Prediction of Arteriovenous Access Dysfunction by Mel Spectrogram-based Deep Learning Model.

Background: The early detection of arteriovenous (AV) access dysfunction is crucial for maintaining the patency of vascular access. This study aimed to use deep learning to predict AV access malfunction necessitating further vascular management. Methods: This prospective cohort study enrolled prevalent hemodialysis (HD) patients with an AV fistula or AV graft from a single HD center. Their AV access bruit sounds were recorded weekly using an electronic stethoscope from three different sites (arterial needle site, venous needle site, and the midpoint between the arterial and venous needle sites) before HD sessions. The audio signals were converted to Mel spectrograms using Fourier transformation and utilized to develop deep learning models. Three deep learning models, (1) Convolutional Neural Network (CNN), (2) Convolutional Recurrent Neural Network (CRNN), and (3) Vision Transformers-Gate Recurrent Unit (ViT-GRU), were trained and compared to predict the likelihood of dysfunctional AV access. Results: Total 437 audio recordings were obtained from 84 patients. The CNN model outperformed the other models in the test set, with an F1 score of 0.7037 and area under the receiver operating characteristic curve (AUROC) of 0.7112. The Vit-GRU model had high performance in out-of-fold predictions, with an F1 score of 0.7131 and AUROC of 0.7745, but low generalization ability in the test set, with an F1 score of 0.5225 and AUROC of 0.5977. Conclusions: The CNN model based on Mel spectrograms could predict malfunctioning AV access requiring vascular intervention within 10 days. This approach could serve as a useful screening tool for high-risk AV access.

Establishing the link between D-mannose and juvenile grass carp (Ctenopharyngodon idella): Improved growth and intestinal structure associated with endoplasmic reticulum stress, mitophagy, and apical junctional complexes.

D-mannose, essential for protein glycosylation, has been reported to have immunomodulatory effects and to maintain intestinal flora homeostasis. In addition to evaluating growth performance, we examined the impact of D-mannose on the structure of epithelial cells and apical junction complexes in the animal intestine. All 1800 grass carp (16.20 ± 0.01 g) were randomly divided into six treatments with six replicates of 50 fish each and fed with six different levels of D-mannose (0.52, 1.75, 3.02, 4.28, 5.50 and 6.78 g/kg diet) for 70 d. The study revealed that D-mannose increased feed intake (P < 0.001) but did not affect the percent weight gain (PWG), special growth rate, and feed conversion ratio (P > 0.05). D-mannose supplementation at 1.75 g/kg increased crude protein content in fish and lipid production value (P < 0.05). D-mannose supplementation at 4.28 g/kg increased intestinal length, intestinal weight and fold height of grass carp compared to the control group (P < 0.05). This improvement may be attributed to the phosphomannose isomerase (PMI)-mediated enhancement of glycolysis. This study found that D-mannose supplementation at 4.28 or 3.02 g/kg reduced serum diamine oxidase activity or D-lactate content (P < 0.05) and improved cellular and intercellular structures for the first time. The improvement of cellular redox homeostasis involves alleviating endoplasmic reticulum (ER) stress through the inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6) signaling pathways. The alleviation of ER stress may be linked to the phosphomannomutase (PMM)-mediated enhancement of protein glycosylation. In addition, ubiquitin-dependent [PTEN-induced putative kinase 1 (PINK1)/Parkin] and ubiquitin-independent [BCL2-interacting protein 3-like (BNIP3L), BCL2-interacting protein 3 (BNIP3), and FUN14 domain containing 1 (FUNDC1)] mitophagy may play a role in maintaining cellular redox homeostasis. The enhancement of intercellular structures includes enhancing tight junction and adherent junction structures, which may be closely associated with the small Rho GTPase protein (RhoA)/the Rho-associated protein kinase (ROCK) signaling pathway. In conclusion, D-mannose improved intestinal cellular redox homeostasis associated with ER stress and mitophagy pathways, and enhanced intercellular structures related to tight junctions and adherent junctions. Furthermore, quadratic regression analysis of the PWG and intestinal reactive oxygen species content indicated that the optimal addition level of D-mannose for juvenile grass carp was 4.61 and 4.59 g/kg, respectively.

Neonatal sex and maternal factors associated with small-for-gestational-age neonates: A nationwide population-based study.

Background and Aims: Small-for-gestational-age (SGA) newborns have a higher risk of morbidity and mortality. Recognizing the risk factors for SGA helps raise early awareness of the issue and provides valuable insights for both healthcare providers and pregnant women. We aimed to identify determinants of SGA using population-based databases in Taiwan. Methods: Data were retrieved from the National Health Insurance, Birth Reporting, and Maternal and Child Health databases for this nationwide case-control study. Live births between 20 and 44 weeks of gestation from 2005 to 2014 were enrolled and linked to their mothers to determine maternal conditions during pregnancy. For every SGA newborn, four controls matched by gestational age and birth year were randomly selected. Multivariable logistic regression was used to identify risk factors for SGA, with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) accounting for potential confounders and interaction terms. Results: A total of 158,405 live SGA births were identified, with 623,584 controls randomly selected. Independent risk factors for SGA included maternal age <20 years (aOR 1.68, 95% CI 1.62, 1.75); female sex in newborns (aOR 1.28, 95% CI 1.27, 1.30); socioeconomic deprivation (aOR 1.29, 95% CI 1.21, 1.38); hypertension (aOR 1.6, 95% CI 1.52, 1.67); kidney disorders (aOR 1.29, 95% CI 1.16, 1.44); thyroid disorders (aOR 1.13, 95% CI 1.09, 1.17); systemic lupus erythematosus (aOR 2.59, 95% CI 2.33, 2.89); antiphospholipid syndrome (aOR 2.08, 95% CI 1.64, 2.64); gestational hypertension (aOR 1.69, 95% CI 1.61, 1.76); pre-eclampsia (aOR 3.12, 95% CI 3.01, 3.25); and antepartum hemorrhage (aOR 1.05, 95% CI 1.03, 1.07) after adjustment for other covariates. Conclusions: SGA was associated with younger maternal age, female newborns, underlying comorbidities, and obstetric conditions. Gestational hypertension and pre-eclampsia were significant risk factors affecting infants of both sexes and all age groups and could mask the effects of maternal age and infant sex.

Methionine deficiency inhibited pyroptosis in primary hepatocytes of grass carp (Ctenopharyngodon idella): possibly via activating the ROS-AMPK-autophagy axis.

BACKGROUND: Methionine (Met) is the only sulfur-containing amino acid among animal essential amino acids, and methionine deficiency (MD) causes tissue damage and cell death in animals. The common modes of cell death include apoptosis, autophagy, pyroptosis, necroptosis. However, the studies about the major modes of cell death caused by MD have not been reported, which worth further study. METHODS: Primary hepatocytes from grass carp were isolated and treated with different doses of Met (0, 0.5, 1, 1.5, 2, 2.5 mmol/L) to examine the expression of apoptosis, pyroptosis, autophagy and necroptosis-related proteins. Based on this, we subsequently modeled pyroptosis using lipopolysaccharides and nigericin sodium salt, then autophagy inhibitors chloroquine (CQ), AMP-activated protein kinase (AMPK) inhibitors compound C (CC) and reactive oxygen species (ROS) scavengers N-acetyl-L-cysteine (NAC) were further used to examine the expression of proteins related to pyroptosis, autophagy and AMPK pathway in MD-treated cells respectively. RESULTS: MD up-regulated B-cell lymphoma protein 2 (Bax), microtubule-associated protein 1 light chain 3 II (LC3 II), and down-regulated the protein expression levels of B-cell lymphoma-2 (Bcl-2), sequestosome 1 (p62), cleaved-caspase-1, cleaved-interleukin (IL)-1ß, and receptor-interacting protein kinase (RIP) 1 in hepatocytes, while it did not significantly affect RIP3. In addition, MD significantly increased the protein expression of liver kinase B1 (LKB1), p-AMPK, and Unc-51-like kinase 1 (ULK1) without significant effect on p-target of rapamycin. Subsequently, the use of CQ increased the protein expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cleaved-caspase-1, and cleaved-IL-1ß inhibited by MD; the use of CC significantly decreased the protein expression of MD-induced LC3 II and increased the protein expression of MD-suppressed p62; then the use of NAC decreased the MD-induced p-AMPK protein expression. CONCLUSION: MD promoted autophagy and apoptosis, but inhibited pyroptosis and necroptosis. MD inhibited pyroptosis may be related regarding the promotion of autophagy. MD activated AMPK by inducing ROS production which in turn promoted autophagy. These results could provide partial theoretical basis for the possible mechanisms of Met in ensuring the normal structure and function of animal organs. Furthermore, ferroptosis is closely related to redox states, it is worth investigating whether MD affects ferroptosis in hepatocytes.

Precision Medicine for Apical Lesions and Peri-Endo Combined Lesions Based on Transfer Learning Using Periapical Radiographs.

An apical lesion is caused by bacteria invading the tooth apex through caries. Periodontal disease is caused by plaque accumulation. Peri-endo combined lesions include both diseases and significantly affect dental prognosis. The lack of clear symptoms in the early stages of onset makes diagnosis challenging, and delayed treatment can lead to the spread of symptoms. Early infection detection is crucial for preventing complications. PAs used as the database were provided by Chang Gung Memorial Medical Center, Taoyuan, Taiwan, with permission from the Institutional Review Board (IRB): 02002030B0. The tooth apex image enhancement method is a new technology in PA detection. This image enhancement method is used with convolutional neural networks (CNN) to classify apical lesions, peri-endo combined lesions, and asymptomatic cases, and to compare with You Only Look Once-v8-Oriented Bounding Box (YOLOv8-OBB) disease detection results. The contributions lie in the utilization of database augmentation and adaptive histogram equalization on individual tooth images, achieving the highest comprehensive validation accuracy of 95.23% with the ConvNextv2 model. Furthermore, the CNN outperformed YOLOv8 in identifying apical lesions, achieving an F1-Score of 92.45%. For the classification of peri-endo combined lesions, CNN attained the highest F1-Score of 96.49%, whereas YOLOv8 scored 88.49%.

Combined assembloid modeling and 3D whole-organ mapping captures the microanatomy and function of the human fallopian tube.

The fallopian tubes play key roles in processes from pregnancy to ovarian cancer where three-dimensional (3D) cellular and extracellular interactions are important to their pathophysiology. Here, we develop a 3D multicompartment assembloid model of the fallopian tube that molecularly, functionally, and architecturally resembles the organ. Global label-free proteomics, innovative assays capturing physiological functions of the fallopian tube (i.e., oocyte transport), and whole-organ single-cell resolution mapping are used to validate these assembloids through a multifaceted platform with direct comparisons to fallopian tube tissue. These techniques converge at a unique combination of assembloid parameters with the highest similarity to the reference fallopian tube. This work establishes (i) an optimized model of the human fallopian tubes for in vitro studies of their pathophysiology and (ii) an iterative platform for customized 3D in vitro models of human organs that are molecularly, functionally, and microanatomically accurate by combining tunable assembloid and tissue mapping methods.

Fructose intake, endogenous biomarkers and latent metabolic construct in adolescents: Exploring path associations and mediating effects.

BACKGROUND: Uric acid (UA) and homeostatic model assessment of insulin resistance (HOMA-IR) are endogenous biomarkers implicated in metabolic disorders and dysfunction. OBJECTIVES: To investigate the structural associations between sugar-sweetened beverage intake (SSB), UA, HOMA-IR and adolescent latent MetS construct (MetsC) representing paediatric metabolic syndrome (MetS). METHODS: A population-based representative adolescent cohort (n = 1454) was evaluated for risk profiles of MetS. Structural equation modelling was performed to identify multifactor structural associations between study parameters and evaluate mediating effects. RESULTS: Adolescents had a single-factor latent construct representing MetS. Increased SSB intake was associated with higher UA and HOMA-IR levels, and the two biomarkers were positively associated with the MetsC score. UA and HOMA-IR exerted three mediating effects on the association between fructose-rich tea beverage (FTB) intake of >500 mL/day and MetsC: adjusted standardized coefficient and mediating effect (%), FTB → UA → MetsC: 0.071, 23.1%; FTB → HOMA-IR → MetsC: 0.034, 11.0%; FTB → UA → HOMA-IR → MetsC: 0.010, 3.1%. The UA-associated pathways accounted for 31.1% of the overall mediation on the association between bottled sugar-containing beverage intake and MetsC. After accounting for the UA- and HOMA-IR-derived detrimental effects, the fructose-rich tea beverage intake of >500 mL/day had a tea-related beneficial effect on MetsC, with an adjusted standardized coefficient of -0.103. CONCLUSIONS: UA and HOMA-IR individually and jointly mediate the adverse effects of high fructose-rich SSB intake on the mechanisms underlying paediatric MetS. Fructose-free tea-based beverages may have a beneficial effect on latent MetS structure in adolescents.

Digital Breast Tomosynthesis Screening Improves Early Breast Cancer Detection and Survival in Taiwan.

OBJECTIVE: Our objective was to compare the efficacy of digital breast tomosynthesis (DBT) and digital mammography (DM) in breast cancer screening and their impact on long-term overall survival (OS). METHODS: The study involved 48 549 consecutive mammography examinations between 2011 and 2015 at a medical center in Taiwan, identifying 545 women who were screened and diagnosed with breast cancer. Digital mammography and DBT examinations were alternated on different days. Patients were categorized based on mammographic modality, breast density, and American Joint Committee on Cancer (AJCC) stage. To determine the long-term outcome until August 2021, survival rates were analyzed using the Kaplan-Meier (K-M) survival analysis. RESULTS: The mean age at breast cancer diagnosis was 53.2 years. Digital breast tomosynthesis examinations were significantly associated with early breast cancer (AJCC stage 0 to 2) (P = .022). The 5- and 9-year OS rates for all patients were 96.8% and 93.0%, respectively. The 5- and 9-year OS was significantly greater in the DBT group (98.4% and 96.8%) compared with the DM group (95.0% and 90.4%) (P = .030 for all). The K-M survival analysis demonstrated a significantly higher OS in the DBT group than the DM group (P = .037). Furthermore, DBT significantly improved OS in a cohort of women with stage II and III cancer (P = .032) and heterogeneously dense breasts (P = .045). CONCLUSION: Screening with DBT is associated with early breast cancer diagnosis and higher survival rates compared with DM.

Endovascular Treatment for Ruptured Intracranial Posterior Circulation Aneurysms: Complications and Clinical Outcomes.

OBJECTIVE: To analyze the complications and long-term follow-up results of endovascular treatment for ruptured intracranial posterior circulation aneurysms and identify outcome predictors. METHODS: A total of 194 patients with ruptured intracranial posterior circulation aneurysms treated at our center between January 2014 and June 2023 were included in this retrospective analysis. Factors influencing complications during hospitalization and clinical and angiographic outcomes were analyzed. RESULTS: Complications occurred in 57 patients (29.4%) during hospitalization. The median clinical follow-up time was 46.5 (IQR 26.0-65.3) months, with favorable outcomes observed in 81.4% (158/194) and unfavorable outcomes in 18.5% (36/194) of cases, resulting in an overall mortality rate of 11.9% (23/194). The overall 1-year and 5-year complication-free survival rates were 76.4% and 70.7%, respectively. The overall 1-year and 5-year overall survival rates were 89.5% and 85.4%, respectively. Multifactorial analysis revealed that involvement of the basilar artery (p=0.032) and perioperative external ventricular drainage (p<0.001) were independent risk factors for complications during hospitalization, while advanced age (p=0.030), poor WFNS grade (p=0.003), and use of closed cell design laser cut stents (p=0.041) were independent risk factors for unfavorable outcomes during follow-up. Among the survivors, angiography follow-up was available for 139 patients, with a follow-up rate of 81.2% (139/171) and a median follow-up time of 8 months (IQR 6-12). During this period, 9 patients experienced aneurysm recanalization, and the complete occlusion rate was 85.6%. CONCLUSION: Endovascular treatment is feasible and effective for treating ruptured intracranial aneurysms; however, there are still risks of complications and unfavorable clinical outcomes. The involvement of the BA trunk increases the risk of complications, and the use of closed cell design laser cut stents is associated with unfavorable outcomes. Clinicians should be cautious to avoid the risk factors when treating ruptured posterior circulation aneurysms and strive to minimize the occurrence of complications and unfavorable clinical outcomes.

Development of Machine Learning-Based Quantitative Structure-Activity Relationship Models for Predicting Plasma Half-Lives of Drugs in Six Common Food Animal Species.

Plasma half-life is a crucial pharmacokinetic parameter for estimating extralabel withdrawal intervals of drugs to ensure the safety of food products derived from animals. This study focuses on developing a quantitative structure-activity relationship (QSAR) model incorporating multiple machine learning and artificial intelligence algorithms, and aims to predict the plasma half-lives of drugs in six food animals, including cattle, chickens, goats, sheep, swine, and turkeys. By integrating four machine learning algorithms with five molecular descriptor types, 20 QSAR models were developed using data from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database. The deep neural network (DNN) algorithm demonstrated the best prediction ability of plasma half-lives. The DNN model with all descriptors achieved superior performance with a high coefficient of determination (R  2) of 0.82±0.19 in 5-fold cross-validation on the training sets and a R  2 of 0.67 on the independent test set, indicating accurate predictions and good generalizability. The final model was converted to a user-friendly web dashboard to facilitate its wide application by the scientific community. This machine learning-based QSAR model serves as a valuable tool for predicting drug plasma half-lives and extralabel withdrawal intervals in six common food animals based on physicochemical properties. It also provides a foundation to develop more advanced models to predict the tissue half-life of drugs in food animals.

Identifying and Validating Extracellular Matrix-Related Gene CTSH in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning.

Background: Diabetic foot ulcer (DFU) is a serious clinical problem with high amputation and mortality rates, yet there is a lack of desirable therapy. While the extracellular matrix (ECM) contributes significantly to wound healing, ECM-related biomarker for DFU is still unknown. The study was designed to identify ECM-related biomarker in DFU using bioinformatics and machine learning and validate it in STZ-induced mice models. Methods: GSE80178 and GSE134431 microarray datasets were fetched from the GEO database, and differentially expressed genes (DEGs) analysis was performed, respectively. By analyzing DEGs and ECM genes, we identified ECM-related DEGs, and functional enrichment analysis was conducted. Subsequently, three machine learning algorithms (LASSO, RF and SVM-RFE) were applied to filter ECM-related DEGs to identify key ECM-related biomarkers. Next, we conducted immune infiltration analysis, GSEA, and correlation analysis to explore the hub gene underlying mechanism. A lncRNA-miRNA-mRNA and drug regulatory network were constructed. Finally, we validated the key ECM-related biomarker in STZ-induced mice models. Results: One hundred and forty-five common DEGs in adult DFU between the two datasets were identified. Taking the intersection of 145 common DEGs and 964 ECM genes, we identified 13 ECM-related DEGs. Thirteen ECM-related DEGs were mainly enriched in pathways associated with tissue remodeling, inflammation and defense against infectious agents. Ultimately, CTSH was identified as the key ECM-related biomarker. CTSH was associated with difference immune cells during the occurrence and development of DFU, and it influenced hedgehog, IL-17 and TNF signaling pathway. Additionally, CTSH expression is correlated with many ECM- and immune-related genes. A lncRNA-miRNA-mRNA and drug regulatory network were constructed with 10 lncRNAs, 2 miRNAs, CTSH and 1 drug. Finally, CTSH was validated as a key biomarker for DFU in animal models. Conclusion: Our study found that CTSH can be used for both diagnostic and prognostic purposes and might be a potential therapeutic target.

Characteristics of sleep disturbance across two waves of the COVID-19 pandemic among nursing staffs.

Objectives: COVID-19 has impacted human lifestyles, including sleep quality. For nursing staff, sleep disorders not only impact their health and daily lives but also have implications for patient safety. The objective of this study is to explore the impact of the COVID-19 pandemic on the psychological and social aspects of nursing staff and the factors influencing their sleep quality through a two-wave survey. Methods: Nursing staff from a psychiatric hospital in southern Taiwan were recruited in two waves during the COVID-19 epidemic. The level of sleep disturbance and related variables, such as Lo's Healthy and Happy Lifestyle Scale (LHHLS) and Societal Influences Survey Questionnaire (SISQ), were collected through self-report questionnaires. Factors related to the level of sleep disturbance were examined using univariate linear regression and multilevel linear regression. Results: 508 nursing staff members were included in the study, with 254 members in each wave. A significant difference was found between the two waves in the positive thinking of LHHLS and all subscales of SISQ. During the second wave, sleep disturbances were mainly related to self-efficacy, positive thinking, social anxiety, and social desirability. At the fourth wave, sleep disturbances were mainly related to self-efficacy, positive thinking, and social anxiety. However, these effects change when the trend of the epidemic shifts, and other factors are taken into account. Conclusions: This study analyzed the factors related to the sleep quality of nursing staff during the COVID-19 pandemic. We preliminarily explored the impact of the COVID-19 pandemic on the sleep quality of nursing staff. However, determining whether the end of the epidemic has reduced the impact on nursing staff requires further research.

Frequent use of percutaneous transluminal angioplasty is not associated with reduced vascular access recreation in a longitudinal ecology study.

The frequency of percutaneous transluminal angioplasty (PTA) procedures has substantially increased, but its effect on vascular access recreation (VAR) remains inconclusive. We conducted a population-based retrospective analysis of Taiwan hemodialysis (HD) centers from 2004 to 2012. Data was accumulated into center-level characteristics, including patients' demographics, baseline characteristics, PTA procedures, and VAR. Center-level characteristics were summarized annually using appropriate measures. A mixed model assessed the association between PTA frequency and VAR rates, considering within-center correlation and adjusting for potential confounders. A total of 82,005 patients (mean age 62.7 ± 13.9 years, 50.5% male, 48.5% with diabetes mellitus) from 820 HD centers were analyzed. From 2004 to 2012, PTA frequency significantly increased from 1.24 to 3.23 per 1000 HD sessions, while VAR rates did not decline as expected (0.5-0.8 per 1000 HD sessions). Compared with the HD centers of infrequent use of PTA (annual lowest quartile, range 0.39-1.20 per 1000 HD sessions), the ones of frequent use (annual highest quartile, range 2.52-5.10 per 1000 HD sessions) didn't have lower VAR (range 0.54-0.99 vs. 0.50-0.91 per 1000 HD sessions, respectively). After controlling the potential confounders, the HD centers' PTA rates were not significantly associated with lower VAR rates (- 2.6, 95% confidence interval: - 30.3; 25.0, p = 0.85). Frequent use of PTA does not seem to improve VA patency at the center level, with no significant association identified with lower VAR. The indication of PTA in daily practice should be re-evaluated in terms of its efficiency in lowering VAR.

Developing a plant microbial fuel cell by planting water spinach in a hanging-submerged plant pot system.

To plant crops (especially dry crops such as water spinach) with concomitant electricity recovery, a hanging-submerged-plant-pot system (HSPP) is developed. The HSPP consists of a soil pot (anodic) partially submerged under the water surface of a cathode tank. The microbial communities changed with conditions were also investigated. It was found that with chemical fertilizers the closed-circuit voltage (CCV, with 1 kΩ) was stable (approximately 250 mV) within 28 d; however, without fertilizer, the water spinach could adjust to the environment to obtain a better power output (approximately 3 mW m-2) at day 28. The microbial-community analyses revealed that the Pseudomonas sp. was the only exoeletrogens found in the anode pots. Using a secondary design of HSPP, for a better water-level adjustment, the maximum power output of each plant was found to be approximately 27.1 mW m-2. During operation, high temperature resulted in low oxygen solubility, and low CCV as well. At this time, it is yet to be concluded whether the submerged water level significantly affects electricity generation.

CasRx-based Wnt activation promotes alveolar regeneration while ameliorating pulmonary fibrosis in a mouse model of lung injury.

Wnt/ß-catenin signaling is an attractive target for regenerative medicine. A powerful driver of stem cell activity and hence tissue regeneration, Wnt signaling can promote fibroblast proliferation and activation, leading to fibrosis, while prolonged Wnt signaling is potentially carcinogenic. Thus, to harness its therapeutic potential, the activation of Wnt signaling must be transient, reversible, and tissue specific. In the lung, Wnt signaling is essential for alveolar stem cell activity and alveolar regeneration, which is impaired in lung fibrosis. Activation of Wnt/ß-catenin signaling in lung epithelium may have anti-fibrotic effects. Here, we used intratracheal adeno-associated virus 6 injection to selectively deliver CasRx into the lung epithelium, where it reversibly activates Wnt signaling by simultaneously degrading mRNAs encoding Axin1 and Axin2, negative regulators of Wnt/ß-catenin signaling. Interestingly, CasRx-mediated Wnt activation specifically in lung epithelium not only promotes alveolar type II cell proliferation and alveolar regeneration but also inhibits lung fibrosis resulted from bleomycin-induced injury, relevant in both preventive and therapeutic settings. Our study offers an attractive strategy for treating pulmonary fibrosis, with general implications for regenerative medicine.

Dietary curcumin alleviates intestinal damage induced by ochratoxin A in juvenile grass carp (Ctenopharyngodon idella): Necroptosis and inflammatory responses.

Ochratoxin A (OTA) is one of the most common pollutants in aquatic feed. As a first line of defense, intestinal barriers could be utilized against OTA in order to prevent disorders. Natural product supplementation is one of the most popular strategies to alleviate toxicity induced by mycotoxins, but there is a lack of knowledge about how it functions in the teleost intestine. In this study, 720 juvenile grass carp of about 11 g were selected and four treatment groups (control group, OTA group, curcumin [Cur] group, and OTA + Cur group) were set up to conduct a 60-day growth test. After the test, the growth performance and intestinal health related indexes of grass carp were investigated. The addition of dietary Cur could have the following main results: (1) inhibit absorption and promote efflux transporters mRNA expression, reducing the residuals of OTA, (2) decrease oxidative stress by reducing oxidative damage and enhancing the expression of antioxidant enzymes, (3) promote mitochondrial fusion proteins to inhibit the expression of mitotic proteins and mitochondrial autophagy proteins and enhance mitochondrial function, (4) reduce necroptosis-related gene expression through inhibiting the tumor necrotic factor receptor-interacting protein kinase/mixed lineage kinase domain-like pathway, (5) reduce the expression of pro-inflammatory factors by inhibiting the Toll-like receptor 4/nuclear factor-κB signaling pathway to alleviate the intestinal inflammatory response. In summary, the results suggested that Cur could alleviate OTA-induced intestinal damage by enhancing antioxidant capacity and mitochondrial function as well as reducing necroptosis and inflammation in the grass carp intestine. This study provided a theoretical basis and production implications for dietary Cur that could improve growth performance and alleviate the intestinal damage induced by OTA in fish.

Continuous adoption of online healthcare platforms: an extension to the expectation confirmation model and network externalities.

BACKGROUND: Online healthcare platforms (OHPs) promote the accessibility of health services while integrating online and offline service delivery. Continuous adoption of these platforms can reduce the information asymmetry between patients and healthcare providers. However, existing study has rarely focused on how the network externalities of these platforms influence patients' continuous adoption. Expectation Confirmation Model (ECM) explains the continuous behavior after initial adoption and reveal the factors influencing satisfaction and continuous adoption intention. Few studies have integrated network externalities with the ECM to understand patients' continuous adoption of OHPs. OBJECTIVE: This study aims to explore what factors affect the continuous adoption of OHPs based on an extension to the ECM and network externalities. We propose a comprehensive model for the continuous adoption of OHPs by patients with chronic diseases. We extend the conceptual framework by incorporating constructs related to perceived value, habits, and switching costs. METHODS: This study utilized a web-based survey to collect data from participants in China. We selected a sample of individuals who had experience with OHPs using a random sampling method. This method ensured that participants was randomly chosen from a pool of patients without any regional bias. A total of 568 questionnaires were collected and 518 valid questionnaires were obtained. Structural equation modeling was applied to assess the relationships among the constructs. Hierarchical regression analysis was utilized to examine the moderating effects, while the mediating effects were investigated using the bootstrapping approach. RESULTS: Direct network externality had significant positive impacts on the confirmation (ß = 0.232, p < 0.001) and perceived value (ß = 0.167, p < 0.010). Cross network externality had significant positive impacts on confirmation (ß = 0.307, p < 0.001) and perceived value (ß = 0.120, p < 0.05). Indirect network externality had significant positive impacts on confirmation (ß = 0.169, p < 0.010) and perceived value (ß = 0.270, p < 0.001). Confirmation had a significant positive impact on perceived value (ß = 0.205, p < 0.001) and satisfaction (ß = 0.508, p < 0.001). In addition, satisfaction had a significant positive impact on continuous adoption intention (ß = 0.579, p < 0.001). Continuous adoption intention had a significant positive impact on continuous adoption behavior (ß = 0.547, p < 0.001). Confirmation and perceived value significantly mediate the relationship between network externalities and satisfaction. Moreover, both confirmation and perceived value enhance continuous adoption intention by positively influencing satisfaction, which serves as a mediator. Additionally, confirmation directly influences satisfaction through the mediating role of perceived value. Habits and switching costs positively moderate the relationship between continuous adoption intention and behavior. CONCLUSIONS: This study contributes by expanding the incorporation of network externalities into the ECM. Results enrich the existing literature on the continuous adoption of professional online platforms.

Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α5ß1 integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.

Gustatory receptor 11 is involved in detecting the oviposition water of Asian tiger mosquito, Aedes albopictus.

BACKGROUND: Aedes albopictus is a major arbovirus vector with small stagnant water containers being its oviposition sites. Mosquitoes search for these sites based on their olfactory cues (odor and moisture emanating from the water at the oviposition site), visual cues (size and color of the site), and gustatory cues (ion and nutrient concentration in that water). The gustatory mechanism through which mosquitoes search for oviposition sites remains unknown. METHODS: To investigate the role of taste receptors in Ae. albopictus oviposition site selection, we developed a laboratory model. This model assessed mosquito behavior in locating and detecting oviposition sites, using a location index to quantify site preference and detection time to measure response to water presence. We compared oviposition site-searching efficiency between mosquitoes with blocked and unblocked appendages, targeting the taste organs. Transcriptome sequencing was conducted to identify differentially expressed genes between water-exposed and unexposed mosquitoes. CRISPR/Cas9 technology was then employed to generate a mutant strain with a targeted gene knockout. RESULTS: There was no significant difference between the blocked and unblocked groups in the location index. In contrast, the detection time of the unblocked group differed significantly from all other groups, including those with blocked foreleg tarsus, midleg tarsus, hindleg tarsus, all tibia, and all tarsus. Transcriptome sequencing analyses of water-exposed and unexposed mosquitoes revealed that the taste-related gene gustatory receptor 11(gr11) was differentially expressed. This gene was knocked out with CRISPR/Cas9 technology to generate a pure mutant strain with 2- and 4-bp deletions, which exhibited a significantly longer detection time than the wild-type strain. CONCLUSIONS: This study reveals the role of Ae. albopictus gr11 in water detection at oviposition sites, thereby providing a theoretical basis and scientific guidelines for managing the breeding sites of these mosquitoes.