A Crucial Role of Adenosine Deaminase in Regulating Gluconeogenesis in mice.

Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine to inosine and regulates adenosine concentration. ADA ubiquitously expresses in various tissues to mediate adenosine receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus (T2DM). Here we show that elevated plasma ADA activity is a compensated response to high level of adenosine in T2DM and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA can reduces adenosine levels and decreases hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat-STZ diabetic mice. Mechanistically, ADA catabolizes adenosine and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway.

Introduction: The Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway has been extensively studied for its role in regulating antioxidant and antiviral responses. The Equid herpesvirus type 8 (EqHV-8) poses a significant threat to the equine industry, primarily manifesting as respiratory disease, abortions, and neurological disorders in horses and donkeys. Oxidative stress is considered a key factor associated with pathogenesis of EqHV-8 infection. Unfortunately, there is currently a dearth of therapeutic interventions available for the effective control of EqHV-8. Rutin has been well documented for its antioxidant and antiviral potential. In current study we focused on the evaluation of Rutin as a potential therapeutic agent against EqHV-8 infection. Methods: For this purpose, we encompassed both in-vitro and in-vivo investigations to assess the effectiveness of Rutin in combatting EqHV-8 infection. Results and Discussion: The results obtained from in vitro experiments demonstrated that Rutin exerted a pronounced inhibitory effect on EqHV-8 at multiple stages of the viral life cycle. Through meticulous experimentation, we elucidated that Rutin's antiviral action against EqHV-8 is intricately linked to the Nrf2/HO-1 signaling pathway-mediated antioxidant response. Activation of this pathway by Rutin was found to significantly impede EqHV-8 replication, thereby diminishing the viral load. This mechanistic insight not only enhances our understanding of the antiviral potential of Rutin but also highlights the significance of antioxidant stress responses in combating EqHV-8 infection. To complement our in vitro findings, we conducted in vivo studies employing a mouse model. These experiments revealed that Rutin administration resulted in a substantial reduction in EqHV-8 infection within the lungs of the mice, underscoring the compound's therapeutic promise in vivo. Conclusion: In summation, our finding showed that Rutin holds promise as a novel and effective therapeutic agent for the prevention and control of EqHV-8 infections.

Design, synthesis, and biological evaluation of 5-(1H-indol-5-yl)isoxazole-3-carboxylic acids as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.

Screening of a Saccharomyces cerevisiae Strain with High 3-Methylthio-1-Propanol Yield and Optimization of Its Fermentation Conditions.

3-Methylthio-1-propanol (3-Met) is an important flavor compound in various alcoholic beverages such as Baijiu and Huangjiu. To maintain the content of 3-Met in these alcoholic beverages, it is necessary to screen a micro-organism with high yield of 3-Met from the brewing environment. In this study, the ability of yeast strains from the Baijiu brewing to produce 3-Met was analyzed, aiming to obtain yeast with high-yield 3-Met, and its fermentation conditions were optimized. Firstly, 39 yeast strains were screened using 3-Met conversion medium. The results showed that the majority of the strains from Baijiu brewing sources could produce 3-Met, and nearly half of the strains produced more than 0.5 g/L of 3-Met. Among these, yeast F10404, Y03401, and Y8#01, produced more than 1.0 g/L of 3-Met, with yeast Y03401 producing the highest amount at 1.30 g/L. Through morphological observation, physiological and biochemical analysis, and molecular biological identification, it was confirmed that yeast Y03401 was a Saccharomyces cerevisiae. Subsequently, the optimal fermentation conditions for 3-Met production by this yeast were obtained through single-factor designs, Plackett-Burman test, steepest ascent path design and response surface methodology. When the glucose concentration was 60 g/L, yeast extract concentration was 0.8 g/L, L-methionine concentration was 3.8 g/L, initial pH was 4, incubation time was 63 h, inoculum size was 1.6%, shaking speed was 150 rpm, loading volume was 50 mL/250 mL, and temperature was 26 °C, the content of 3-Met produced by S. cerevisiae Y03401 reached a high level of 3.66 g/L. It was also noteworthy that, in contrast to other study findings, this yeast was able to create substantial amounts of 3-Met even in the absence of L-methionine precursor. Based on the clear genome of S. cerevisiae and its characteristics in 3-Met production, S. cerevisiae Y03401 had broad prospects for application in alcoholic beverages such as Baijiu.

Association of serum creatinine to cystatin C to waist circumference ratios and hypertension: evidence from China health and retirement longitudinal study.

Background: The objective of this study was to explore the association between the ratio of serum creatinine to cystatin C to waist circumference (CCR/WC) and hypertension. Methods: The study utilized data extracted from the China Health and Retirement Longitudinal Study. In the cross-sectional analysis, logistic regression analyses were employed to examine the association between the CCR/WC ratio and hypertension. By utilizing restricted cubic splines, potential non-linear associations between the CCR/WC ratio and hypertension were explored. In the longitudinal analysis, the association between CCR/WC quartiles (Q1-Q4) and the risk of new-onset hypertension was evaluated by Cox proportional-hazards models. Results: In total, 7,253 participants were enrolled. The study unveiled an inverse association with hypertension, demonstrating an odds ratio (OR) of 0.29 (95% confidence interval [CI]: 0.23-0.37, P < 0.001). Among males, an OR of 0.38 (95% CI: 0.25-0.58, P < 0.001) was observed, while among females, an OR of 0.41 (95% CI: 0.28-0.60, P < 0.001) was noted. There was an absence of a nonlinear association between the CCR/WC ratio and hypertension. Cox regression analysis unveiled a reduced risk of hypertension in Q3 (Hazard ratios [HR]: 0.69, 95% CI: 0.58-0.82, P < 0.001) and Q4: (HR: 0.70, 95% CI: 0.59-0.83, P < 0.001) in compared to the Q1 of the CCR/WC ratio, and sex-specific analysis yielded consistent results. Conclusion: This study emphasizes the potential association between an elevated CCR/WC ratio and a reduced risk of hypertension.

Liver fibrosis automatic diagnosis utilizing dense-fusion attention contrastive learning network.

BACKGROUND: Liver fibrosis poses a significant public health challenge given its elevated incidence and associated mortality rates. Diffusion-Weighted Imaging (DWI) serves as a non-invasive diagnostic tool for supporting the identification of liver fibrosis. Deep learning, as a computer-aided diagnostic technology, can assist in recognizing the stage of liver fibrosis by extracting abstract features from DWI images. However, gathering samples is often challenging, posing a common dilemma in previous research. Moreover, previous studies frequently overlooked the cross-comparison information and latent connections among different DWI parameters. Thus, it is becoming a challenge to identify effective DWI parameters and dig potential features from multiple categories in a dataset with limited samples. PURPOSE: A self-defined Multi-view Contrastive Learning Network is developed to automatically classify multi-parameter DWI images and explore synergies between different DWI parameters. METHODS: A Dense-fusion Attention Contrastive Learning Network (DACLN) is designed and used to recognize DWI images. Concretely, a multi-view contrastive learning framework is constructed to train and extract features from raw multi-parameter DWI. Besides, a Dense-fusion module is designed to integrate feature and output predicted labels. RESULTS: We evaluated the performance of the proposed model on a set of real clinical data and analyzed the interpretability by Grad-CAM and annotation analysis, achieving average scores of 0.8825, 0.8702, 0.8933, 0.8727, and 0.8779 for accuracy, precision, recall, specificity and F-1 score. Of note, the experimental results revealed that IVIM-f, CTRW-ß, and MONO-ADC exhibited significant recognition ability and complementarity. CONCLUSION: Our method achieves competitive accuracy in liver fibrosis diagnosis using the limited multi-parameter DWI dataset and finds three types of DWI parameters with high sensitivity for diagnosing liver fibrosis, which suggests potential directions for future research.

Activation pattern of the coronary sinus facilitates the differentiation for ventricular outflow tract arrhythmias.

INTRODUCTION: The accuracy of surface ECG algorithms for predicting the origin of outflow tract ventricular arrhythmias (OT-VAs) might be questioned. Intracardiac electrograms recorded at anatomic landmarks could provide new predictive insights. We aim to evaluate the efficacy of a novel criterion utilizing the activation pattern of the coronary sinus (CS) in localizing OT-VAs, including VAs originating from the right ventricular outflow tract (RVOT), endocardial left ventricular outflow tract (Endo-LVOT), and epicardial left ventricular outflow tract (Epi-LVOT). METHODS: We measured the ventricular activation time of the mitral annulus (MA) from the onset of the earliest QRS complex of VAs to the initial deflection over the isoelectric line at local signals, namely the QRS-MA interval. The activation at 3 and 12 o'clock of the MA was recorded as the QRS-MA3 and QRS-MA12 intervals, respectively. Their predictive values were compared to previous ECG algorithms. RESULTS: A total of 68 patients with OT-VAs were enrolled (51 for development and 17 for validation). From early to late, the ventricular activation sequences at MA12 were as follows: Epi-LVOT, Endo-LVOT, and RVOT. In LBBB morphology OT-VAs, the QRS-MA12 interval was significantly earlier for LVOT origins than RVOT origins. In the combined cohort of development and validation cohort, a cut-off value of ≤10 ms predicted the LVOT origin with a sensitivity of 100% and specificity of 78%. The QRS-MA12 interval ≤ -24 ms additionally predicted epicardial LVOT sites of origin. CONCLUSIONS: The QRS-MA interval could accurately differentiate the OT-VAs localization.

1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts.

Late sodium current (INa) inhibitors are a new subclass of antiarrhythmic agents. To overcome the drawbacks, e.g., low efficacy and inhibition effect on K+ current, of the FDA-approved late INa inhibitor ranolazine, chain amide 6a-6q, 1,4-disubstituted piperazin-2-ones 7a-7s, and their derivatives 8a-8n were successively designed, synthesized, and evaluated in vitro on the NaV1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 µM. Among the new skeleton compounds, 7d showed the highest efficacy (IC50 = 2.7 µM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice (T1/2 of 3.5 h, F = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late INa phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of 7d in the treatments of arrhythmias related to the enhancement of late INa.

A two-photon fluorescent probe for highly selective detection of Cys over GSH and Hcy based on the Michael addition and transcyclization mechanism and its application in bioimaging and protein straining in SDS-PAGE.

BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.

A Spatiotemporal Probabilistic Graphical Model Based on Adaptive Expectation-Maximization Attention for Individual Trajectory Reconstruction Considering Incomplete Observations.

Spatiotemporal information on individual trajectories in urban rail transit is important for operational strategy adjustment, personalized recommendation, and emergency command decision-making. However, due to the lack of journey observations, it is difficult to accurately infer unknown information from trajectories based only on AFC and AVL data. To address the problem, this paper proposes a spatiotemporal probabilistic graphical model based on adaptive expectation maximization attention (STPGM-AEMA) to achieve the reconstruction of individual trajectories. The approach consists of three steps: first, the potential train alternative set and the egress time alternative set of individuals are obtained through data mining and combinatorial enumeration. Then, global and local potential variables are introduced to construct a spatiotemporal probabilistic graphical model, provide the inference process for unknown events, and state information about individual trajectories. Further, considering the effect of missing data, an attention mechanism-enhanced expectation-maximization algorithm is proposed to achieve maximum likelihood estimation of individual trajectories. Finally, typical datasets of origin-destination pairs and actual individual trajectory tracking data are used to validate the effectiveness of the proposed method. The results show that the STPGM-AEMA method is more than 95% accurate in recovering missing information in the observed data, which is at least 15% more accurate than the traditional methods (i.e., PTAM-MLE and MPTAM-EM).

Reconfiguring the Hydrogen Networks of Aqueous Electrolyte to Stabilize Iron Hexacyanoferrate for High-Voltage Decoupled Cell.

Prussian blue analogs (PBAs) as insertion-type cathodes have attracted significant attention in various aqueous batteries to accommodate metal or non-metal ions while suffering from serious dissolution and consequent inferior lifespan. Herein, we reveal that the dissolution of PBAs primarily originates from the locally elevated pH of electrolytes that are caused by proton co-insertion during discharge. To address this issue, a water-locking electrolyte (WLE) has been strategically implemented, which interrupts the generation and Grotthuss diffusion of protons by breaking the well-connected hydrogen bonding network in aqueous electrolytes. As a result, the WLE enables the iron hexacyanoferrate to endure over 1000 cycles at a 1C rate and supports a high-voltage decoupled cell with an average voltage of 1.95 V. These findings provide insights for mitigating dissolution problems in electrode materials, thereby enhancing the viability and performance of aqueous batteries.

Prediction of 24-Hour Urinary Sodium Excretion Using Machine-Learning Algorithms.

BACKGROUND: Accurate quantification of sodium intake based on self-reported dietary assessments has been a persistent challenge. We aimed to apply machine-learning (ML) algorithms to predict 24-hour urinary sodium excretion from self-reported questionnaire information. METHODS AND RESULTS: We analyzed 3454 participants from the NHS (Nurses' Health Study), NHS-II (Nurses' Health Study II), and HPFS (Health Professionals Follow-Up Study), with repeated measures of 24-hour urinary sodium excretion over 1 year. We used an ensemble approach to predict averaged 24-hour urinary sodium excretion using 36 characteristics. The TOHP-I (Trial of Hypertension Prevention I) was used for the external validation. The final ML algorithms were applied to 167 920 nonhypertensive adults with 30-year follow-up to estimate confounder-adjusted hazard ratio (HR) of incident hypertension for predicted sodium. Averaged 24-hour urinary sodium excretion was better predicted and calibrated with ML compared with the food frequency questionnaire (Spearman correlation coefficient, 0.51 [95% CI, 0.49-0.54] with ML; 0.19 [95% CI, 0.16-0.23] with the food frequency questionnaire; 0.46 [95% CI, 0.42-0.50] in the TOHP-I). However, the prediction heavily depended on body size, and the prediction of energy-adjusted 24-hour sodium excretion was modestly better using ML. ML-predicted sodium was modestly more strongly associated than food frequency questionnaire-based sodium in the NHS-II (HR comparing Q5 versus Q1, 1.48 [95% CI, 1.40-1.56] with ML; 1.04 [95% CI, 0.99-1.08] with the food frequency questionnaire), but no material differences were observed in the NHS or HPFS. CONCLUSIONS: The present ML algorithm improved prediction of participants' absolute 24-hour urinary sodium excretion. The present algorithms may be a generalizable approach for predicting absolute sodium intake but do not substantially reduce the bias stemming from measurement error in disease associations.

Adherence to Healthy and Unhealthy Plant-Based Diets and the Risk of Gout.

Importance: Plant-based diets are increasing in popularity due, in part, to their health benefits for selected cardiometabolic diseases as well as favorable environmental impact. Little is known about how such a diet is related to gout risk. Objective: To examine associations between adherence to a plant-based diet (including healthy and unhealthy versions of this diet), as well as its 18 individual food groups, and incident gout. Design, Setting, and Participants: This prospective cohort study used data from population-based cohorts of US men and women enrolled in the Health Professionals Follow-Up Study (1986-2012) and Nurses' Health Study (1984-2010). Participants were men and women free of gout at baseline. Statistical analyses were performed over March 2020 to August 2023. Exposures: An overall plant-based diet index (PDI), as well as healthy (hPDI) and unhealthy (uPDI) versions of this index that emphasize healthy and less healthy plant-based foods, respectively. These diet indices were comprised of 18 food groups, assessed using a validated semiquantitative food frequency questionnaire. Main Outcomes and Measures: Incident cases of gout that were confirmed with a supplementary questionnaire to meet the preliminary American College of Rheumatology survey criteria for gout. Cox proportional hazards regression models were used to evaluate multivariable-adjusted associations of all 3 PDIs with incident gout using quintiles (Q) of adherence. Results: Among a total of 122 679 participants (mean [SD] age, 53.8 [9.8] years among 43 703 men; mean [SD] age, 50.9 [7.2] years among 78 976 women) over 2 704 899 person-years of follow-up, 2709 participants experienced incident gout. The overall PDI was not significantly associated with gout in either cohort (Q5 vs Q1 pooled hazard ratio [HR], 1.02 [95% CI, 0.89-1.17]; P for trend = .63). In the pooled analysis, hPDI was significantly inversely associated with risk of gout (Q5 vs Q1 HR, 0.79 [95% CI, 0.69-0.91]; P for trend = .002), while the uPDI was positively associated with risk of gout (Q5 vs Q1 HR, 1.17 [95% CI, 1.03-1.33]; P for trend = .02), particularly in women (Q5 vs Q1 HR, 1.31 [95% CI, 1.05-1.62]; P for trend = .01). In analysis of individual food groups, higher intakes of certain healthy plant foods, such as whole grains (pooled HR per 1 serving/d, 0.93 [95% CI, 0.89-0.97]) and tea and coffee (pooled HR per 1 serving/d, 0.95 [95% CI, 0.92-0.97]), as well as dairy (pooled HR per 1 serving/d, 0.86 [95% CI, 0.82-0.90]), were independently associated with a lower risk of gout, while selected unhealthy plant foods, such as fruit juice (pooled HR per 1 serving/d, 1.06 [95% CI, 1.00-1.13]) and sugar-sweetened beverages (pooled HR per 1 serving/d, 1.16 [95% CI, 1.07-1.26]) were associated with increased risk of gout. Conclusions and Relevance: The findings of this prospective cohort study of PDIs and gout support current dietary recommendations to increase consumption of healthy plant foods while lowering intake of unhealthy plant foods to mitigate gout risk.

Engineered Bacteriophage-Based In Situ Vaccine Remodels a Tumor Microenvironment and Elicits Potent Antitumor Immunity.

In situ vaccines (ISVs) utilize the localized delivery of chemotherapeutic agents or radiotherapy to stimulate the release of endogenous antigens from tumors, thereby eliciting systemic and persistent immune activation. Recently, a bioinspired ISV strategy has attracted tremendous attention due to its features such as an immune adjuvant effect and genetic plasticity. M13 bacteriophages are natural nanomaterials with intrinsic immunogenicity, genetic flexibility, and cost-effectiveness for large-scale production, demonstrating the potential for application in cancer vaccines. In this study, we propose an ISV based on the engineered M13 bacteriophage targeting CD40 (M13CD40) for dendritic cell (DC)-targeted immune stimulation, named H-GM-M13CD40. We induce immunogenic cell death and release tumor antigens through local delivery of (S)-10-hydroxycamptothecin (HCPT), followed by intratumoral injection of granulocyte-macrophage colony stimulating factor (GM-CSF) and M13CD40 to enhance DC recruitment and activation. We demonstrate that this ISV strategy can result in significant accumulation and activation of DCs at the tumor site, reversing the immunosuppressive tumor microenvironment. In addition, H-GM-M13CD40 can synergize with the PD-1 blockade and induce abscopal effects in cold tumor models. Overall, our study verifies the immunogenicity of the engineered M13CD40 bacteriophage and provides a proof of concept that the engineered M13CD40 phage can function as an adjuvant for ISVs.

Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.

Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca2+ release from the sarcoplasmic reticulum through the ryanodine receptor/Ca2+-release channel RyR1. The RyR1 contains ∼100 Cys thiols of which ∼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood. Although aberrant S-nitrosylation of multiple unidentified sites has been associated with dystrophic diseases, malignant hyperthermia and other myopathic syndromes, S-nitrosylation in physiological situations is reportedly specific to a single (1 of ∼100) Cys in RyR1, Cys3636 in a manner gated by pO2. Using mice expressing a form of RyR1 with a Cys3636→Ala point mutation to prevent S-nitrosylation at this site, we showed that Cys3636 was the principal target of endogenous S-nitrosylation during normal muscle function. The absence of Cys3636 S-nitrosylation suppressed stimulus-evoked Ca2+ release at physiological pO2 (at least in part by altering the regulation of RyR1 by Ca2+/calmodulin), eliminated pO2 coupling, and diminished skeletal myocyte contractility in vitro and measures of muscle strength in vivo. Furthermore, we found that abrogation of Cys3636 S-nitrosylation resulted in a developmental defect reflected in diminished myofiber diameter, altered fiber subtypes, and altered expression of genes implicated in muscle development and atrophy. Thus, our findings establish a physiological role for pO2-coupled S-nitrosylation of RyR1 in skeletal muscle contractility and development and provide foundation for future studies of RyR1 modifications in physiology and disease.

24-h urinary sodium and potassium excretions, plasma metabolomic profiles, and cardiometabolic biomarkers in the United States adults: a cross-sectional study.

BACKGROUND: High-sodium and low-potassium intakes are associated with a higher risk of hypertension and cardiovascular disease, but there are limited data on the circulating metabolomics profiles of 24-h urinary sodium and potassium excretions in free-living individuals. OBJECTIVES: We aimed to characterize the metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study. METHODS: In 1028 healthy older adults from the Women's and Men's Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2 to 4 24-h urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-h urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the doubly labeled water method. We then assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers. RESULTS: Higher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman's rank correlation coefficient ρ = 0.27), C-peptide (ρ = 0.30), and triglyceride (ρ = 0.46), and negatively with adiponectin (ρ = -0.40), and high-density lipoprotein cholesterol (ρ = -0.42). CONCLUSIONS: We discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium low-potassium diet is associated with multiple components of elevated cardiometabolic risk.

A comprehensive review of aptamer screening and application for lateral flow strip: Current status and future perspectives.

The detection of biomarkers is of great significance for medical diagnosis, food safety, environmental monitoring, and agriculture. However, bio-detection technology at present often necessitates complex instruments, expensive reagents, specialized expertise, and prolonged procedures, making it challenging to fulfill the demand for rapid, sensitive, user-friendly, and economical testing. In contrast, lateral flow strip (LFS) technology offers simple, fast, and visually accessible detection modality, allowing real-time analysis of clinical specimens, thus finding widespread utility across various domains. Within the realm of LFS, the application of aptamers as molecular recognition probes presents distinct advantages over antibodies, including cost-effectiveness, smaller size, ease of synthesis, and chemical stability. In recent years, aptamer-based LFS has found extensive application in qualitative, semi-quantitative, and quantitative detection across food safety, environmental surveillance, clinical diagnostics, and other domains. This review provided a concise overview of different aptamer screening methodologies, selection strategies, underlying principles, and procedural, elucidating their respective advantages, limitations, and applications. Additionally, we summarized recent strategies and mechanisms for aptamer-based LFS, such as the sandwich and competitive methods. Furthermore, we classified LFSs constructed based on aptamers, considering the rapid advancements in this area, and discussed their applications in biological and chemical detection. Finally, we delved into the current challenges and future directions in the development of aptamer and aptamer-based LFS. Although this review was not thoroughly, it would serve as a valuable reference for understanding the research progress of aptamer-based LFS and aid in the development of new types of aptasensors.

Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.