Anti-inflammatory effects of MerTK by inducing M2 macrophage polarization via PI3K/Akt/GSK-3ß pathway in gout.

Mer tyrosine kinase (MerTK) has been found to regulate the secretion of inflammatory factors and exert immunosuppressive effects, but its role in gout remains unclear. In this study, we aimed to clarify the immnue effects of MerTK in gout. MerTK in synovium or serum of gout patients was determined by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). In monosodium urate (MSU)-induced gout mice, the effect of MerTK inhibitor (UNC2250) on inflammation and polarization was also assessed. After inhibition, knockdown or overexpression of MerTK, inflammatory response and polarization level in THP1-derived macrophages were evaluated by RT-qPCR and flow cytometry. Regulation of MerTK inhibitors on mitochondrial function and downstream pathway in THP1-derived macrophages were detected. MerTK in synovium and serum of gout patients were increased. MerTK inhibitor stimulated the inflammation and M1 polarization in MSU-induced gout mice. MerTK inhibition, knock-down, or overexpression affected inflammatory response, polarization and mitochondrial function in vitro in gout model. The PI3K/Akt/GSK-3ß pathway was identified to reduce after MerTK inhibition and the relevant results were as expected, validated by knock-down or overexpressing MerTK. In conclusion, MerTK was detected to increase in both gout patients and model. MerTK influenced inflammatory response and polarization markers through PI3K/Akt/GSK-3ß pathway. Interfering MerTK/PI3K/Akt/GSK-3ß axis may provide a new therapeutic target for gout.

Trends in disease burden and risk factors of asthma from 1990 to 2019 in Belt and Road Initiative countries: evidence from the Global Burden of Disease Study 2019.

This study outlines asthma burden trends across age, sex, regions and risk factors in 'Belt and Road' (B&R) countries from 1990 to 2019 using the Global Burden of Disease Study 2019 data. Incidence, mortality, prevalence, years lived with disability (YLDs), disability-adjusted life years (DALYs) and risk factors for asthma were measured. India, China and Indonesia bore the heaviest burden in 2019. Despite the significant decline in the average annual percent change for age-standardized mortality and years of life lost from 1990 to 2019, increases were observed in several East Asian, Central Asian, North African and Middle Eastern countries between 2010 and 2019. For both sexes, YLDs decreased in most B&R countries but increased in Montenegro, Saudi Arabia, Armenia, Vietnam and Oman. YLDs in Georgia, the United Arab Emirates and Albania increased in males but decreased in females. YLDs increased for those aged <15 years in Central Asia and Europe, while China's 50-74-year age group showed the lowest YLD change. High body mass index (BMI) led to increased YLDs in East, Central and Southeast Asia; North Africa; and the Middle East. Conclusively, asthma burden varies significantly by country. Tailoring control efforts to specific regions, sex and high BMI could enhance asthma management.

Meta-analysis of hybrid immunity to mitigate the risk of Omicron variant reinfection.

Background: Hybrid immunity (a combination of natural and vaccine-induced immunity) provides additional immune protection against the coronavirus disease 2019 (COVID-19) reinfection. Today, people are commonly infected and vaccinated; hence, hybrid immunity is the norm. However, the mitigation of the risk of Omicron variant reinfection by hybrid immunity and the durability of its protection remain uncertain. This meta-analysis aims to explore hybrid immunity to mitigate the risk of Omicron variant reinfection and its protective durability to provide a new evidence-based basis for the development and optimization of immunization strategies and improve the public's awareness and participation in COVID-19 vaccination, especially in vulnerable and at-risk populations. Methods: Embase, PubMed, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases were searched for publicly available literature up to 10 June 2024. Two researchers independently completed the data extraction and risk of bias assessment and cross-checked each other. The Newcastle-Ottawa Scale assessed the risk of bias in included cohort and case-control studies, while criteria recommended by the Agency for Health Care Research and Quality (AHRQ) evaluated cross-sectional studies. The extracted data were synthesized in an Excel spreadsheet according to the predefined items to be collected. The outcome was Omicron variant reinfection, reported as an Odds Ratio (OR) with its 95% confidence interval (CI) and Protective Effectiveness (PE) with 95% CI. The data were pooled using a random- or fixed-effects model based on the I2 test. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Thirty-three articles were included. Compared with the natural immunity group, the hybrid immunity (booster vaccination) group had the highest level of mitigation in the risk of reinfection (OR = 0.43, 95% CI:0.34-0.56), followed by the complete vaccination group (OR = 0.58, 95% CI:0.45-0.74), and lastly the incomplete vaccination group (OR = 0.64, 95% CI:0.44-0.93). Compared with the complete vaccination-only group, the hybrid immunity (complete vaccination) group mitigated the risk of reinfection by 65% (OR = 0.35, 95% CI:0.27-0.46), and the hybrid immunity (booster vaccination) group mitigated the risk of reinfection by an additional 29% (OR = 0.71, 95% CI:0.61-0.84) compared with the hybrid immunity (complete vaccination) group. The effectiveness of hybrid immunity (incomplete vaccination) in mitigating the risk of reinfection was 37.88% (95% CI, 28.88-46.89%) within 270-364 days, and decreased to 33.23%% (95% CI, 23.80-42.66%) within 365-639 days; whereas, the effectiveness after complete vaccination was 54.36% (95% CI, 50.82-57.90%) within 270-364 days, and the effectiveness of booster vaccination was 73.49% (95% CI, 68.95-78.04%) within 90-119 days. Conclusion: Hybrid immunity was significantly more protective than natural or vaccination-induced immunity, and booster doses were associated with enhanced protection against Omicron. Although its protective effects waned over time, vaccination remains a crucial measure for controlling COVID-19. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier, CRD42024539682.

Concrete Defect Localization Based on Multilevel Convolutional Neural Networks.

Concrete structures frequently manifest diverse defects throughout their manufacturing and usage processes due to factors such as design, construction, environmental conditions and distress mechanisms. In this paper, a multilevel convolutional neural network (CNN) combined with array ultrasonic testing (AUT) is proposed for identifying the locations of hole defects in concrete structures. By refining the detection area layer by layer, AUT is used to collect ultrasonic signals containing hole defect information, and the original echo signal is input to CNN for the classification of hole locations. The advantage of the proposed method is that the corresponding defect location information can be obtained directly from the input ultrasonic signal without manual discrimination. It effectively addresses the issue of traditional methods being insufficiently accurate when dealing with complex structures or hidden defects. The analysis process is as follows. First, COMSOL-Multiphysics finite element software is utilized to simulate the AUT detection process and generate a large amount of ultrasonic echo data. Next, the extracted signal data are trained and learned using the proposed multilevel CNN approach to achieve progressive localization of internal structural defects. Afterwards, a comparative analysis is conducted between the proposed multilevel CNN method and traditional CNN approaches. The results show that the defect localization accuracy of the proposed multilevel CNN approach improved from 85.38% to 95.27% compared to traditional CNN methods. Furthermore, the computation time required for this process is reduced, indicating that the method not only achieves higher recognition precision but also operates with greater efficiency. Finally, a simple experimental verification is conducted; the results show that this method has strong robustness in recognizing noisy ultrasonic signals, provides effective solutions, and can be used as a reference for future defect detection.

Clinical stratification of 1318 Primary Sjögren's Syndrome patients.

OBJECTIVE: Primary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by diverse clinical manifestations yet lacking effective therapeutic strategies currently. This study aims to gain a thorough understanding of the clinical landscape of pSS and further delineate its clinical subtypes, thereby enabling the efficient management for pSS. METHODS: We conducted a cross-sectional observational study of 1318 pSS patients. The pSS patients were categorized and compared based on gender, anti-SSA antibodies, and labial salivary gland biopsies (LGSB). Unsupervised clustering analysis was employed to identify pSS subtypes using systemic involvement among patients. Furthermore, we assessed clinical and biological variances among these subtypes. RESULTS: Through group comparisons, we observed more pronounced extraglandular manifestations among male patients, SSA-negative group, and those with positive LGSB results. Based on systemic involvement, pSS patients were categorized into four groups. C1 exhibited minimal systemic involvement, lacking hematologic or serologic manifestations, with the lowest ESSDAI scores. C2 presented with serologic changes in all patients, partial joint involvement, and no hematologic systemic manifestations. C3 lacked joint involvement but all members displayed hematologic systemic involvement, with higher rates of renal, cutaneous, and systemic manifestations. C4 encompassed patients with joint and hematologic involvement, displaying the highest ESSDAI scores. The positivity rates of antibodies, immunological parameters, and inflammatory markers exhibited significant differences among the groups. Furthermore, notable variances were observed in the expression of peripheral blood transcriptomic modules among these groups. CONCLUSION: In this cohort study, we summarized the clinical characteristics of Chinese patients with pSS and identified four distinct subgroups of pSS based on systemic involvement, revealing clinical and molecular disparities that unveil distinct pathobiological endotypes. Our findings hold significant implications for clinical management.

Advanced nitrogen removal of sulfur-driven autotrophic denitrification from landfill leachate after partial nitrification and denitrification pretreatment.

Sulfur-driven autotrophic denitrification (S0dAD) was employed to remove residual nitrogen from the biological effluent of landfill leachate after partial nitrification and denitrification pretreatment. The performance of S0dAD were assessed with various NOx--N (NO2--N and NO3--N) loadings over a 185-day operational period. The results demonstrated that a notable NOx--N removal efficiency of 97.8 ± 2.0% was achieved under nitrogen removal rates of 0.12 ± 0.02 kg N/(m3· d), leading to total nitrogen concentrations of 8.6 ± 3.8 mg/L in the effluent. Batch experiments revealed competitive utilization of nitrogenous electron acceptors, with NO2--N demonstrating 2-4 times higher denitrification rates than NO3--N under coexistence conditions. Genus-level microbial community identified that Thiobacillus and Sulfurovum was highly enriched with as key denitrifying bacteria in the S0dAD system. These findings provide insights for advanced nitrogen removal coupling S0dAD with partial nitrification and denitrification process for landfill leachate treatment.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Primary hepatic lymphoma presenting as pyogenic liver abscess: A case report.

BACKGROUND: Primary hepatic lymphoma (PHL) is a lymphoproliferative disorder confined to the liver without peripheral lymph node involvement and bone marrow invasion. PHL is extremely rare in clinical practice. The etiology and pathogenesis of PHL are largely unknown. There are no common standard protocols or guidelines for the treatment of PHL. CASE SUMMARY: We report the case of a 66-year-old man who presented with fever and abdominal pain for three weeks. Computed tomography and magnetic resonance imaging scans showed a pyogenic liver abscess. The patient underwent a right posterior hepatectomy. The surgical pathology revealed aggressive B-cell lymphoma, with a primary consideration of diffuse large B-cell lymphoma of non-germinal center origin. CONCLUSION: This article reviews the characteristics, mechanism and treatment of PHL and provides insight into the diagnosis of PHL.

Dynamic influence of maternal education on height among Chinese children aged 0-18 years.

Background: Maternal education is one of key factors affecting nurturing environment which significantly impacts children's height levels throughout their developmental stages. However, the influence of maternal education on children's height is less studied. This study aims to investigate the dynamic influence of maternal education on children's height among Chinese children aged 0-18 years. Methods: Children undergoing health examinations from January 2021 to September 2023 were included in this study. Clinical information including height, weight, maternal pregnancy history, blood specimens for bone metabolism-related indicators and maternal education level was collected. Children's height was categorized into 14 groups based on age and gender percentiles, following WHO 2006 growth standards. One-way analysis of variance (ANOVA), linear regression, chi-square test and Fisher's exact test were applied for data analysis. Results: A total of 6269 samples were collected, including 3654 males and 2615 females, with an average age of 8.38 (3.97) for males and 7.89 (3.55) for females. Significant correlations between maternal education level, birth weight, birth order, weight percentile, vitamin D, serum phosphorus, alkaline phosphatase levels, and children's height were identified. Birth weight's influence on height varied across age groups. Compared with normal birth weight children, low birth weight children exhibited catch-up growth within the first 6 years and a subsequent gradual widening of the height gap from 6 to 18 years old. Remarkably, the impact of maternal education on height became more pronounced among children above 3-6 years old, which can mitigate the effect of low birth weight on height. Conclusion: We found that weight percentile, birth weight, birth order, bone marker levels, and maternal education level have significant effect on height. Maternal education attenuates the impact of low birth weight on height. The findings indicated that maternal education plays a consistent and critical role in promoting robust and healthy growth.

Emerging role of circulating cell-free RNA as a non-invasive biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a severe neoplastic disease associated with high morbidity and mortality rates. HCC is often detected at advanced stages leading to ineffective curative treatments. Recently, liquid biopsy has emerged as a non-invasive method to identify highly specific HCC biomarkers in bodily fluids such as blood, serum, urine, and saliva. Circulating cell-free nucleic acids (cfNAs), particularly cell-free DNA (cfDNA) and cell-free RNA (cfRNA), have become promising candidates for biomarkers in liquid biopsy applications. While cfDNA presented significant challenges, researchers have turned their attention to cfRNA, which can be efficiently identified through various methods and is considered a potential biomarker for cancer diagnosis and prognosis. This review primarily focuses on studies related to detecting various cfRNA in body fluids as biomarkers. The aim is to provide a summary of available information to assist researchers in their investigations and the development of new diagnostic and prognostic tools.

HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.

Real-world effectiveness of molnupiravir, azvudine and paxlovid against mortality and viral clearance among hospitalized patients with COVID-19 infection during the omicron wave in China: A retrospective cohort study.

OBJECTIVES: In this retrospective cohort study, we aimed to assess clinical effectiveness and viral clearance following the use of molnupiravir, azvudine and paxlovid in hospitalized patients with COVID-19 in China dominated by the omicron BA.5.2 and BF.7 subvariant of SARS-CoV-2. METHODS: Enrolled patients were assigned to the molnupiravir group or the azvudine group or the paxlovid group or the control group (not taking any antiviral drugs). The primary outcome of the cohort study was viral clearance and viral burden rebound after treatment and the secondary outcome was 28-day all-cause mortality. The four groups were propensity score-matched (1:1). We plotted viral load trends for each antiviral drug intervention using locally weighted regression (LOWESS) smoothed data. Multivariate logistic regression (stepwise algorithm) models were used to determine any risk factors for 28-day mortality. RESULTS: Of the 1537 patients receiving any treatment, 886 (57.6 %) received molnupiravir, 390 (25.4 %) received azvudine, 94 (6.1 %) received paxlovid, and 167 (10.9 %) did not use any antiviral drugs. Our data analysis showed that age (OR = 1.05, 95 % CI: 1.03-1.07, P < 0.001), Charlson comorbidty index (OR = 1.32, 95 % CI: 1.18-1.48, P < 0.001), severity of COVID-19 (P < 0.001), gamma globulin (OR = 2.04, 95 % CI: 1.03-3.99, P = 0.039) and corticosteroids use (OR = 2.3, 95 % CI: 1.19-4.69, P = 0.017) were independent prognostic factors for 28-day mortality in COVID-19 patients. After propensity score matching (PSM), the paxlovid recipients (OR = 0.22, 95 % CI: 0.05-0.83, P = 0.036) or azvudine recipients (OR = 0.27, 95 % CI: 0.07-0.91, P = 0.046) had lower 28-day mortality compared to their matched controls. Viral rebound occurred in the control group around days 9-16, while no viral rebound was found in any of the three oral antiviral groups. We found that molnupiravir group performed comparably in terms of the rate of nucleic acid conversion negative compared with the paxlovid group, while azvudine group performed slightly worse compared with the paxlovid group or molnupiravir group. CONCLUSIONS: In our retrospective cohort of hospitalized patients with COVID-19 during the wave of omicron strain, the molnupiravir, paxlovid and azvudine recipients showed a faster and more stable decrease in viral load and rare virus rebound in response to antiviral treatments when compared to the controls. The study supported that initiation treatment with paxlovid and azvudine was associated with significantly lower risk of all-cause death within 28 days.

Mast Cells in the Microenvironment of Hepatocellular Carcinoma Confer Favorable Prognosis: A Retrospective Study using QuPath Image Analysis Software.

The insights provided by in-situ detection of immune cells within hepatocellular carcinoma (HCC) might present information on patient outcomes. Studies investigating the expression and localization of immune cells within tumor tissues are associated with several challenges, including a lack of precise annotation for tumor regions and random selection of microscopic fields of view. QuPath is an open-source, user-friendly software that could meet the growing need for digital pathology in whole-slide image (WSI) analysis. The infiltration of HCC and adjacent tissues by CD1a+ immature dendritic cells (iDCs), CD117+ mast cells, and NKp46+ natural killer cells (NKs) cells was assessed immunohistochemically in representative specimens of 67 patients with HCC who underwent curative resection. The area fraction (AF) of positively stained cells was assessed automatically in WSIs using QuPath in the tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). The AF of mast cells was significantly greater than the AF of NKs, and the AF of iDCs was significantly lower compared to NKs in each region of interest. High AFs of mast cells in the IM and PT areas were associated with longer DFS. In addition, high AF of mast cells in IM was associated with longer OS. Computer-assisted analysis using this software is a suitable tool for obtaining prognostic information for tumor-infiltrating immune cells (iDCs, mast cells, and NKs) in different regions of HCC after resection. Mast cells displayed the greatest AF in all regions of interest (ROIs). Mast cells in the peritumor region and IM showed a positive prognostic significance.

Dynamic encoding of temperature in the central circadian circuit coordinates physiological activities.

The circadian clock regulates animal physiological activities. How temperature reorganizes circadian-dependent physiological activities remains elusive. Here, using in-vivo two-photon imaging with the temperature control device, we investigated the response of the Drosophila central circadian circuit to temperature variation and identified that DN1as serves as the most sensitive temperature-sensing neurons. The circadian clock gate DN1a's diurnal temperature response. Trans-synaptic tracing, connectome analysis, and functional imaging data reveal that DN1as bidirectionally targets two circadian neuronal subsets: activity-related E cells and sleep-promoting DN3s. Specifically, behavioral data demonstrate that the DN1a-E cell circuit modulates the evening locomotion peak in response to cold temperature, while the DN1a-DN3 circuit controls the warm temperature-induced nocturnal sleep reduction. Our findings systematically and comprehensively illustrate how the central circadian circuit dynamically integrates temperature and light signals to effectively coordinate wakefulness and sleep at different times of the day, shedding light on the conserved neural mechanisms underlying temperature-regulated circadian physiology in animals.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc).

OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.

Serum Uric Acid Levels among Chinese Children: Reference Values and Association With Overweight/Obesity.

This study aimed to investigate the reference values for serum uric acid (SUA) levels and their association with overweight/obese in children. We conducted a retrospective analysis of 8522 participants, including 6227 normal weight children, aged 2 to 18 years in China. Among normal children, SUA levels increased with age, showing significant sex differences in children over 10 years. Age-specific and sex-specific 95% reference intervals for SUA levels were established. Furthermore, we observed that the percentage of overweight/obesity significantly increased as SUA quartiles rose. Elevated SUA levels were associated with a high odds ratio (OR) for overweight/obesity (OR = 4.45, 95% confidence interval = 3.33, 5.93). We propose that the 97.5th percentile is a suitable value for defining elevated SUA levels, and there is a positive correlation between SUA levels and the presence of overweight or obesity.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Learning Stiffness Tensors in Self-Activated Solids via a Local Rule.

Mechanical metamaterials are often designed with particular properties for specific load-bearing functions. Alternatively, this study aims to create a class of active lattice metamaterials, dubbed self-activated solids, that can learn desired stiffness tensors from the elastic deformations they experienced, a crucial feature to improve the performance, efficiency, and functionality of materials. Artificial adaptive matters that combine sensory, control, and actuation elements can offer appealing solutions. However, challenges still remain: The designs will rely on accurate off-line and global computations, as well as intricate coordination among individual elements. Here, a simple online and local learning strategy is initiated based on contrastive Hebbian learning to gradually guide self-activated solids to possess sought-after stiffness tensors autonomously and reversibly. During learning, the bond stiffness of the active lattice varies depending only on its local strain. The numerical tests show that the self-activated solid can not only achieve the desired bulk, shear, and coupling moduli but also manifest uni-mode and bi-mode extremal materials by itself after experiencing the corresponding elastic deformations. Further, the self-activated solid can also achieve the desired time-varying moduli when exposed to temporally different loads. The design is applicable to any lattice geometries and is resistant to damage and instabilities. The material design approach and the physical learning strategy suggested can benefit the design of autonomous materials, physical learning machines, and adaptive robots.

In-situ sparse-array imaging for through-thickness cracks in plates with A0 Lamb waves and an efficient waveform inversion algorithm.

Structural health monitoring (SHM) requires efficient online crack detection and characterization to prevent structural failures, which mainly arise from fatigue cracks. Existing solutions for crack characterization involve analyzing sensed wave signals directly, but these approaches usually require onerous steps or many sensors to obtain sufficient and clear wave packets. An alternative strategy is a model-based inversion, which takes the full waveform into consideration and does not require analysis on a single wave packet. This approach can achieve accurate characterization with fewer sensors and simpler implementation. We propose an efficient model based on the Huygens' principle and the no-mode-conversion property of the A0 mode Lamb waves to meet the requirements of online monitoring. We then verify the proposed model-based crack imaging method through simulation and experiments on smooth and rough cracks. The proposed method is easy, cheap, and efficient, making it a desirable option for SHM tasks.

Histone Variant H3.3 Controls Arabidopsis Fertility by Regulating Male Gamete Development.

Reprograming of chromatin structures and changes in gene expression are critical for plant male gamete development, and epigenetic marks play an important role in these processes. Histone variant H3.3 is abundant in euchromatin and is largely associated with transcriptional activation. The precise function of H3.3 in gamete development remains unclear in plants. Here, we report that H3.3 is abundantly expressed in Arabidopsis anthers and its knockout mutant h3.3-1 is sterile due to male sterility. Transcriptome analysis of young inflorescence has identified 2348 genes downregulated in h3.3-1 mutant, among which 1087 target genes are directly bound by H3.3, especially at their 3' ends. As a group, this set of H3.3 targets is enriched in the reproduction-associated processes including male gamete generation, pollen sperm cell differentiation and pollen tube growth. The function of H3.3 in male gamete development is dependent on the Anti-Silencing Factor 1A/1B (ASF1A/1B)-Histone regulator A (HIRA)-mediated pathway. Our results suggest that ASF1A/1B-HIRA-mediated H3.3 deposition at its direct targets for transcription activation forms the regulatory networks responsible for male gamete development.