Polygenic Risk Score Modifies the Association of HbA1c With Hearing Loss in Middle-Aged and Older Chinese: The Dongfeng-Tongji Cohort.

OBJECTIVE: Evidence regarding the modifying effect of the polygenic risk score (PRS) on the associations between glycemic traits and hearing loss (HL) was lacking. We aimed to examine whether these associations can be influenced by genetic susceptibility. RESEARCH DESIGN AND METHODS: This cross-sectional study included 13,275 participants aged 64.9 years from the Dongfeng-Tongji cohort. HL was defined according to a pure tone average >25 dB in the better ear and further classified by severity. Prediabetes and type 2 diabetes (T2D) were defined based on the 2013 criteria from the American Diabetes Association. A PRS was derived from 37 single-nucleotide polymorphisms associated with HL. Multivariable logistic regression models were fitted to estimate the associations of PRS and glycemic traits with HL and its severity. RESULTS: Elevated fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and T2D were positively associated with higher HL risks and its severity, with odds ratios (ORs) ranging from 1.04 (95% CI 1.00, 1.08) to 1.25 (95% CI 1.06, 1.46). We also found significant interaction between HbA1c and PRS on risks of overall HL and its severity (P for multiplicative interaction <0.05), and the effects of HbA1c on HL risks were significant only in high PRS. Additionally, compared with normoglycemia in the low PRS, T2D was respectively associated with an OR of up to 2.00 and 2.40 for overall HL and moderate to severe HL in the high PRS (P for additive interaction <0.05). CONCLUSIONS: PRS modifies the association of HbA1c with HL prevalence among middle-aged and older Chinese.

Polycyclic aromatic hydrocarbons exposure and arterial stiffness-related plasma miRNAs: A panel study.

The underlying mechanisms between polycyclic aromatic hydrocarbons (PAHs) exposure and arterial stiffness are poorly understood. We carried out a panel study involving three repeated surveys to examine the associations of individual and mixture of PAHs exposure with arterial stiffness-related miRNAs among 123 community adults. In linear mixed-effect (LME) models, we found that urinary 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 9-hydroxyphenanthrene (9-OHPh) at lag 0 day were positively linked to miR-146a and/or miR-222. The Bayesian kernel machine regression (BKMR) analyses revealed positive overall associations of PAHs mixture at lag 0 day with miR-146a and miR-222, and urinary 9-OHFlu contributed the most. In addition, an inter-quartile range (IQR) increase in urinary 9-OHFlu at lag 0 day was associated with elevated miR-146a and miR-222 by 0.16 (95% CI: 0.02, 0.30) to 0.34 (95% CI: 0.13, 0.54). Accordingly, exposure to PAHs, especially 9-OHFlu at lag 0 day, was related to elevated arterial stiffness-related plasma miRNAs.

Changes in sleep score and leisure-time physical activity, their combination, and all-cause mortality in middle-aged and older Chinese adults: The Dongfeng-Tongji cohort study.

OBJECTIVES: To prospectively investigate the associations of longitudinal changes in sleep score and LTPA and their combination with all-cause mortality. METHODS: Among 12,543 participants (mean age: 66.1 years) from the Dongfeng-Tongji cohort, we calculated sleep score (range, 0-4, integrating bedtime, sleep duration, sleep quality, and midday napping, higher score indicating healthier sleep) and LTPA at baseline (2008-2010) and the first follow-up (2013) surveys and their 5-year changes (defining stable sleep score as no change and stable LTPA as change within 150 min/week). We prospectively documented deaths from the first follow-up survey (2013) through December 31, 2018. RESULTS: During a mean 5.5-year follow-up, 792 deaths occurred. The 5-year changes in sleep score and LTPA were inversely associated with all-cause mortality risk, regardless of their initial values. When assessing 5-year changes in sleep score and LTPA jointly, compared with the stable sleep score-stable LTPA group, the decreased sleep score-decreased LTPA group had a 40 % (5-85 %) higher all-cause mortality risk, whereas the increased sleep score-increased LTPA group had a 34 % (9-52 %) lower risk. The direction of the joint association was mainly driven by sleep score change. Participants maintaining sleep scores ≥ 3 and LTPA ≥ 150 min/week over 5 years had a 44 % (28-56 %) lower all-cause mortality risk. CONCLUSIONS: Promoting sleep hygiene and LTPA together may benefit efforts in reducing mortality risk, with particular attention to monitoring long-term sleep health.

Clinical and Transcriptional Profiles Reveal the Treatment Effect of Adalimumab in Patients with Initial-Onset and Recurrent Vogt-Koyanagi-Harada Disease.

PURPOSE: We aimed to evaluate adalimumab efficacy in patients with initial-onset or recurrent Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A retrospective clinical study was performed to examine the therapeutic effect of adalimumab in 22 VKH patients,16 with initial-onset and six with recurrent VKH. Another 22 patients with initial-onset VKH who did not receive adalimumab were included as controls. The main observational parameters included the central macular thickness (CMT), subfoveal choroidal thickness (SCT), best-corrected visual acuity (BCVA), anterior chamber cell grade (ACC), glucocorticoid dose (GCD), and the development of sunset glow fundus. MRNA sequencing was used to profile the tumor necrosis factor (TNF)-α pathway in peripheral blood mononuclear cells obtained from nine patients with initial-onset VKH disease, six patients with recurrent VKH, and eight healthy controls. RESULTS: In the initial-onset group, adalimumab therapy significantly improved the BCVA, CMT, SCT, and ACC. Furthermore, adalimumab significantly decreased GCD in patients with initial-onset. In patients with recurrent VKH, the SCT significantly improved after adalimumab treatment, but no significant changes in BCVA, CMT, and ACC were observed. All six patients experienced relapse during follow-up. The TNF-α pathway exhibited a significant increase in initial-onset VKH when compared with that in both healthy controls and recurrent patients. Conversely, it was suppressed in recurrent VKH when compared with that in the initial-onset or healthy control groups. CONCLUSIONS: In patients with initial-onset VKH, adalimumab effectively reduces glucocorticoid dependence. However, adalimumab may not be effective for preventing relapse or providing long-term inflammation relief in patients with recurrent VKH.

In Situ Self-Assembled Active and Stable Ir@MnOx/La0.7Sr0.3Cr0.9Ir0.1O3-δ Interfaces for CO2 Electrolysis.

Solid oxide electrolysis cells are prospective approaches for CO2 utilization but face significant challenges due to the sluggish reaction kinetics and poor stability of the fuel electrodes. Herein, we strategically addressed the long-standing trade-off phenomenon between enhanced exsolution and improved structural stability via topotactic ion exchange. The surface dynamic reconstruction of the MnOx/La0.7Sr0.3Cr0.9Ir0.1O3-δ (LSCIr) catalyst was visualized at the atomic scale. Compared with the Ir@LSCIr interface, the in situ self-assembled Ir@MnOx/LSCIr interface exhibited greater CO2 activation and easily removable carbonate intermediates, thus reached a 42% improvement in CO2 electrolysis performance at 1.6 V. Furthermore, an improved CO2 electrolysis stability was achieved due to the uniformly wrapped MnOx shell of the Ir@MnOx/LSCIr cathode. Our approach enables a detailed understanding of the dynamic microstructure evolution at active interfaces and provides a roadmap for the rational design and evaluation of efficient metal/oxide catalysts for CO2 electrolysis.

The relationship between exercise commitment and college students' exercise adherence: The chained mediating role of exercise atmosphere and exercise self-efficacy.

OBJECTIVE: This study aims to explore the mechanisms underlying exercise commitment, exercise atmosphere, exercise self-efficacy, and exercise adherence among college students, as well as the impact of gender differences on these mechanisms. METHODS: Using a stratified cluster sampling method, 984 college students (aged 19.74 ± 1.25 years) from six universities in Anhui, Shandong, and Shaanxi provinces were randomly selected, with 403 male students and 581 female students. They had completed the Exercise Commitment Scale (ECC), Physical Exercise Atmosphere Scale (PEAS), Exercise Self-Efficacy Scale (ESES), and Exercise Adherence Scale (EPS). The study variables were analyzed in sequence for reliability and validity, correlation analysis, regression analysis, structural equation model testing, and bias-corrected percentile Bootstrap testing using SPSS 23.0 software and Hayes' (2013) Process plug-in. RESULTS: Exercise commitment significantly positively predicted exercise adherence (ß = 0.796, p < 0.01), exercise commitment significantly positively predicted exercise environment and exercise self-efficacy (ß = 0.645, p < 0.01, ß = 0.356, p < 0.01), exercise environment significantly positively predicted exercise self-efficacy and exercise adherence (ß = 0.344, p < 0.01, ß = 0.144, p < 0.01), and exercise self-efficacy significantly positively predicted exercise adherence (ß = 0.934, p < 0.01). The mediating role of exercise environment in the relationship between exercise commitment and exercise adherence does not exist in male college students, while it exists in female college students. CONCLUSIONS: Exercise atmosphere and exercise self-efficacy play a mediating role between exercise commitment and exercise adherence, with a total mediating effect value of 0.796. This study indicates that exercise commitment not only directly predicts exercise adherence, but also indirectly predicts exercise adherence through the chained mediating effects of exercise atmosphere and exercise self-efficacy. The above-mentioned mediating effect exists in female college students, while some mediating effects do not exist in male college students, thus gender has a significant impact on this mediating effect.

Synaptic vesicle glycoprotein 2 A in serum is an ideal biomarker for early diagnosis of Alzheimer's disease.

BACKGROUND: Previous studies have demonstrated that early intervention was the best plan to inhibit the progression of Alzheimer's disease (AD), which relied on the discovery of early diagnostic biomarkers. In this study, synaptic vesicle glycoprotein 2 A (SV2A) was examined to improve the early diagnostic efficiency in AD. METHODS: In this study, biomarker testing was performed through the single-molecule array (Simoa). A total of 121 subjects including cognitively unimpaired controls, amnestic mild cognitive impairment (aMCI), AD and other types of dementia underwent cerebrospinal fluid (CSF) SV2A testing; 430 subjects including health controls, aMCI, AD and other types of dementia underwent serum SV2A, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and p-tau217 testing; 92 subjects including aMCI and AD underwent both CSF SV2A and serum SV2A testing; 115 cognitively unimpaired subjects including APOE ε4 carriers and APOE ε4 non-carriers were tested for serum SV2A, GFAP, NfL and p-tau217. Then, the efficacy of SV2A for the early diagnosis of AD and its ability to identify those at high risk of AD from a cognitively unimpaired population were further analyzed. RESULTS: Both CSF and serum SV2A significantly and positively correlated with cognitive performance in patients with AD, and their levels gradually decreased with the progression of AD. Serum SV2A demonstrated excellent diagnostic efficacy for aMCI, with a sensitivity of 97.8%, which was significantly higher than those of NfL, GFAP, and p-tau217. The SV2A-positive rates ranged from 92.86 to 100% in aMCI cases that were negative for the above three biomarkers. Importantly, of all the biomarkers tested, serum SV2A had the highest positivity rate (81.82%) in individuals at risk for AD. CONCLUSIONS: Serum SV2A was demonstrated to be a novel and ideal biomarker for the early diagnosis of AD, which can effectively distinguish those at high risk of AD in cognitively unimpaired populations.

Changes in Sleep Patterns, Genetic Susceptibility, and Incident Cardiovascular Disease in China.

Importance: The associations of changes in sleep patterns with incident cardiovascular disease (CVD) are not fully elucidated, and whether these associations are modified by genetic susceptibility remains unknown. Objectives: To investigate the associations of 5-year changes in sleep patterns with incident CVD and whether genetic susceptibility modifies these associations. Design, Setting, and Participants: This prospective cohort study of the Dongfeng-Tongji cohort was conducted from 2008 to 2018 in China. Eligible participants included those with complete sleep information at baseline survey (2008-2010) and the first follow-up survey (2013); participants who had no CVD or cancer in 2013 were prospectively assessed until 2018. Statistical analysis was performed in November 2023. Exposures: Five-year changes in sleep patterns (determined by bedtime, sleep duration, sleep quality, and midday napping) between 2008 and 2013, and polygenic risk scores (PRS) for coronary heart disease (CHD) and stroke. Main Outcomes and Measures: Incident CVD, CHD, and stroke were identified from 2013 to 2018. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% CIs. Results: Among 15 306 individuals (mean [SD] age, 65.8 [7.4] years; 8858 [57.9%] female and 6448 male [42.1%]), 5474 (35.78%) had persistent unfavorable sleep patterns and 3946 (25.8%) had persistent favorable sleep patterns. A total of 3669 incident CVD cases were documented, including 2986 CHD cases and 683 stroke cases, over a mean (SD) follow-up of 4.9 (1.5) years. Compared with those with persistent unfavorable sleep patterns, individuals with persistent favorable sleep patterns over 5 years had lower risks of incident CVD (HR, 0.80; 95% CI, 0.73-0.87), CHD (HR, 0.84; 95% CI, 0.76-0.92), and stroke (HR, 0.66; 95% CI, 0.54-0.82) in the subsequent 5-year period. No significant effect modification by PRS was observed for sleep pattern change and CHD or stroke risk. However, sleep pattern changes and PRS were jointly associated with the CHD and stroke risk in a dose-dependent manner, with the lowest risk being among those with persistent favorable sleep patterns combined with low PRS (HR for CHD, 0.65; 95% CI, 0.52-0.82 and HR for stroke, 0.48; 95% CI, 0.29-0.79). Conclusions and Relevance: In this cohort study of middle-aged and older Chinese adults, individuals with persistent favorable sleep patterns had a lower CVD risk, even among those with higher genetic risk. These findings highlight the importance of maintaining favorable sleep patterns for CVD prevention.

Effects of plasma-activated slightly acidic electrolyzed water on salmon myofibrillar protein: Insights from structure and molecular docking.

The present study investigated the impact of plasma-activated water (PAW), slightly acidic electrolytic water (SAEW) and plasma-activated slightly acidic electrolytic water (PASW) treatment on myofibrillar protein (MP) in salmon fillets. Additionally, the interaction mechanism between myosin and reactive oxygen species was explored by molecular docking. Compared with the control group (719.26 nm), PASW treatment group exhibited the smallest particle size (408.97 nm). The PASW treatment exhibited efficacy in reducing MP aggregation and inhibiting protein oxidation. In comparison with other treatments, PASW treatment demonstrated a greater ability to mitigate damage to the secondary and tertiary structures of MP. O3 and H2O2 interact with myosin through hydrogen bonding. Specifically, O3 interacts with Lys676, Gly677, and Met678 of myosin while H2O2 binds to Thr681, Asp626, Arg680, and Met678. This study offers novel insights into the impact of PASW on MP, and provides a theoretical foundation for its application in aquatic product processing.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

BACKGROUND: The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. AIM: To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. METHODS: We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). RESULTS: Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. CONCLUSION: In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

GluN2B-containing NMDA receptor attenuated neuronal apoptosis in the mouse model of HIBD through inhibiting endoplasmic reticulum stress-activated PERK/eIF2α signaling pathway.

Introduction: Neonatal hypoxic-ischemic brain damage (HIBD) refers to brain damage in newborns caused by hypoxia and reduced or even stopped cerebral blood flow during the perinatal period. Currently, there are no targeted treatments for neonatal ischemic hypoxic brain damage, primarily due to the incomplete understanding of its pathophysiological mechanisms. Especially, the role of NMDA receptors is less studied in HIBD. Therefore, this study explored the molecular mechanism of endogenous protection mediated by GluN2B-NMDAR in HIBD. Method: Hypoxic ischemia was induced in mice aged 9-11 days. The brain damage was examined by Nissl staining and HE staining, while neuronal apoptosis was examined by Hoechst staining and TTC staining. And cognitive deficiency of mice was examined by various behavior tests including Barnes Maze, Three Chamber Social Interaction Test and Elevated Plus Maze. The activation of ER stress signaling pathways were evaluated by Western blot. Results: We found that after HIBD induction, the activation of GluN2B-NMDAR attenuated neuronal apoptosis and brain damage. Meanwhile, the ER stress PERK/eIF2α signaling pathway was activated in a time-dependent manner after HIBE. Furthermore, after selective inhibiting GluN2B-NMDAR in HIBD mice with ifenprodil, the PERK/eIF2α signaling pathway remains continuously activated, leading to neuronal apoptosis, morphological brain damage. and aggravating deficits in spatial memory, cognition, and social abilities in adult mice. Discussion: The results of this study indicate that, unlike its role in adult brain damage, GluN2B in early development plays a neuroprotective role in HIBD by inhibiting excessive activation of the PERK/eIF2α signaling pathway. This study provides theoretical support for the clinical development of targeted drugs or treatment methods for HIBD.

Efficient Absorption of CO2 by Protic-Ionic-Liquid Based Deep Eutectic Solvents.

Carbon capture, utilization, and storage (CCUS) are among the key technologies to achieve large-scale carbon emission reduction globally. Deep eutectic solvents (DESs) are considered as designable solvents, which has attracted intensive attention for CO2 capture. Here, a series of binary DESs are synthesized through one-step mixing with the starting materials of protic ionic liquid (PIL) and amine. The eutectic behavior was investigated by measuring the melting point of PILs and amine. The saturated vapor of these DESs and industrial MDEA solution were measured and compared. These DESs are investigated to have high absorption capacity (0.1 g ⋅ g-1 at 1.0 bar and 25 °C), superior apparent absorption rate constant (0.381 min-1 vs 0.012 min-1 of 70 wt.% MDEA), moderate interaction with CO2 (the enthalpy change is as low as -34.8 kJ ⋅ mol-1). The absorption mechanism is also investigated by NMR analysis. Eight absorption/desorption regeneration experiments are carried out to show their reversibility. Considering the advantages, including convenience of synthesis, large absorption capacity, fast absorption rate, and moderate interaction energy as well as good regeneration, these DESs are believed to be as potential CO2 absorbent in practical applications.

Radiative Thermal Management in Face Masks with a Micro/Nanofibrous Filter.

Micro/nanofiber-based face masks are recommended as personal protective equipment (PPE) against particulate matter (PM), especially PM0.3. Ensuring thermal comfort in daily use face masks is essential in many situations. Here, radiative thermal management is introduced into face masks to elevate the user comfort. An interlayered poly(lactic acid) (PLA) micro/nanofibrous filter effectively captures PM0.3 (99.69%) with minimal pressure drop (49 Pa). Thermal regulation is accomplished by controlling the mid-infrared (MIR) emissivity of the face mask's outer surface. Cooling face masks feature cotton nonwovens with high MIR emissivity (90.7%) for heat dissipation, while warming face masks utilize perforated Al/PE films with minimal MIR emissivity (10.7%) for warmth retention. Skin temperature measurements indicate that the skin covered by the cooling face mask could be 1.1 °C lower than that covered by the 3M face mask, while the skin covered by the warming face mask could be 1.3 °C higher than that covered by the 3M face mask.

Highly efficient upconversion luminescence in narrow-bandgap Y2Mo4O15.

Lanthanide-doped upconversion (UC) materials have been extensively investigated for their unique capability to convert low-energy excitation into high-energy emission. Contrary to previous reports suggesting that efficient UC luminescence (UCL) is exclusively observed in materials with a wide bandgap, we have discovered in this study that Y2Mo4O15:Yb3+/Tm3+ microcrystals, a narrowband material, exhibit highly efficient UC emission. Remarkably, these microcrystals do not display any four- or five-photon UC emission bands. This particular optical phenomenon is independent of the variation in doping ion concentration, temperature, phonon energy, and excitation power density. Combining theoretical calculations and experimental results, we attribute the vanishing emission bands to the strong interaction between the bandgap of the Y2Mo4O15 host matrix (3.37 eV) and the high-energy levels (1I6 and 1D2) of Tm3+ ions. This interaction can effectively catalyze the UC emission process of Tm3+ ions, which leads to Y2Mo4O15:Yb3+/Tm3+ microcrystals possessing very strong UCL intensity. The brightness of these microcrystals outshines commercial UC NaYF4:Yb3+,Er3+ green phosphors by a factor of 10 and is 1.4 times greater than that of UC NaYF4:Yb3+,Tm3+ blue phosphors. Ultimately, Y2Mo4O15:Yb3+/Tm3+ microcrystals, with their distinctive optical characteristics, are being tailored for sophisticated anti-counterfeiting and information encryption applications.

New-onset or relapse of uveitis after rapid spreading of COVID-19 infection in China and risk factor analysis for relapse.

BACKGROUND: The aim of this study was to report the clinical profile of new-onset and relapse of uveitis following rapid spreading of coronavirus disease 2019 (COVID-19) infection due to change of anti-COVID-19 policies in China and investigate potential risk factors for inflammation relapse. METHODS: In this retrospective case-control study, patients with new-onset or a history of uveitis between December 23, 2022, and February 28, 2023, were included to assess the influence of COVID-19 infection on uveitis. Detailed information on demographic data, clinical characteristics, treatment measures, treatment response, and ocular inflammatory status before and after COVID-19 infection was collected. RESULTS: This study included 349 patients with a history of uveitis. The uveitis relapse rate was higher (28.8%, n = 288) in those with COVID-19 infection than in patients without COVID-19 infection (14.8%, n = 61) (P = 0.024). Among the relapse cases, 50.8% experienced a relapse of anterior uveitis, while 49.2% had a relapse of uveitis involving the posterior segment. Multivariable regression analysis indicated a positive correlation between disease duration and uveitis relapse, while the last relapse exceeding one year before COVID-19 infection and the use of methotrexate during COVID-19 infection were negatively correlated with relapse of uveitis. Thirteen patients who developed new-onset uveitis following COVID-19 infection were included; among them, three (23.1%) had anterior uveitis and 10 (76.9%) had uveitis affecting the posterior segment. Regarding cases involving the posterior segment, four patients (30.8%) were diagnosed with Vogt-Koyanagi-Harada disease. CONCLUSIONS: COVID-19 infection increases the rate of uveitis relapse. Long disease duration is a risk factor, while time since the last relapse more than 1 year and methotrexate use are protective factors against uveitis relapse.

Comprehensive Proteomic Profiling of Aqueous Humor in Idiopathic Uveitis and Vogt-Koyanagi-Harada Syndrome.

Idiopathic uveitis (IU) and Vogt-Koyanagi-Harada (VKH) syndrome are common types of uveitis. However, the exact pathological mechanisms of IU and VKH remain unclear. Proteomic analysis of aqueous humor (AH), the most easily accessible intraocular fluid and a key site of uveitis development, may reveal potential biomarkers and elucidate uveitis pathogenesis. In this study, 44 AH samples, including 12 IU cases, 16 VKH cases, and 16 controls, were subjected to label-free quantitative proteomic analysis. We identified 557 proteins from a comprehensive spectral library of 634 proteins across all samples. The AH proteomic profiles of the IU and VKH groups were different from those of the control group. Differential analysis revealed a shared pattern of extracellular matrix disruption and downregulation of retinal cellular proteins in the IU and VKH groups. Enrichment analysis revealed a protein composition indicative of inflammation in the AH of the IU and VKH groups but not in that of the control group. In the IU and VKH groups, innate immunity played an important role, as indicated by complement cascade activation and overexpression of innate immune cell markers. Extreme gradient boosting (XGBoost), an efficient and robust machine learning algorithm, was subsequently used to screen potential biomarkers for classifying the IU, VKH, and control groups. Transferrin and complement factor B were deemed the most important and represent a promising biomarker panel. These proteins were validated by high-resolution multiple reaction monitoring (HR-MRM) in an independent validation cohort. A classification decision tree was subsequently built for the diagnosis. Our findings further the understanding of the underlying molecular mechanisms in IU and VKH and facilitate the development of potential therapeutic and diagnostic strategies.

Uncertainty-driven mixture convolution and transformer network for remote sensing image super-resolution.

Recently, convolutional neural networks (CNNs) and Transformer-based Networks have exhibited remarkable prowess in the realm of remote sensing image super-resolution (RSISR), delivering promising results in the field. Nevertheless, the effective fusion of the inductive bias inherent in CNNs and the long-range modeling capabilities encapsulated within the Transformer architecture remains a relatively uncharted terrain in the context of RSISR endeavors. Accordingly, we propose an uncertainty-driven mixture convolution and transformer network (UMCTN) to earn a performance promotion. Specifically, to acquire multi-scale and hierarchical features, UMCTN adopts a U-shape architecture. Utilizing the dual-view aggregation block (DAB) based residual dual-view aggregation group (RDAG) in both encoder and decoder, we solely introduce a pioneering dense-sparse transformer group (DSTG) into the latent layer. This design effectively eradicates the considerable quadratic complexity inherent in vanilla Transformer structures. Moreover, we introduce a novel uncertainty-driven Loss (UDL) to steer the network's attention towards pixels exhibiting significant variance. The primary objective is to elevate the reconstruction quality specifically in texture and edge regions. Experimental outcomes on the UCMerced LandUse and AID datasets unequivocally affirm that UMCTN achieves state-of-the-art performance in comparison to presently prevailing methodologies.

TransGEM: a molecule generation model based on Transformer with gene expression data.

MOTIVATION: It is difficult to generate new molecules with desirable bioactivity through ligand-based de novo drug design, and receptor-based de novo drug design is constrained by disease target information availability. The combination of artificial intelligence and phenotype-based de novo drug design can generate new bioactive molecules, independent from disease target information. Gene expression profiles can be used to characterize biological phenotypes. The Transformer model can be utilized to capture the associations between gene expression profiles and molecular structures due to its remarkable ability in processing contextual information. RESULTS: We propose TransGEM (Transformer-based model from gene expression to molecules), which is a phenotype-based de novo drug design model. A specialized gene expression encoder is used to embed gene expression difference values between diseased cell lines and their corresponding normal tissue cells into TransGEM model. The results demonstrate that the TransGEM model can generate molecules with desirable evaluation metrics and property distributions. Case studies illustrate that TransGEM model can generate structurally novel molecules with good binding affinity to disease target proteins. The majority of genes with high attention scores obtained from TransGEM model are associated with the onset of the disease, indicating the potential of these genes as disease targets. Therefore, this study provides a new paradigm for de novo drug design, and it will promote phenotype-based drug discovery. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/hzauzqy/TransGEM.

Adherence to the atrial fibrillation better care pathway and its associated factors among rural patients with atrial fibrillation in China: A cross-sectional study.

BACKGROUND: The atrial fibrillation better care (ABC) pathway is an effective strategy for the integrated management of atrial fibrillation (AF). Current data on adherence to the ABC pathway among rural patients with AF in China are limited. OBJECTIVES: To investigated adherence to the ABC pathway and its associated factors among rural patients with AF in China. METHODS: In the cross-sectional study, we recruited 870 rural patients with AF from July 2022 to July 2023 in China. AF-related sociodemographic and clinical data was collected. RESULTS: Among the 870 rural patients with AF, 437 (50.23 %) were male, 714 (82.07 %) were ≥65 years old. The level of adherence to ABC pathway was extremely low (5.75 %), and its associated factors included patients ≥75 years (compared with those <65 years, OR=0.165, 95 %CI: 0.065-0.417, P < 0.001), junior middle school and senior middle school education or above (compared with primary school education or below, OR=3.441, 95 %CI: 1.144-10.351, P = 0.028; OR=11.438, 95 %CI: 3.758-34.814, P < 0.001), average monthly household income per capita 1000-3000 RMB and >3000 RMB (compared with <1000 RMB, OR=3.993, 95 %CI: 1.343-11.877, P = 0.013; OR=4.474, 95 %CI: 1.478-13.541, P = 0.008), persistent AF (compared with paroxysmal AF, OR=0.062, 95 %CI: 0.008-0.466, P = 0.007) and multimorbidity (OR=0.356, 95 %CI: 0.163-0.781, P = 0.010). CONCLUSIONS: There is an urgent need to develop targeted interventions and national policies to improve the adherence to the ABC pathway of rural AF patients in China.

Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function.

RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.