Robust controller design and experimental validation based on bounded uncertainty for collaborative industrial robots.

In this paper, derived from the proportional-derivative control and robust control, a novel practical robust control method based on a dynamic feedforward model is established by taking six-axis motion cooperative industrial robots as the research object. The nonlinear friction, parameter uncertainty, and external disturbance are taken into consideration while establishing the dynamic model of the cooperative industrial robot. The method includes a proportional-derivative control and a robust control. Lyapunov theory is used to analyze the proposed controller, and it is shown that this method can guarantee uniformly bounded and uniformly final bounded systems. Simulation and experiment results show that the proposed controller is better than proportional-integral-derivative control and mode-based proportional-derivative control in stability tracking performance and robustness. In addition, the CSPACE platform for rapid controller prototyping may reduce the arduous programming effort and offer a lot of ease for the trials.

Efficacy and safety of oncoplastic breast-conserving surgery versus conventional breast-conserving surgery: An updated meta-analysis.

INTRODUCTION: Breast cancer is the most common cancer among women. The surgical treatment of breast cancer has transitioned progressively from radical mastectomy to breast-conserving surgery. In this meta-analysis, we are aiming to compare oncoplastic breast-conserving surgery (OS) with conventional breast-conserving surgery (BCS) in terms of efficacy and safety. METHODS: We searched Medline, Web of Science, Embase, Cochrane databases, Clinicaltrial.gov, and CNKI until April 30, 2024. Data from cohort studies and randomized controlled trials (RCTs) were included. Outcomes included primary outcomes (re-excision, local recurrence, positive surgical margin, mastectomy), secondary outcomes and safety outcomes. The Cochrane Risk of Bias Assessment Tool and Newcastle-Ottawa Scale were used to evaluate the quality of outcomes. RESULTS: Our study included 52 studies containing 46,835 patients. Primary outcomes comprise re-excision, local recurrence, positive surgical margin, and mastectomy, there were significant differences favoring OS over BCS (RR 0.68 [0.56, 0.82], RR 0.62 [0.47, 0.82], RR 0.76 [0.59, 0.98], RR 0.66 [0.44, 0.98] respectively), indicating superior efficacy of OS. Additionally, OS demonstrated significant aesthetic benefits (RR 1.17 [1.03, 1.33] and RR 1.34 [1.18, 1.52]). While total complications were significantly fewer in the OS group (RR 0.70 [0.53, 0.94]), the differences in specific complications were not significant. Furthermore, subgroup analyses were conducted based on nationality, sample size, quality, and type. CONCLUSION: OS demonstrates either superior or at least comparable outcomes across various aspects when compared to BCS.

Leachate derived humic-like substances drive the variation in microbial communities in landfill-affected groundwater.

Landfills are commonly used for waste disposal in many countries, and pose a significant threat of groundwater contamination. Dissolved organic matter (DOM) plays a crucial role as a carbon and energy source, supporting the growth and activity of microorganisms. However, the changes in the DOM signature and microbial community composition in landfill-affected groundwater and their bidirectional relationships remain inadequately explored. Herein, we showed that DOM originating from more recent landfills mainly comprises microbially produced substances resembling tryptophan and tyrosine. Conversely, DOM originating from older landfills predominantly comprises fulvic-like and humic-like compounds. Leachate leakage increases microbial diversity and richness and facilitates the transfer of foreign bacteria from landfills to groundwater, thereby increasing the vulnerability of the microbial ecosystem in groundwater. Deterministic processes dominated the assembly of the groundwater microbial community, while stochastic processes accounted for an increased proportion of the microbial community in the old landfills. The dominant phyla observed in groundwater were Proteobacteria, Bacteroidota, and Actinobacteriota, and humic-like substances play a crucial role in driving the variation in microbial communities in landfill-affected groundwater. Predictions using PICRUSt2 suggested significant associations between various metabolic pathways and microbial communities, with the Kyoto Encyclopedia of Genes and Genomes pathway "Metabolism" being the most predominant. The findings contribute to advancing our understanding of the transformation of DOM and its interplay with microbial communities and can serve as a scientific reference for decision-making regarding groundwater pollution monitoring and remediation.

Pseudorabies virus usurps non-muscle myosin heavy chain IIA to dampen viral DNA recognition by cGAS for antagonism of host antiviral innate immunity.

Alphaherpesvirus pseudorabies virus (PRV) causes severe economic losses to the global pig industry and has garnered increasing attention due to its broad host range including humans. PRV has developed a variety of strategies to antagonize host antiviral innate immunity. However, the underlying mechanisms have not been fully elucidated. In our previous work, we demonstrated that non-muscle myosin heavy chain IIA (NMHC-IIA), a multifunctional cytoskeleton protein, attenuates innate immune responses triggered by RNA viruses. In the current study, we reported a previously unrecognized role of NMHC-IIA in counteracting PRV-induced cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) production. Mechanistically, PRV infection led to an elevation of NMHC-IIA, strengthening the interaction between poly (ADP-ribose) polymerase 1 (PARP1) and cGAS. This interaction impeded cGAS recognition of PRV DNA and hindered downstream signaling activation. Conversely, inhibition of NMHC-IIA by Blebbistatin triggered innate immune responses and enhanced resistance to PRV proliferation both in vitro and in vivo. Taken together, our findings unveil that PRV utilizes NMHC-IIA to antagonize host antiviral immune responses via impairing DNA sensing by cGAS. This in-depth understanding of PRV immunosuppression not only provides insights for potential PRV treatment strategies but also highlights NMHC-IIA as a versatile immunosuppressive regulator usurped by both DNA and RNA viruses. Consequently, NMHC-IIA holds promise as a target for the development of broad-spectrum antiviral drugs.IMPORTANCECyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in counteracting alphaherpesvirus infections. Alphaherpesviruses exploit various strategies for antagonizing cGAS-STING-mediated antiviral immune responses. However, limited examples of pseudorabies virus (PRV)-caused immunosuppression have been documented. Our findings reveal a novel role of non-muscle myosin heavy chain IIA (NMHC-IIA) in suppressing PRV-triggered innate immune responses to facilitate viral propagation both in vitro and in vivo. In detail, NMHC-IIA recruits poly (ADP-ribose) polymerase 1 (PARP1) to augment its interaction with cGAS, which impairs cGAS recognition of PRV DNA. Building on our previous demonstration of NMHC-IIA's immunosuppressive role during RNA virus infections, these findings indicate that NMHC-IIA acts as a broad-spectrum suppressor of host antiviral innate immunity in response to both DNA and RNA viruses. Therefore, NMHC-IIA will be a promising target for the development of comprehensive antiviral strategies.

[Dynamic Analysis on Carbon Metabolism of the Northern Region of China Under the Background of Carbon Emission Trading Policy].

The launch of the national carbon emissions trading market in China is a policy to carry out the Beautiful China initiative and to establish a low-carbon economic development system that promotes carbon emission and waste reduction. In order to detect the carbon metabolic processes of the pilot and nonpilot municipalities or provinces in the northern region of China， the theory of urban carbon metabolism and the methods of input-output analysis and ecological network analysis were introduced and used. The results showed that the direct carbon emissions of Beijing and Tianjin had decreased， but their embodied carbon emissions had increased since 2012. The direct and embodied carbon emissions of the pilot sectors in Beijing and Tianjin had the same trend； specifically， the emissions of the sectors of mining and washing of coal， extraction of petroleum and natural gas， and manufacture of non-metallic mineral products decreased significantly， but the sectors of production and supply of electric power and steam with high carbon emission increased. The same trend of the embodied carbon emission intensities of sectors with that of their embodied carbon emissions verified that the embodied added values were not growing with the promotion of the carbon emission trading market. Subsequently， the embodied carbon emission of the pilot sectors in all the municipalities and provinces of the northern region were all contributed mainly by the emissions embodied by a path length less than 6； therefore， it showed that more attention should be paid to the trade among sectors with a path length less than 6 and reducing their carbon emissions. Furthermore， from 2007 to 2012， products or service trading among sectors mostly concentrated on sectors within one municipality or province， and these products or services had the characteristics of low carbon emission. Since 2012， the integration development of the Beijing-Tianjin-Hebei urban agglomeration and the new regional economic patterns established in the northern region both promoted the trading across provinces and across sectors. This research is based on the background of the carbon emission trading policy and aims to build a methodology to identify the key actors and paths in a metabolic system. This could provide a scientific basis for regional policy implementation and regional long-term sustainable development.

Ruxolitinib attenuates microglial inflammatory response by inhibiting NF-κB/MAPK signaling pathway.

Neuroinflammation is involved in the physiological and pathological processes of numerous neurological diseases, and its inhibition seems to be a promising therapeutic direction for these diseases. Ruxolitinib is a classical Janus kinase (JAK) inhibitor that is oral, highly potent and bioavailable, which has recently gained approval from the US Food and Drug Administration (FDA) for the treatment of inflammatory disorders. The potential inhibitory effect of ruxolitinib on neuroinflammation has not been fully studied. In the lipopolysaccharide (LPS) induced neuroinflammatory cell model, we observed that ruxolitinib reduced the levels of IL-1ß, IL-6 and tumor necrosis factor-α (TNF-α) expression, and neuroinflammation by inhibiting the Mitogen-Activated Protein Kinase/Nuclear factor-κ B (MAPK/NF-κB) signaling pathway. Similarly, mice injected intracerebroventricular with ruxolitinib exhibited significantly reduced LPS-stimulated activation of microglia and astrocytes, and expression of proinflammatory cytokine IL-1ß, TNF-α and IL-6. These results demonstrate that ruxolitinib attenuates the neuroinflammatory responses both in vivo and in vitro, at least in part by inhibiting MAPK/NF-κB signaling pathway. Our findings suggest that ruxolitinib may serve as a potential drug for the treatment of microglia-mediated neuroinflammation.

Automatic Detection of 30 Fundus Diseases Using Ultra-Widefield Fluorescein Angiography with Deep Experts Aggregation.

INTRODUCTION: Inaccurate, untimely diagnoses of fundus diseases leads to vision-threatening complications and even blindness. We built a deep learning platform (DLP) for automatic detection of 30 fundus diseases using ultra-widefield fluorescein angiography (UWFFA) with deep experts aggregation. METHODS: This retrospective and cross-sectional database study included a total of 61,609 UWFFA images dating from 2016 to 2021, involving more than 3364 subjects in multiple centers across China. All subjects were divided into 30 different groups. The state-of-the-art convolutional neural network architecture, ConvNeXt, was chosen as the backbone to train and test the receiver operating characteristic curve (ROC) of the proposed system on test data and external test date. We compared the classification performance of the proposed system with that of ophthalmologists, including two retinal specialists. RESULTS: We built a DLP to analyze UWFFA, which can detect up to 30 fundus diseases, with a frequency-weighted average area under the receiver operating characteristic curve (AUC) of 0.940 in the primary test dataset and 0.954 in the external multi-hospital test dataset. The tool shows comparable accuracy with retina specialists in diagnosis and evaluation. CONCLUSIONS: This is the first study on a large-scale UWFFA dataset for multi-retina disease classification. We believe that our UWFFA DLP advances the diagnosis by artificial intelligence (AI) in various retinal diseases and would contribute to labor-saving and precision medicine especially in remote areas.

MyD88 signaling pathways: role in breast cancer.

MyD88 plays a central role in breast cancer, exerting a multitude of effects that carry substantial implications. Elevated MyD88 expression is closely associated with aggressive tumor characteristics, suggesting its potential as a valuable prognostic marker and therapeutic target. MyD88 exerts influence over several critical aspects of breast cancer, including metastasis, recurrence, drug resistance, and the regulation of cancer stem cell properties. Furthermore, MyD88 modulates the release of inflammatory and chemotactic factors, thereby shaping the tumor's immune microenvironment. Its role in immune response modulation underscores its potential in influencing the dynamic interplay between tumors and the immune system. MyD88 primarily exerts intricate effects on tumor progression through pathways such as Phosphoinositide 3-kinases/Protein kinase B (PI3K/Akt), Toll-like Receptor/Nuclear Factor Kappa B (TLR/NF-κB), and others. Nevertheless, in-depth research is essential to unveil the precise mechanisms underlying the diverse roles of MyD88 in breast cancer. The translation of these findings into clinical applications holds great promise for advancing precision medicine approaches for breast cancer patients, ultimately enhancing prognosis and enabling the development of more effective therapeutic strategies.

G3BP1 Interact with JAK2 mRNA to Promote the Malignant Progression of Nasopharyngeal Carcinoma via Activating JAK2/STAT3 Signaling Pathway.

Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is an RNA-binding protein implicated in various malignancies. However, its role in nasopharyngeal carcinoma (NPC) remains elusive. This study elucidates the potential regulation mechanisms of G3BP1 and its significance in NPC advancement. Through knockdown and overexpression approaches, we validate G3BP1's oncogenic role by promoting proliferation, migration, and invasion in vitro and in vivo. Moreover, G3BP1 emerges as a key regulator of the JAK2/STAT3 signaling pathway, augmenting JAK2 expression via mRNA binding. Notably, epigallocatechin gallate (EGCG), a green tea-derived antioxidant, counteracts G3BP1-mediated pathway activation. Clinical analysis reveals heightened G3BP1, JAK2, and p-STAT3 as powerful prognostic markers, with G3BP1's expression standing as an independent indicator of poorer outcomes for NPC patients. In conclusion, the study unveils the oncogenic prowess of G3BP1, its orchestration of the JAK2/STAT3 signaling pathway, and its pivotal role in NPC progression.

RELATIONSHIP BETWEEN RETINAL HEMORRHAGE ON GREEN AND RED CHANNELS OF ULTRA-WIDEFIELD FUNDUS IMAGES AND RETINAL PERFUSION IN ACUTE BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To explore the relationship between retinal hemorrhage in the green and red channels on ultra-widefield fundus images and the nonperfusion area (NPA) on ultra-widefield fundus fluorescein angiography in patients with acute branch retinal vein occlusion (BRVO). METHODS: This was a retrospective cross-sectional study with 96 patients, including 46 with ischemic BRVO and 50 with nonischemic BRVO. Correlation analysis between green channel hemorrhage (GCH), red channel hemorrhage (RCH), and NPA was performed. Panretina was divided into posterior and peripheral areas. RESULTS: Ischemic BRVO showed significantly higher GCH% and RCH% than nonischemic BRVO in the peripheral regions (both P < 0.001), whereas no significant differences were observed in the panretinal and posterior areas (all P > 0.05). Significant correlations were found between NPA% in the panretinal and peripheral areas and the corresponding GCH% and RCH% (all P < 0.01). However, no significant correlation was observed between posterior NPA% and posterior GCH% or RCH% (both P > 0.05). In addition, peripheral GCH% and RCH% were related to panretinal NPA% (r = 0.506, P < 0.001; r = 0.558, P < 0.001). CONCLUSION: Retinal hemorrhage on ultra-widefield fundus image was significantly associated with NPA, providing insights for assessing retinal perfusion status in acute BRVO patients.

Somatostatin receptor2 (SSTR2) expression, prognostic implications, modifications and potential therapeutic strategies associates with head and neck squamous cell carcinomas.

Head and neck squamous cell carcinomas (HNSCC) constitute a heterogeneous cluster of tumors celebrated for their predisposition to metastasize and exhibit local recurrence. Recent explorations have illuminated the intricate involvement of Somatostatin Receptor 2 (SSTR2), a growth-regulatory receptor traditionally classified as a tumor suppressor, yet concurrently implicated in bolstering specific tumor phenotypes. Advances in the realm of SSTR2 investigation within HNSCC, with a specific spotlight on laryngeal squamous cell carcinomas (LSCC), tongue squamous cell carcinomas (TSCC), and nasopharyngeal carcinomas (NPC), have been established. This study aims to provide a comprehensive overview of SSTR2 expression patterns, prognostic implications, distinctive signaling pathways, epigenetic modifications, and potential therapeutic strategies associated with SSTR2 in HNSCC.

Non-adherent culture method affects the proliferation and apoptosis of mesenchymal stem cells through inhibiting LINC00707 to promote RNF6-mediated QKI ubiquitination.

Exploration of the molecular mechanisms of mesenchymal stem cell (MSC) growth has significant clinical benefits. Long non-coding RNAs (lncRNAs) have been reported to play vital roles in the regulation of the osteogenic differentiation of MSCs. However, the mechanism by which lncRNA affects the proliferation and apoptosis of MSCs is unclear. In this study, sequencing analysis revealed that LINC00707 was significantly decreased in non-adherent human MSCs (non-AC-hMSCs) compared to adherent human MSCs. Moreover, LINC00707 overexpression promoted non-AChMSC proliferation, cell cycle progression from the G0/G1 phase to the S phase and inhibited apoptosis, whereas LINC00707 silencing had the opposite effect. Furthermore, LINC00707 interacted directly with the quaking (QKI) protein and enhanced the E3 ubiquitin-protein ligase ring finger protein 6 (RNF6)-mediated ubiquitination of the QKI protein. Additionally, the overexpression of QKI rescued the promotive effects on proliferation and inhibitory effects on apoptosis in non-AC-hMSCs induced by the ectopic expression of LINC00707. Thus, LINC00707 contributes to the proliferation and apoptosis in non-AChMSCs by regulating the ubiquitination and degradation of the QKI protein.

Relationship between ischemic index, leakage index, and macular edema in branch retinal vein occlusion.

PURPOSE: To investigate the combined association of the ischemic index and leakage index with macular edema on ultra-widefield fluorescein angiography (UWFFA) in patients with branch retinal vein occlusion (BRVO). METHODS: Retrospective image analysis study. The leakage index and ischemic index were calculated using Fiji after aligning early and late UWFFA images. Differences in the ischemic index, leakage index, and central macular thickness (CMT) between ischemic and non-ischemic BRVO were compared. Moreover, the association between the ischemic index, leakage index, and macular edema was analyzed. RESULTS: Eighty-three patients with BRVO were enrolled, including 53 non-ischemic BRVO and 30 ischemic BRVO patients. No significant differences were observed in leakage index and CMT between ischemic BRVO and non-ischemic BRVO (all P > 0.05). In all included patients, CMT correlated with the panretina and all subregion leakage indexes (all P < 0.01), but not with the ischemic index (all P > 0.05). In the ischemic BRVO group, CMT showed a correlation with the leakage index in several regions, but not with the ischemic index. After adjusting for the ischemic index and other clinical features, CMT remained significantly correlated with the leakage index in all regions. CONCLUSION: The leakage index may be a more effective biomarker for monitoring BRVO-associated macular edema compared to the ischemic index. Further follow-up studies are warranted to validate these findings.

Classification of diabetic maculopathy based on optical coherence tomography images using a Vision Transformer model.

PURPOSE: To develop a Vision Transformer model to detect different stages of diabetic maculopathy (DM) based on optical coherence tomography (OCT) images. METHODS: After removing images with poor quality, a total of 3319 OCT images were extracted from the Eye Center of the Renmin Hospital of Wuhan University and randomly split the images into training and validation sets in a 7:3 ratio. All macular cross-sectional scan OCT images were collected retrospectively from the eyes of DM patients from 2016 to 2022. One of the OCT stages of DM, including early diabetic macular oedema (DME), advanced DME, severe DME and atrophic maculopathy, was labelled on the collected images, respectively. A deep learning (DL) model based on Vision Transformer was trained to detect four OCT grading of DM. RESULTS: The model proposed in our paper can provide an impressive detection performance. We achieved an accuracy of 82.00%, an F1 score of 83.11%, an area under the receiver operating characteristic curve (AUC) of 0.96. The AUC for the detection of four OCT grading (ie, early DME, advanced DME, severe DME and atrophic maculopathy) was 0.96, 0.95, 0.87 and 0.98, respectively, with an accuracy of 90.87%, 89.96%, 94.42% and 95.13%, respectively, a precision of 88.46%, 80.31%, 89.42% and 87.74%, respectively, a sensitivity of 87.03%, 88.18%, 63.39% and 89.42%, respectively, a specificity of 93.02%, 90.72%, 98.40% and 96.66%, respectively and an F1 score of 87.74%, 84.06%, 88.18% and 88.57%, respectively. CONCLUSION: Our DL model based on Vision Transformer demonstrated a relatively high accuracy in the detection of OCT grading of DM, which can help with patients in a preliminary screening to identify groups with serious conditions. These patients need a further test for an accurate diagnosis, and a timely treatment to obtain a good visual prognosis. These results emphasised the potential of artificial intelligence in assisting clinicians in developing therapeutic strategies with DM in the future.

Relationship between the circulating N-terminal pro B-type natriuretic peptide and the risk of carotid artery plaque in different glucose metabolic states in patients with coronary heart disease: a CSCD-TCM plus study in China.

OBJECTIVE: Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a marker for heart failure in patients with coronary heart disease (CHD) and associated with glycemic abnormalities. Studies on the association and diagnostic value of NT-proBNP in carotid plaques (CAP) in patients with CHD are limited. METHODS: The relationships between NT-proBNP and the risk of CAP in different glucose metabolic states, sexes, and age categories were also examined using 5,093 patients diagnosed with CHD. The NT-proBNP tertiles were used to divide patients into three groups in which the NT-proBNP levels, blood glucose levels, the occurrence of CAP, and the number and nature of CAP were measured using normoglycemic (NG), prediabetes (Pre-DM), and diabetes mellitus (DM) glucose metabolic statuses. Logistic regression analyses were used to compare the relationship between NT-proBNP and the risk of CAP occurrence and the number and nature of CAP. The diagnostic value of NT-proBNP for CAP risk was measured using receiver operating characteristic (ROC) curves. RESULTS: We found a 37% relative increase in the correlation between changes in NT-proBNP per standard deviation (SD) and the incidence of CAP. After adjusting for potential confounders, NT-proBNP at the T3 level was found to be associated with an increased CAP odds ratio (OR) when T1 was used as the reference. This relationship was also present in males, patients aged > 60 years, or both pre-DM and DM states. NT-proBNP was more likely to present as hypoechoic plaques at T1 and as mixed plaques at T3. We also measured the diagnostic accuracy of CAP for NT-proBNP in patients with CHD, with an AUC value of 0.627(95% CI 0.592-0.631), sensitivity of 50.7%, and specificity of 68.0%. CONCLUSION: An increase in NT-proBNP was significantly associated with the risk of CAP in patients with CHD, especially in males and patients aged > 60 years, and exhibited specific characteristics under different glucose metabolism states. Trial registration The study was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (Approval number TJUTCM-EC20210007) and certified by the Chinese Clinical Trials Registry on April 4, 2022 (Registration number ChiCTR2200058296) and March 25, 2022 by ClinicalTrials.gov (registration number NCT05309343).

Left atrial appendage occlusion using the LAmbre device in atrial fibrillation patients with a history of ischemic stroke: 1-Year outcomes from a multicenter study in China.

BACKGROUND: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke have a significantly higher risk of stroke recurrence. This study aimed to examine the safety and efficacy of the LAmbre left atrial appendage occlusion device in NVAF patients with a history of stroke. METHODS: We examined 103 consecutive NVAF patients in 11 Chinese medical centers who had a history of stroke or transient ischemic attacks (TIA) and underwent placement of the LAmbre device. Follow-up was conducted 1, 3, 6, and 12 months after the procedure. The primary endpoints were the incidence of new ischemic or hemorrhagic stroke, TIA, systemic embolism, or cardiac death. Secondary endpoints were serious perioperative or device-related complications and cerebral, gastrointestinal, or other bleeding events requiring transfusion of at least 2 units of packed red blood cells. RESULTS: Mean patient age was 67.63 ± 7.14 years; mean CHA2DS2-VASc score was 4.72 ± 1.18 and mean HAS-BLED score was 1.90 ± 1.00. LAmbre device placement was successful in 101 patients (98.05%). Mean follow-up was 12.2 months. Five patients (4.95%) developed a new pericardial effusion after the procedure; none required treatment. Eighty-six patients (85.15%) exhibited no peri-device leak (PDL). However, 13 (12.8%) had a small (0-3 mm) PDL and two (2.3%) had a moderate PDL (3-5 mm). One recurrent stroke occurred during follow-up (1.1%). No other complications occurred. CONCLUSIONS: This multicenter study shows the safety and efficacy of LAmbre left atrial appendage occlusion for NVAF patients with a history of stroke or TIA.

RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

Deep Learning-Based Model for Automatic Assessment of Anterior Angle Chamber in Ultrasound Biomicroscopy.

OBJECTIVE: The goal of the work described here was to develop and assess a deep learning-based model that could automatically segment anterior chamber angle (ACA) tissues; classify iris curvature (I-Curv), iris root insertion (IRI), and angle closure (AC); automatically locate scleral spur; and measure ACA parameters in ultrasound biomicroscopy (UBM) images. METHODS: A total of 11,006 UBM images were obtained from 1538 patients with primary angle-closure glaucoma who were admitted to the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. The UNet++ network was used to segment ACA tissues automatically. In addition, two support vector machine (SVM) algorithms were developed to classify I-Curv and AC, and a logistic regression (LR) algorithm was developed to classify IRI. Meanwhile, an algorithm was developed to automatically locate the scleral spur and measure ACA parameters. An external data set of 1,658 images from Huangshi Aier Eye Hospital was used to evaluate the performance of the model under different conditions. An additional 439 images were collected to compare the performance of the model with experts. RESULTS: The model achieved accuracies of 95.2%, 88.9% and 85.6% in classification of AC, I-Curv and IRI, respectively. Compared with ophthalmologists, the model achieved an accuracy of 0.765 in classifying AC, I-Curv and IRI, indicating that its high accuracy was as high as that of the ophthalmologists (p > 0.05). The average relative errors (AREs) of ACA parameters were smaller than 15% in the internal data sets. Intraclass correlation coefficients (ICCs) of all the angle-related parameters were greater than 0.911. ICC values of all iris thickness parameters were greater than 0.884. The accurate measurement of ACA parameters partly depended on accurate localization of the scleral spur (p < 0.001). CONCLUSION: The model could effectively and accurately evaluate the ACA automatically based on fully automated analysis of UBM images, and it can potentially be a promising tool to assist ophthalmologists. The present study suggested that the deep learning model can be extensively applied to the evaluation of ACA and AC-related biometric risk factors, and it may broaden the application of UBM imaging in the clinical research of primary angle-closure glaucoma.

Lysosome and related protein degradation technologies.

Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway. In addition, we thoroughly examine the potential applications and limitations of this technology and engage in insightful discussions on potential avenues for future research. Our primary objective is to foster preclinical research on this technology and facilitate its successful clinical implementation.

Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer.

Oncogenic KRAS mutations are a key driver for initiation and progression in non-small cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, is recruited and promotes KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results define a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.