical discectomy and fusion (ACDF). This study aimed to investigate the incidence and severity of ABL in single-level CDR and ACDF and explore the association of cervical sagittal alignment with ABL. Methods: This is a single-center retrospective cohort study. A total of 113 patients treated with CDR and 99 patients treated with ACDF were retrospectively reviewed from January 2014 to December 2018 in West China Hospital. Radiological data were collected at pre-operation, 1 week, 3 months postoperatively, and the last follow-up. The incidence and severity of ABL after both CDR and ACDF were evaluated. Cervical sagittal alignment parameters, including C0-C2 angle, cervical lordosis (CL), C2-C7 sagittal vertical axis (cSVA), T1 slope, functional spinal unit angle, disc angle, and surgical level slope, were evaluated. Results: ABL was identified in 75 (66.4%) patients in the CDR group and 57 (57.6%) patients in the ACDF group. There were no significant differences in the incidence, severity, and location of ABL between the ACDF and CDR groups. For patients who underwent ACDF, the proportion of females was significantly higher in the ABL group (64.9% vs. 33.3%, P=0.002), whereas the body mass index (BMI) was significantly lower in the ABL group compared to the non-ABL group (22.72±3.09 vs. 24.60±3.04, P=0.002). No effect of ABL on the short-term clinical outcomes of ACDF and CDR was observed. In the ACDF group, patients with ABL had significantly smaller postoperative CL (11.83°±8.24° vs. 15.25°±8.32°, P=0.04) and cSVA (17.77±10.08 vs. 23.35±9.86 mm, P=0.007). In the CDR group, no significant differences were found in the cervical sagittal parameters between patients with and without ABL (CL: 12.58±8.70 vs. 15.46±8.50, P=0.10; cSVA: 20.95±8.54 vs. 19.40±9.43, P=0.38). Conclusions: ABL is common after both CDR and ACDF with comparable incidence and severity. Cervical sagittal alignment was closely related to ABL after ACDF yet had less influence on ABL after CDR.

Dihydroartemisinin, a potential PTGS1 inhibitor, potentiated cisplatin-induced cell death in non-small cell lung cancer through activating ROS-mediated multiple signaling pathways.

Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.

Optical ReLU-like activation function based on a semiconductor laser with optical injection.

Artificial neural networks usually consist of successive linear multiply-accumulate operations and nonlinear activation functions. However, most optical neural networks only achieve the linear operation in the optical domain, while the optical implementation of activation function remains challenging. Here we present an optical ReLU-like activation function (with 180° rotation) based on a semiconductor laser subject to the optical injection in an experiment. The ReLU-like function is achieved in a broad regime above the Hopf bifurcation of the injection-locking diagram and is operated in the continuous-wave mode. In particular, the slope of the activation function is reconfigurable by tuning the frequency difference between the master laser and the slave laser.

A dual-modal dynamic contour-based method for cervical vascular ultrasound image instance segmentation.

OBJECTIVES: We intend to develop a dual-modal dynamic contour-based instance segmentation method that is based on carotid artery and jugular vein ultrasound and its optical flow image, then we evaluate its performance in comparison with the classic single-modal deep learning networks. METHOD: We collected 2432 carotid artery and jugular vein ultrasound images and divided them into training, validation and test dataset by the ratio of 8:1:1. We then used these ultrasound images to generate optical flow images with clearly defined contours. We also proposed a dual-stream information fusion module to fuse complementary features between different levels extracted from ultrasound and optical flow images. In addition, we proposed a learnable contour initialization method that eliminated the need for manual design of the initial contour, facilitating the rapid regression of nodes on the contour to the ground truth points. RESULTS: We verified our method by using a self-built dataset of carotid artery and jugular vein ultrasound images. The quantitative metrics demonstrated a bounding box detection mean average precision of 0.814 and a mask segmentation mean average precision of 0.842. Qualitative analysis of our results showed that our method achieved smoother segmentation boundaries for blood vessels. CONCLUSIONS: The dual-modal network we proposed effectively utilizes the complementary features of ultrasound and optical flow images. Compared to traditional single-modal instance segmentation methods, our approach more accurately segments the carotid artery and jugular vein in ultrasound images, demonstrating its potential for reliable and precise medical image analysis.

The transcription factor ZEB2 drives the formation of age-associated B cells.

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.

Comparative efficacy and tolerability of different anesthetics in electroconvulsive therapy for major depressive disorder: A systematic review and network meta-analysis.

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder. Modern ECT is conducted with anesthesia, however, the optimal anesthetic agent for ECT is yet to be understood. This study is aimed to compare the effects of different anesthetic agents on antidepressant efficacy and tolerability in depressed individuals undergoing ECT. We searched MEDLINE, EMBASE, the CENTRAL and PsycINFO for randomized controlled trials from database inception until Nov 13, 2022 (PROSPERO: CRD42022375407). Global and local inconsistencies, heterogeneity and publication bias were assessed. Rankings were calculated with the surface under the cumulative ranking curve. A total of 33 studies involving 1898 patients were enrolled. Remission rates were higher for ketamine anesthesia as compared to adjunctive ketamine and propofol. In terms of ranking, ketamine was found to be first in terms of response/remission rates and depressive scores after the 1st, 3rd and 6th ECT and at the end of ECT session, while a higher incidence of adverse events was also observed. No significant advantage of any anesthetic was revealed for the cognitive function after ECT. In summary, based on current evidence, no specific anesthetic is recommended for ECT anesthesia. However, despite more side effects, ketamine monoanesthesia seems to reveal a potential benefit in improving antidepressant efficacy of ECT, and further studies are needed to investigate the relationship between anesthetic agents and the therapeutic effect of ECT.

Biomarkers for systemic lupus erythematosus - a focus on organ damage.

INTRODUCTION: Systemic lupus erythematosus (SLE) is complex autoimmune disease with heterogenous manifestations, unpredictable disease course and response to treatment. One of the critical needs in SLE management is the identification of reliable biomarkers that can aid in early diagnosis, accurate monitoring of disease activity, and assessment of treatment response. AREAS COVERED: In the current review, we focus on the commonly affected organs (skin, kidney, and nervous system) in SLE to summarize the emerging biomarkers that show promise in disease diagnosis, monitoring and treatment response assessment. The subtitles within each organ domain were determined based on the most relevant and promising biomarkers for that specific organ damage. EXPERT OPINION: Biomarkers have the potential to significantly benefit the management of SLE by aiding in diagnosis, disease activity monitoring, prognosis, and treatment response assessment. However, despite decades of research, none has been validated and implemented for routine clinical use. Novel biomarkers could lead to the development of precision medicine for SLE, guide personalized treatment, and improve patient outcomes. Challenges in biomarker research in SLE include defining clear and clinically relevant questions, accounting for the heterogeneity of SLE, and confirming initial findings in larger, multi-center, multi-ethnic, independent cohorts that reflect real-world clinical scenarios.

Three-Dimensional Chromosomal Landscape Revealing miR-146a Dysfunctional Enhancer in Lupus and Establishing a CRISPR-Mediated Approach to Inhibit the Interferon Pathway.

OBJECTIVE: The diminished expression of microRNA-146a (miR-146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE-affected enhancers responsible for modulating miR-146a expression. Additionally, we aim to elucidate the mechanisms by which these enhancers influence the contribution of miR-146a to the activation of the interferon pathway. METHODS: Circular chromosome conformation capture sequencing and epigenomic profiles were applied to identify candidate enhancers of miR-146a. CRISPR activation was performed to screen functional enhancers. Differential analysis of chromatin accessibility was used to identify SLE-dysregulated enhancers, and the mechanism underlying enhancer dysfunction was investigated by analyzing transcription factor binding. The therapeutic value of a lupus-related enhancer was further evaluated by targeting it in the peripheral blood mononuclear cells (PBMCs) of patients with SLE through a CRISPR activation approach. RESULTS: We identified shared and cell-specific enhancers of miR-146a in distinct immune cells. An enhancer 32.5 kb downstream of miR-146a possesses less accessibility in SLE, and its chromatin openness was negatively correlated with SLE disease activity. Moreover, CCAAT/enhancer binding protein α, a down-regulated transcription factor in patients with SLE, binds to the 32.5-kb enhancer and induces the epigenomic change of this locus. Furthermore, CRISPR-based activation of this enhancer in SLE PBMCs could inhibit the activity of interferon pathway. CONCLUSION: Our work defines a promising target for SLE intervention. We adopted integrative approaches to define cell-specific and functional enhancers of the SLE critical gene and investigated the mechanism underlying its dysregulation mediated by a lupus-related enhancer.

Corrigendum: Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

[This corrects the article DOI: 10.3389/fimmu.2023.1200167.].

Exploring Spatio-Spectral Electroencephalogram Modulations of Imbuing Emotional Intent During Active Piano Playing.

Imbuing emotional intent serves as a crucial modulator of music improvisation during active musical instrument playing. However, most improvisation-related neural endeavors have been gained without considering the emotional context. This study attempts to exploit reproducible spatio-spectral electroencephalogram (EEG) oscillations of emotional intent using a data-driven independent component analysis framework in an ecological multiday piano playing experiment. Through the four-day 32-ch EEG dataset of 10 professional players, we showed that EEG patterns were substantially affected by both intra- and inter-individual variability underlying the emotional intent of the dichotomized valence (positive vs. negative) and arousal (high vs. low) categories. Less than half (3-4) of the 10 participants analogously exhibited day-reproducible ( ≥ three days) spectral modulations at the right frontal beta in response to the valence contrast as well as the frontal central gamma and the superior parietal alpha to the arousal counterpart. In particular, the frontal engagement facilitates a better understanding of the frontal cortex (e.g., dorsolateral prefrontal cortex and anterior cingulate cortex) and its role in intervening emotional processes and expressing spectral signatures that are relatively resistant to natural EEG variability. Such ecologically vivid EEG findings may lead to better understanding of the development of a brain-computer music interface infrastructure capable of guiding the training, performance, and appreciation for emotional improvisatory status or actuating music interaction via emotional context.

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

Objective: There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts. Methods: uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA. A longitudinal cohort includes 20 active Chinese LN patients. Results: uL-selectin was significantly increased in active LN patients compared to active non-renal SLE, inactive LN, inactive non-renal SLE, chronic kidney disease patients, and healthy controls. uL-selectin positively correlated with global and renal disease activities as well as histological activity index and chronicity index (CI). Low uL-selectin was an independent predictor for high CI. During follow-up, uL-selectin levels decreased significantly in the complete renal remission group. Conclusion: uL-selectin is a novel biomarker of disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.

Corrigendum: Identification of immune-associated genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning.

[This corrects the article DOI: 10.3389/fimmu.2023.1134412.].

Artificial intelligence can accurately distinguish IgA nephropathy from diabetic nephropathy under Masson staining and becomes an important assistant for renal pathologists.

Introduction: Hyperplasia of the mesangial area is common in IgA nephropathy (IgAN) and diabetic nephropathy (DN), and it is often difficult to distinguish them by light microscopy alone, especially in the absence of clinical data. At present, artificial intelligence (AI) is widely used in pathological diagnosis, but mainly in tumor pathology. The application of AI in renal pathological is still in its infancy. Methods: Patients diagnosed as IgAN or DN by renal biopsy in First Affiliated Hospital of Zhejiang Chinese Medicine University from September 1, 2020 to April 30, 2022 were selected as the training set, and patients who diagnosed from May 1, 2022 to June 30, 2022 were selected as the test set. We focused on the glomerulus and captured the field of the glomerulus in Masson staining WSI at 200x magnification, all in 1,000 × 1,000 pixels JPEG format. We augmented the data from training set through minor affine transformation, and then randomly split the training set into training and adjustment data according to 8:2. The training data and the Yolov5 6.1 algorithm were used to train the AI model with constant adjustment of parameters according to the adjusted data. Finally, we obtained the optimal model, tested this model with test set and compared it with renal pathologists. Results: AI can accurately detect the glomeruli. The overall accuracy of AI glomerulus detection was 98.67% and the omission rate was only 1.30%. No Intact glomerulus was missed. The overall accuracy of AI reached 73.24%, among which the accuracy of IgAN reached 77.27% and DN reached 69.59%. The AUC of IgAN was 0.733 and that of DN was 0.627. In addition, compared with renal pathologists, AI can distinguish IgAN from DN more quickly and accurately, and has higher consistency. Discussion: We constructed an AI model based on Masson staining images of renal tissue to distinguish IgAN from DN. This model has also been successfully deployed in the work of renal pathologists to assist them in their daily diagnosis and teaching work.

Acorus calamus recycled as an additional carbon source in a microbial fuel cell-constructed wetland for enhanced nitrogen removal.

Acorus calamus was recycled as an additional carbon source in microbial fuel cell-constructed wetlands (MFC-CWs), for efficient nitrogen removal of low carbon wastewater. The pretreatment methods, adding positions, and nitrogen transformations were investigated. Results indicated that alkali-pretreatment cleaved the benzene rings in dominant released organics, producing chemical oxygen demand of 164.5 mg from per gram of A. calamus. Pretreated biomass addition in the anode of MFC-CW attained the maximum total nitrogen removal of 97.6% and power generation of 12.5 mW/m2, which were higher than those with biomass in the cathode (97.6% and 1.6 mW/m2, respectively). However, the duration of a cycle with biomass in the cathode (20-25 days) was longer than that in the anode (10-15 days). Microbial metabolisms related to organics degradation, nitrification, denitrification, and anammox were intensified after biomass recycling. This study provides a promising method to improve nitrogen removal and energy recovery in MFC-CWs.

Identification of immune-associated genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning.

Background: In the pathogenesis of osteoarthritis (OA) and metabolic syndrome (MetS), the immune system plays a particularly important role. The purpose of this study was to find key diagnostic candidate genes in OA patients who also had metabolic syndrome. Methods: We searched the Gene Expression Omnibus (GEO) database for three OA and one MetS dataset. Limma, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms were used to identify and analyze the immune genes associated with OA and MetS. They were evaluated using nomograms and receiver operating characteristic (ROC) curves, and finally, immune cells dysregulated in OA were investigated using immune infiltration analysis. Results: After Limma analysis, the integrated OA dataset yielded 2263 DEGs, and the MetS dataset yielded the most relevant module containing 691 genes after WGCNA, with a total of 82 intersections between the two. The immune-related genes were mostly enriched in the enrichment analysis, and the immune infiltration analysis revealed an imbalance in multiple immune cells. Further machine learning screening yielded eight core genes that were evaluated by nomogram and diagnostic value and found to have a high diagnostic value (area under the curve from 0.82 to 0.96). Conclusion: Eight immune-related core genes were identified (FZD7, IRAK3, KDELR3, PHC2, RHOB, RNF170, SOX13, and ZKSCAN4), and a nomogram for the diagnosis of OA and MetS was established. This research could lead to the identification of potential peripheral blood diagnostic candidate genes for MetS patients who also suffer from OA.

Biomechanical performance of the novel assembled uncovertebral joint fusion cage in single-level anterior cervical discectomy and fusion: A finite element analysis.

Introduction: Anterior cervical discectomy and fusion (ACDF) is widely accepted as the gold standard surgical procedure for treating cervical radiculopathy and myelopathy. However, there is concern about the low fusion rate in the early period after ACDF surgery using the Zero-P fusion cage. We creatively designed an assembled uncoupled joint fusion device to improve the fusion rate and solve the implantation difficulties. This study aimed to assess the biomechanical performance of the assembled uncovertebral joint fusion cage in single-level ACDF and compare it with the Zero-P device. Methods: A three-dimensional finite element (FE) of a healthy cervical spine (C2-C7) was constructed and validated. In the one-level surgery model, either an assembled uncovertebral joint fusion cage or a zero-profile device was implanted at the C5-C6 segment of the model. A pure moment of 1.0 Nm combined with a follower load of 75 N was imposed at C2 to determine flexion, extension, lateral bending, and axial rotation. The segmental range of motion (ROM), facet contact force (FCF), maximum intradiscal pressure (IDP), and screw-bone stress were determined and compared with those of the zero-profile device. Results: The results showed that the ROMs of the fused levels in both models were nearly zero, while the motions of the unfused segments were unevenly increased. The FCF at adjacent segments in the assembled uncovertebral joint fusion cage group was less than that that of the Zero-P group. The IDP at the adjacent segments and screw-bone stress were slightly higher in the assembled uncovertebral joint fusion cage group than in those of the Zero-P group. Stress on the cage was mainly concentrated on both sides of the wings, reaching 13.4-20.4 Mpa in the assembled uncovertebral joint fusion cage group. Conclusion: The assembled uncovertebral joint fusion cage provided strong immobilization, similar to the Zero-P device. When compared with the Zero-P group, the assembled uncovertebral joint fusion cage achieved similar resultant values regarding FCF, IDP, and screw-bone stress. Moreover, the assembled uncovertebral joint fusion cage effectively achieved early bone formation and fusion, probably due to proper stress distributions in the wings of both sides.

Asynchronous photonic time-delay reservoir computing.

Time-delay reservoir computing uses a nonlinear node associated with a feedback loop to construct a large number of virtual neurons in the neural network. The clock cycle of the computing network is usually synchronous with the delay time of the feedback loop, which substantially constrains the flexibility of hardware implementations. This work shows an asynchronous reservoir computing network based on a semiconductor laser with an optical feedback loop, where the clock cycle (20 ns) is considerably different to the delay time (77 ns). The performance of this asynchronous network is experimentally investigated under various operation conditions. It is proved that the asynchronous reservoir computing shows highly competitive performance on the prediction task of Santa Fe chaotic time series, in comparison with the synchronous counterparts.