A novel polydiacetylene-functionalized fibrinogen paper-based biosensor for on-spot and rapid detection of Staphylococcus aureus.

Staphylococcus aureus contamination continues to be a harmful foodborne pathogen threatening of human health, and there is a growing need for rapid detection technologies. This study proposed a novel paper biosensor based on a polydiacetylene (PDA) polymer functionalized fibrinogen (Fg) for the detection of S. aureus in food sources. The fluorophore was developed based on the high binding ability of fibrinogen-binding proteins on the surface of S. aureus. This binding caused twisting in the PDA backbone, leading to changes in chromatic and fluorescent. The detection limit of this method was 50.1 CFU/mL for S. aureus-contaminated foodstuffs and 65.0 CFU/mL for the pure S. aureus culture, and the novelty came from its rapidity and selectivity for S. aureus compared to other foodborne bacteria. In summary, the present work provides a rapid detection method for S. aureus detection, which will help in addressing food safety-related issues.

A deep neural network prediction method for diabetes based on Kendall's correlation coefficient and attention mechanism.

Diabetes is a chronic disease, which is characterized by abnormally high blood sugar levels. It may affect various organs and tissues, and even lead to life-threatening complications. Accurate prediction of diabetes can significantly reduce its incidence. However, the current prediction methods struggle to accurately capture the essential characteristics of nonlinear data, and the black-box nature of these methods hampers its clinical application. To address these challenges, we propose KCCAM_DNN, a diabetes prediction method that integrates Kendall's correlation coefficient and an attention mechanism within a deep neural network. In the KCCAM_DNN, Kendall's correlation coefficient is initially employed for feature selection, which effectively filters out key features influencing diabetes prediction. For missing values in the data, polynomial regression is utilized for imputation, ensuring data completeness. Subsequently, we construct a deep neural network (KCCAM_DNN) based on the self-attention mechanism, which assigns greater weight to crucial features affecting diabetes and enhances the model's predictive performance. Finally, we employ the SHAP model to analyze the impact of each feature on diabetes prediction, augmenting the model's interpretability. Experimental results show that KCCAM_DNN exhibits superior performance on both PIMA Indian and LMCH diabetes datasets, achieving test accuracies of 99.090% and 99.333%, respectively, approximately 2% higher than the best existing method. These results suggest that KCCAM_DNN is proficient in diabetes prediction, providing a foundation for informed decision-making in the diagnosis and prevention of diabetes.

Non-linear association of liver enzymes with cognitive performance in the elderly: A cross-sectional study.

BACKGROUND: Although liver metabolic dysfunction has been found to potentially elevate susceptibility to cognitive impairment and dementia, there is still insufficient evidence to explore the non-linear association of liver enzymes with cognitive performance. Therefore, we aimed to elucidate the non-linear relationship between liver enzymes and cognitive performance. METHODS: In this cross-sectional study, 2764 individuals aged ≥ 60 who participated in the National Health and Nutrition Survey (NHANES) between 2011 and 2014 were included. The primary data comprised liver enzyme levels (alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, and gamma-glutamyl transferase (GGT)), and cognitive performance was the major measured outcome. The associations were analyzed using weighted multivariate logistic regression, subgroup analysis, a generalized additive model, smooth fitting curves, and threshold effects. RESULTS: The results of the fully adjusted model indicated that ALP was negatively associated with the animal fluency test (AFT) score (OR = 1.48, 95% CI: 1.11-1.98), whereas ALT demonstrated a positive association with the consortium to establish a registry for Alzheimer's disease (CERAD) test score (OR = 0.72, 95% CI: 0.53-0.97). Additionally, the AST/ALT ratio was negatively associated with the global cognitive test (OR = 2.39, 95% CI: 1.53-3.73), CERAD (OR = 2.61, 95% CI: 1.77-3.84), and digit symbol substitution test (DSST) scores (OR = 2.51, 95% CI: 1.57-4.02). GGT was also negatively associated with the AFT score (OR = 1.16, 95% CI: 1.01-1.33) in unadjusted model. A non-linear relationship was observed between liver enzymes and the risk of cognitive impairment as assessed by the global cognitive test. Specifically, when ALP > 60 U/L, 0.77 < AST/ALT < 1.76, and 25 < GGT < 94 U/L, higher liver enzyme levels were significantly associated with an elevated cognitive impairment risk, while a lower cognitive impairment risk when ALT level was > 17 U/L. CONCLUSIONS: There is a non-linear relationship between liver enzymes and cognitive performance, indicating that liver enzyme levels should be maintained within a certain level to mitigate the risk of cognitive impairment.

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis.

Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.

Effect of Intergenerational Trends on Parental Child-Rearing Gender Role Attitudes (PCGAs) in Single-Parent Families: A Relative Mediation.

Family structures are diverse, with single-parent families being special. Single-parent families have garnered interest regarding their impact on their children's development in relation to gender roles and social adaptation. This study investigated 532 children from single-parent families (mean age = 14.81, SD = 1.62) and their parents. We collected data on the parental child-rearing gender role attitudes (PCGAs) of grandparents and parents, as well as the gender role and social adaptation of the children. The results revealed four intergenerational trends in PCGAs: progression between generations, undesirability in both generations, desirability in both generations, and retrogression between generations. An ANOVA showed that families with intergenerational desirability tended to have children with the highest gender role and social adaptation scores among the four intergenerational trends, while families with intergenerational undesirability had the lowest. A relative mediation analysis showed that compared to intergenerational undesirable PCGAs, intergenerational progress and intergenerational desirable PCGAs are beneficial for children's gender traits, and their social adaptation development is also better. The results confirm the positive effect of children's gender roles on their social adaptation, which suggests that parents should pay attention to children's gender role education, transform their PCGAs, and create a nurturing environment for children's gender role development.

Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport Guanosine diphosphate-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 ( Slc35c1 cKO ) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T cell, neutrophil, and F4/80 macrophage infiltration but did not affect the levels of serum and liver BA in mouse models of cholestasis. Liquid chromatography with tandem mass spectrometry analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5- ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

T cell receptor repertoire deciphers anti-tuberculosis immunity.

T cell induced cellular immunity is considered to be extremely important for the control of tuberculosis (TB). T cell receptor (TCR), the key component responsible for the specificity and clustering of T cells, holds the potential to advance our understanding of T cell immunity against TB infection. This review systematically expounded the study progressions made in the field of TB-relevant TCRs based on single cell sequencing together with GLIPH2 technology and initiated a comparison of the T cell distribution between peripheral blood and infected organs. We divided clonal expanded T cell clones into recirculation subsets and local subsets to summarize their distinctions in clonal abundance, TCR sequences and antigenic specificity. Notably, local expansion appears to drive the primary variances in T cell subsets between these two contexts, indicating the necessity for further exploration into the functions and specificity of local subsets.

Development and External Validation of a Machine Learning-based Fall Prediction Model for Nursing Home Residents: A Prospective Cohort Study.

OBJECTIVES: To develop and externally validate a machine learning-based fall prediction model for ambulatory nursing home residents. The focus is on predicting fall occurrences within 6 months after baseline assessment through a binary classification task, aiming to provide staff with an effective and user-friendly fall-risk assessment tool. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 864 older residents living in 4 nursing homes between May 2022 and March 2023 in China. METHODS: Potential fall-risk predictors were collected through in-person interviews and assessments of anthropometric and physical function. Participants were followed for 6 months, with falls recorded by trained nurses. Seven machine learning algorithms, including Logistic Regression (LR), Gradient Boosting Machine (GBM), eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Support Vector Machine (SVM), Neural Networks (NN), and Decision Tree (DT), were used to develop prediction models. Performance was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) and Precision-Recall curve (PR-AUC), with calibration assessed via a calibration curve. Feature importance was visualized using SHapley Additive exPlanations (SHAP). RESULTS: The 6 selected predictors were balance, grip strength, fatigue, fall history, age, and comorbidity. The ROC-AUC for the models ranged from 0.710 to 0.750, PR-AUC from 0.415 to 0.473, sensitivity from 0.704 to 0.914, and specificity from 0.511 to 0.687 in the validation cohort. The LR model was converted into a nomogram. CONCLUSIONS AND IMPLICATIONS: The machine learning-based fall-prediction models effectively identified nursing home residents at high risk of falls. The developed nomogram can be integrated into clinical practice to enhance fall risk assessment protocols, ultimately improving patient safety and care in nursing homes.

Inhibition of SIRT1 relieves hepatocarcinogenesis via alleviating autophagy and inflammation.

Imbalanced Sirtuin 1 (SIRT1) levels may lead to liver diseases through abnormal regulation of autophagy, but the roles of SIRT1-regulated autophagy in hepatocellular carcinoma are still controversial. In this study, we found that SIRT1 mRNA and protein levels were upregulated in hepatocellular carcinoma, and high SIRT1 expression hinted an advanced stage and a poor prognosis. The differentially expressed proteins were significantly elevated in autophagy, cellular response to stress, and immune signaling pathways. In a thioacetamide-induced hepatocellular carcinoma mouse model, we found that SIRT1 expression was highly increased with increased autophagy and excessive macrophage inflammatory response. Next, we established a Hepa 1-6 cells and macrophage co-culture system in vitro to model the alteration of tumor microenvironment, and found that the medium from CCl4-treated or SIRT1-overexpressing Hepa 1-6 cells triggered the polarization of macrophage M1, and the culture medium derived from M1 macrophage promoted Hepa 1-6 cells growth and intracellular oxidative stress. The progression of liver fibrosis in the CCl4-induced liver fibrosis mouse model showed that inhibition of SIRT1 alleviated inflammatory response and ameliorated liver fibrosis. These findings suggest that SIRT1-regulated autophagy and inflammation are oncogenic in hepatocarcinogenesis.

Association of complete blood count parameters with the risk of incident pulmonary heart disease in pneumoconiosis: a retrospective cohort study.

BACKGROUND: Pneumoconiosis mostly combines pulmonary and cardiovascular diseases, among which pulmonary heart disease (PHD) is of major concern due to its significant impact on the survival of pneumoconiosis patients. White cell count (WCC), red cell distribution width (RDW) and platelet parameters are thought to affect inflammatory responses and may be predictors of various cardiovascular diseases. However, very few studies have focused on PHD. OBJECTIVES: To examine the relationship between baseline complete blood count parameters (WCC, RDW, platelet parameters) and the risk of incident PHD in pneumoconiosis patients. DESIGN: A retrospective cohort study. SETTING: This was a single-centre, retrospective cohort study that used data from an Occupational Disease Hospital, Chengdu, Sichuan. PARTICIPANTS: A total of 946 pneumoconiosis patients from January 2012 to November 2021 were included in the study. Female patients and patients who had PHD, coronary heart disease, hypertensive heart disease, cardiomyopathy, heart failure, oncological disease, multiple organ dysfunction, AIDS at baseline and follow-up time of less than 6 months were also excluded. OUTCOME MEASURES: We identified PHD according to the patient's discharge diagnosis. We constructed Cox proportional hazard regression models to assess the HR of incident PHD in pneumoconiosis, as well as 95% CIs. RESULTS: In the multiple Cox proportional hazard regression analysis, platelet count (PLT) and plateletcrit (PCT) above the median at baseline were associated with an increased risk of PHD in pneumoconiosis with adjusted HR of 1.52 (95% CI 1.09 to 2.12) and 1.42 (95% CI 1.02 to 1.99), respectively. CONCLUSION: Higher baseline PLT and PCT are associated with a higher risk of PHD in pneumoconiosis.

Testosterone Mediates Reproductive Toxicity in Caenorhabditis elegans by Affecting Sex Determination in Germ Cells through nhr-69/mpk-1/fog-1/3.

Testosterone (T), an environmental androgen, significantly disrupts endocrine systems in wildlife and ecosystems. Despite growing concern over its high levels in aquatic environments, the reproductive toxicity of testosterone and its mechanisms are not well understood. In this study, we investigated the reproductive toxicity and mechanisms of testosterone using Caenorhabditis elegans (C. elegans) and assessed its ecological toxicity through the benchmark dose (BMD) method. Our results indicate that T concentrations exceeding 0.01 µg/L significantly reduce the brood size, decrease germ cell counts, and prolong the generation time in C. elegans as T concentrations increase. Furthermore, to elucidate the specific mechanisms, we analyzed the expression of nhr-69, mpk-1, and other genes involved in sex determination. These findings suggest that the nhr-69-mediated reproductive toxicity of T primarily affects sperm formation and the offspring number by influencing its downstream targets, mpk-1 and fog-1/3, which are critical in the germ cell sex-determining pathway. Additionally, this study determined that the 10% lower boundary of the baseline dose (BMDL10) is 1.160 ng/L, offering a more protective reference dose for the ecological risk assessment of T. The present study suggests that nhr-69 mediates the reproductive toxicity of T by influencing mpk-1 and fog-1/3, critical genes at the end of the germ cell sex-determining pathway, thereby providing a basis for establishing reproductive toxicity thresholds for T.

[Effects of cochlear implantation on tinnitus in patients with single-sided deafness and asymmetrical hearing loss].

Objective:To evaluate the effects of cochlear implantation in patients with single-sided deafness（SSD） and asymmetrical hearing loss（AHL）. Methods:Seventeen Mandarin-speaking CI patients diagnosed as SSD/AHL were recruited in our study. The Tinnitus Handicap Inventory（THI） and the Visual Analogue Scale（VAS） were used to assess changes in tinnitus distress and tinnitus loudness in SSD patients at each time point（pre-operation and post-operation）. Results:The THI score and all 3 dimensions were significant decreased with CI-on than pre-operation（P<0.05）. Tinnitus VAS scores were also decreased, and VAS scores were lower with CI-on than with CI-off, and were both significantly different at each time point after CI switch-on（P<0.05）. Conclusion:CI could help SSD/AHL patients to suppress tinnitus and reduce the loudness of tinnitus. However, CI should not be a treatment of tinnitus.

New Cytotoxic γ-Lactam Alkaloids from the Mangrove-Derived Fungus Talaromyces hainanensis sp. nov. Guided by Molecular Networking Strategy.

The fungus Talaromyces hainanensis, isolated from the mangrove soil, was characterized as a novel species by morphology observation and phylogenetic analyses. Four new γ-lactam alkaloids talaroilactams A-D (1-4) and two reported compounds harzianic acid (5) and isoharzianic acid (6) were identified from the fungus T. hainanensis WHUF0341, assisted by OSMAC along with molecular networking approaches. Their structures were determined through ECD calculations and spectroscopic analyses. Moreover, the biosynthetic route of 1-4 was also proposed. Compound 1 displayed potent cytotoxicity against HepG2 cell lines, with an IC50 value of 10.75 ± 1.11 µM. In addition, network pharmacology was employed to dissect the probable mechanisms contributing to the antihepatocellular carcinoma effects of compound 1, revealing that cytotoxicity was mainly associated with proteolysis, negative regulation of autophagy, inflammatory response, and the renin-angiotensin system. These results not only expanded the chemical space of natural products from the mangrove associated fungi but also afforded promising lead compounds for developing the antihepatocellular carcinoma agents.

[Effects of Straw and Fertilizer Managements on Nitrogen Loss in Rice Cultivation in Taihu Lake Basin].

Nitrogen loss from rice systems is an important source of agricultural non-point source pollution. Many studies revolve around reducing the rate of nitrogen fertilizer application. However, studies examining the characteristics of nitrogen loss in multiple loss paths （runoff, leaching, and lateral seepage） under different straw and fertilizer managements are lacking. Therefore, a study was carried out based on a rice field planted for more than 20 years with straw continuously returned to the field for more than 5 years in Taihu lake basin. The effects of straw and fertilizer managements on nitrogen loss in different paths during the whole growth period of rice were studied. Moreover, straw and fertilizer managements were evaluated by their production suitability and environmental friendliness based on crop yield, nitrogen use efficiency, and nitrogen loss. The results showed that straw removal from the field increased the response sensitivity of nitrogen accumulation in plant tissue to nitrogen application. The nitrogen loss in the rice season was 9-17 kg·hm-2, accounting for 5%-7% of the nitrogen application rate. Straw removal increased the risk of nitrogen loss when soaking water discharged. Straw returning could decrease the nitrogen loss by more than 15%, though the effect of straw on nitrogen loss via lateral seepage was not clear. Furthermore, the suitable substitution of organic fertilizer （30% in this study） could respectively reduce the amount of nitrogen loss via runoff, leaching, and lateral seepage by 16%, 26%, and 37% compared with the fertilizer application under the same nitrogen gradient. In conclusion, the implementation of straw returning and fertilizer type optimization measures effectively reduced the nitrogen loss for unit weight of rice production and realized the balance between agricultural production and environmental protection.

Innovative Delivery System Combining CRISPR-Cas12f for Combatting Antimicrobial Resistance in Gram-Negative Bacteria.

Antimicrobial resistance poses a significant global challenge, demanding innovative approaches, such as the CRISPR-Cas-mediated resistance plasmid or gene-curing system, to effectively combat this urgent crisis. To enable successful curing of antimicrobial genes or plasmids through CRISPR-Cas technology, the development of an efficient broad-host-range delivery system is paramount. In this study, we have successfully designed and constructed a novel functional gene delivery plasmid, pQ-mini, utilizing the backbone of a broad-host-range Inc.Q plasmid. Moreover, we have integrated the CRISPR-Cas12f system into the pQ-mini plasmid to enable gene-curing in broad-host of bacteria. Our findings demonstrate that pQ-mini facilitates the highly efficient transfer of genetic elements to diverse bacteria, particularly in various species in the order of Enterobacterales, exhibiting a broader host range and superior conjugation efficiency compared to the commonly used pMB1-like plasmid. Notably, pQ-mini effectively delivers the CRISPR-Cas12f system to antimicrobial-resistant strains, resulting in remarkable curing efficiencies for plasmid-borne mcr-1 or blaKPC genes that are comparable to those achieved by the previously reported pCasCure system. In conclusion, our study successfully establishes and optimizes pQ-mini as a broad-host-range functional gene delivery vector. Furthermore, in combination with the CRISPR-Cas system, pQ-mini demonstrates its potential for broad-host delivery, highlighting its promising role as a novel antimicrobial tool against the growing threat of antimicrobial resistance.

Trans-complementation of the viral movement protein mediates efficient expression of large target genes via a tobacco mosaic virus vector.

The development of plant virus-based expression systems has expanded rapidly owing to their potential applications in gene functional and disease resistance research, and industrial production of pharmaceutical proteins. However, the low yield of certain proteins, especially high-molecular-mass proteins, restricts the production scale. In this study, we observed that the tobacco mosaic virus (TMV)-mediated expression of a foreign protein was correlated with the amount of the movement protein (MP) and developed a TMV-derived pAT-transMP vector system incorporating trans-complementation expression of MP. The system is capable of efficient expression of exogenous proteins, in particular those with a high molecular mass, and enables simultaneous expression of two target molecules. Furthermore, viral expression of competent CRISPR-Cas9 protein and construction of CRISPR-Cas9-mediated gene-editing system in a single pAT-transMP construct was achieved. The results demonstrated a novel role for TMV-MP in enhancing the accumulation of a foreign protein produced from the viral vector or a binary expression system. Further investigation of the mechanism underlying this role will be beneficial for optimization of plant viral vectors with broad applications.

Current Applications of Colorectal Cancer Organoids: A Review.

Colorectal cancer is a prevalent malignancy, with advanced and metastatic forms exhibiting poor treatment outcomes and high relapse rates. To enhance patient outcomes, a comprehensive understanding of the pathophysiological processes and the development of targeted therapies are imperative. The high heterogeneity of colorectal cancer demands precise and personalized treatment strategies. Colorectal cancer organoids, a three-dimensional in vitro model, have emerged as a valuable tool for replicating tumor biology and exhibit promise in scientific research, disease modeling, drug screening, and personalized medicine. In this review, we present an overview of colorectal cancer organoids and explore their applications in research and personalized medicine, while also discussing potential future developments in this field.

Prolactin upregulates amino acids uptake in dairy cow mammary epithelial cells via LAT1.

The uptake of AA in mammary tissues is affected by prolactin (PRL). To investigate whether PRL-induced AA uptake is involved in L-type AA transporter 1 (LAT1), we analyzed the changes of AA in the medium of dairy cow mammary epithelial cells in the presence of PRL or PRL plus BCH, an inhibitor of LAT1. Then Western blot and luciferase assay were used to detect the regulation mechanism of PRL on LAT1 expression and function. Our results showed that Thr, Val, Met, Ile, Leu, Tyr, Lys, Phe, and His are LAT1 substrates and could be transported into mammary epithelial cells via LAT1. PRL stimulation increased the uptake of most AA into mammary epithelial cells of dairy cows, however, inhibition of LAT1 transport activity reduced PRL-induced AA uptake, suggesting that the effect of PRL on AA transport depends on LAT1 expression and function. PRL stimulation upregulated LAT1 expression and plasma membrane location not only in dairy cow mammary epithelial cells, but also in mouse mammary epithelial cell line HC11. Western blot showed that PI3K-AKT-mTOR signaling could be activated in PRL-stimulated mammary epithelial cells. Treatment of cells with LY294002 decreased PI3K-AKT-mTOR activation, as well LAT1 expression, that in turn decreased milk protein synthesis. Luciferase assay showed PRL treatment increased the promoter activity of LAT1 promoter fragment -419∼-86 bp. Treatment of cells with LY294002, an inhibitor of PI3K, or SC79, an activator of AKT abolished or promoted the transcriptional activity of this promoter fragment in the presence of PRL. These results suggested that the -419∼-86 bp fragment of LAT1 promoter mediates the action of PI3K-AKT-mTOR signaling on LAT1 transcription in mammary epithelial cells of dairy cows, which in turn increased LAT1 expression and AA uptake.

Prevalence of physical inactivity and its determinants among older adults living in nursing homes: A cross-sectional study based on COM-B model.

AIMS: To investigate the prevalence of physical inactivity in older adults living in nursing homes and explore the determinants of physical inactivity by using the Capability, Opportunity, Motivation-Behaviour model. DESIGN: A multisite, cross-sectional study was performed by convenience sampling and questionnaire survey. METHODS: A total of 390 nursing home residents were recruited from three nursing homes in Southern China from May 2022 to April 2023. The participants completed a self-designed general information questionnaire, Physical Activity Scale for the Elderly, Self-Efficacy for Exercise Scale, Exercise Benefits Scale, Patient Health Questionnaire-9 and the Short Physical Performance Battery test. Descriptive statistics, univariate analysis, Spearman correlation analysis, and ordinal logistic regression were applied for data analysis. RESULTS: The prevalence of physical inactivity among the nursing home residents reached 88.46%. Ordinal logistic regression results showed that exercise self-efficacy, perceived exercise benefits, physical function, availability of physical activity instruction, having depression, number of chronic diseases and living with spouse were the main influencing determinants of physical inactivity and explained 63.7% of the variance. CONCLUSIONS: Physical inactivity was considerable in nursing home residents in China and influenced by complex factors. Tailored measures should be designed and implemented based on these factors to enhance physical activity while considering the uniqueness of Chinese culture. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Healthcare professionals should enhance physical activity of residents by increasing benefits understanding, boosting self-efficacy, improving physical function, alleviating depression and integrating personalized physical activity guidance into routine care services. And more attention should be paid to the residents who had more chronic diseases or did not live with spouse. IMPACT: Physical inactivity is a significant problem in nursing home residents. Understanding physical inactivity and its determinants enables the development of tailored interventions to enhance their physical activity level. REPORTING METHOD: This study was reported conforming to the STROBE statement. PATIENTS OR PUBLIC CONTRIBUTION: Nursing home residents who met the inclusion criteria were recruited.

Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.