A Dynamic Analysis of IRS-PKR Signaling in Liver Cells: A Discrete Modeling Approach

A major challenge in systems biology is to develop a detailed dynamic understanding of the functions and behaviors in a particular cellular system, which depends on the elements and their inter-relationships in a specific network. Computational modeling plays an integral part in the study of network dynamics and uncovering the underlying mechanisms. Here we proposed a systematic approach that incorporates discrete dynamic modeling and experimental data to reconstruct a phenotype-specific network of cell signaling. A dynamic analysis of the insulin signaling system in liver cells provides a proof-of-concept application of the proposed methodology. Our group recently identified that double-stranded RNA-dependent protein kinase (PKR) plays an important role in the insulin signaling network. The dynamic behavior of the insulin signaling network is tuned by a variety of feedback pathways, many of which have the potential to cross talk with PKR. Given the complexity of insulin signaling, it is inefficient to experimentally test all possible interactions in the network to determine which pathways are functioning in our cell system. Our discrete dynamic model provides an in silico model framework that integrates potential interactions and assesses the contributions of the various interactions on the dynamic behavior of the signaling network. Simulations with the model generated testable hypothesis on the response of the network upon perturbation, which were experimentally evaluated to identify the pathways that function in our particular liver cell system. The modeling in combination with the experimental results enhanced our understanding of the insulin signaling dynamics and aided in generating a context-specific signaling network

Does warfarin or rivaroxaban at low anticoagulation intensity provide a survival benefit to Asian patients with atrial fibrillation?

Background: Low-dose rivaroxaban and low-intensity warfarin are widely used in Asia for patients with atrial fibrillation (AF). However, in Asians, it is unclear whether low-dose rivaroxaban and low-intensity warfarin can improve the prognosis of AF. In this study, we investigate the survival benefits of low-dose rivaroxaban and low-intensity warfarin in Asian patients with AF in clinical practice. Methods: This cohort study used medical records in a single tertiary hospital in China, between 2019 and 2020, to identify patients with AF who used rivaroxaban or warfarin, or had no anticoagulant therapy. Follow-ups were performed through telephone contact or medical record review. Cox proportional hazards models were used to compare the risk of mortality of patients in the anticoagulant-untreated group vs. warfarin-treated groups and rivaroxaban-treated groups. Results: A total of 1727 AF patients, discharged between 2019 and 2020, were enrolled in this cohort, of which 873 patients did not use any anticoagulant, 457 patients received warfarin and 397 patients used rivaroxaban. Multivariable analysis showed that, of all the warfarin groups, patients with an international normalized ratio (INR) below 2, good INR control, or poor INR control had a significantly lower risk of mortality compared with that of patients without anticoagulants (HR 0.309, p = 0.0001; HR 0.387, p = 0.0238; HR 0.363, p \u3c 0.0001). Multivariable Cox proportional hazard analyses also demonstrated that, compared with the no anticoagulant group, all rivaroxaban dosage groups (≤ 10 mg, HR 0.456, p = 0.0129; 15 mg, HR 0.246, p = 0.0003; 20 mg, HR 0.264, p = 0.0237) were significantly associated with a lower risk of mortality. Conclusion: Despite effects being smaller than observed with recommended optimal anticoagulation, the use of warfarin with an INR below 2, poor INR control and the use of low-dose rivaroxaban may still provide survival benefits, suggesting viable alternatives that enable physicians to better resolve decisional conflicts concerning the risks and benefits of anticoagulant therapies, as well as for patients in need of but unable to receive standard anticoagulant therapy due to bleeding risk or other factors, such as financial burden, concerns of adverse outcomes, as well as low treatment compliance and persistence

Dysnatremia is associated with increased risk of all-cause mortality within 365 days post-discharge in patients with atrial fibrillation without heart failure: A prospective cohort study

Aim: The aim of this study is to evaluate the association between serum sodium concentrations at hospital admission and all-cause mortality within 365 days post-discharge in patients with atrial fibrillation (AF) without heart failure (HF). Methods: The prospective cohort study enrolled 1,446 patients with AF without HF between November 2018 and October 2020. A follow-up was performed 30, 90, 180, and 365 days after enrollment through outpatient visits or telephone interviews. All-cause mortality was estimated in three groups according to serum sodium concentrations: hyponatremia ( \u3c 135 mmol/L), normonatremia (135 – 145 mmol/L), and hypernatremia ( \u3e 145 mmol/L). We estimated the risk of all-cause mortalities using univariable and multivariable Cox proportional hazards models with normonatremia as the reference. Results: The all-cause mortalities of hyponatremia, normonatremia, and hypernatremia were 20.6, 9.4, and 33.3 % within 365 days post-discharge, respectively. In the univariable analysis, hyponatremia (HR: 2.19, CI 1.5 – 3.2) and hypernatremia (HR: 4.03, CI 2.32 – 7.02) increased the risk of all-cause mortality. The HRs for hyponatremia and hypernatremia were 1.55 (CI 1.05 – 2.28) and 2.55 (CI 1.45 – 4.46) after adjustment for age, diabetes mellitus, loop diuretics, antisterone, antiplatelet drugs, and anticoagulants in the patients with AF without HF. The association between serum sodium concentrations and the HRs of all-cause mortality was U-shaped. Conclusion: Dysnatremia at hospital admission was an independent factor for all-cause mortality in patients with AF without HF within 365 days post-discharge

Predicting 1-, 3-, 5-, and 8-year all-cause mortality in a community-dwelling older adult cohort: relevance for predictive, preventive, and personalized medicine

Background: Population aging is a global public health issue involving increased prevalence of age-related diseases, and concomitant burden on medical resources and the economy. Ninety-two diseases have been identified as age-related, accounting for 51.3% of the global adult disease burden. The economic cost per capita for older people over 60 years is 10 times that of the younger population. From the aspects of predictive, preventive, and personalized medicine (PPPM), developing a risk-prediction model can help identify individuals at high risk for all-cause mortality and provide an opportunity for targeted prevention through personalized intervention at an early stage. However, there is still a lack of predictive models to help community-dwelling older adults do well in healthcare. Objectives: This study aims to develop an accurate 1-, 3-, 5-, and 8-year all-cause mortality risk-prediction model by using clinical multidimensional variables, and investigate risk factors for 1-, 3-, 5-, and 8-year all-cause mortality in community-dwelling older adults to guide primary prevention. Methods: This is a two-center cohort study. Inclusion criteria: (1) community-dwelling adult, (2) resided in the districts of Chaonan or Haojiang for more than 6 months in the past 12 months, and (3) completed a health examination. Exclusion criteria: (1) age less than 60 years, (2) more than 30 incomplete variables, (3) no signed informed consent. The primary outcome of the study was all-cause mortality obtained from face-to-face interviews, telephone interviews, and the medical death database from 2012 to 2021. Finally, we enrolled 5085 community-dwelling adults, 60 years and older, who underwent routine health screening in the Chaonan and Haojiang districts, southern China, from 2012 to 2021. Of them, 3091 participants from Chaonan were recruited as the primary training and internal validation study cohort, while 1994 participants from Haojiang were recruited as the external validation cohort. A total of 95 clinical multidimensional variables, including demographics, lifestyle behaviors, symptoms, medical history, family history, physical examination, laboratory tests, and electrocardiogram (ECG) data were collected to identify candidate risk factors and characteristics. Risk factors were identified using least absolute shrinkage and selection operator (LASSO) models and multivariable Cox proportional hazards regression analysis. A nomogram predictive model for 1-, 3-, 5- and 8-year all-cause mortality was constructed. The accuracy and calibration of the nomogram prediction model were assessed using the concordance index (C-index), integrated Brier score (IBS), receiver operating characteristic (ROC), and calibration curves. The clinical validity of the model was assessed using decision curve analysis (DCA). Results: Nine independent risk factors for 1-, 3-, 5-, and 8-year all-cause mortality were identified, including increased age, male, alcohol status, higher daily liquor consumption, history of cancer, elevated fasting glucose, lower hemoglobin, higher heart rate, and the occurrence of heart block. The acquisition of risk factor criteria is low cost, easily obtained, convenient for clinical application, and provides new insights and targets for the development of personalized prevention and interventions for high-risk individuals. The areas under the curve (AUC) of the nomogram model were 0.767, 0.776, and 0.806, and the C-indexes were 0.765, 0.775, and 0.797, in the training, internal validation, and external validation sets, respectively. The IBS was less than 0.25, which indicates good calibration. Calibration and decision curves showed that the predicted probabilities were in good agreement with the actual probabilities and had good clinical predictive value for PPPM. Conclusion: The personalized risk prediction model can identify individuals at high risk of all-cause mortality, help offer primary care to prevent all-cause mortality, and provide personalized medical treatment for these high-risk individuals from the PPPM perspective. Strict control of daily liquor consumption, lowering fasting glucose, raising hemoglobin, controlling heart rate, and treatment of heart block could be beneficial for improving survival in elderly populations

Natural polysaccharide-based hydrogel bioprinting for articular cartilage repair

Tissue engineering represents a promising approach for impaired articular cartilage tissue regeneration. 3D printed hydrogels have become an emerging tissue engineering strategy because they closely mimic the physical and biochemical characteristics of the extracellular matrix. The formulation of hydrogel ink holds significant importance in attaining a precisely defined scaffold, which could exhibit excellent shape fidelity post-printing. Natural polysaccharide-based hydrogels are a highly promising class of scaffold biomaterials for articular cartilage regeneration in the field of material science and tissue engineering. These hydrogels are particularly advantageous due to their exceptional water absorption capacity, biodegradability, adjustable porosity, and biocompatibility, which closely resemble those of the natural extracellular matrix. This review aims to provide a comprehensive overview of the key characteristics, functions, and research progress in 3D printing technology for natural polysaccharide-based hydrogels. Specifically, this review categorizes the commonly used natural polysaccharide-based hydrogel materials in cartilage tissue engineering, and summarizes the classic literature in this area. In the end, we provide a comprehensive analysis of the challenges and potential applications of natural polysaccharide-based hydrogels in cartilage tissue engineering

Diagnostic accuracy of autoverification and guidance system for COVID-19 RT-PCR results

Background: To date, most countries worldwide have declared that the pandemic of COVID-19 is over, while the WHO has not officially ended the COVID-19 pandemic, and China still insists on the personalized dynamic COVID-free policy. Large-scale nucleic acid testing in Chinese communities and the manual interpretation for SARS-CoV-2 nucleic acid detection results pose a huge challenge for labour, quality and turnaround time (TAT) requirements. To solve this specific issue while increase the efficiency and accuracy of interpretation, we created an autoverification and guidance system (AGS) that can automatically interpret and report the COVID-19 reverse transcriptase-polymerase chain reaction (RT-PCR) results relaying on computer-based autoverification procedure and then validated its performance in real-world environments. This would be conductive to transmission risk prediction, COVID-19 prevention and control and timely medical treatment for positive patients in the context of the predictive, preventive and personalized medicine (PPPM). Methods: A diagnostic accuracy test was conducted with 380,693 participants from two COVID-19 test sites in China, the Hong Kong Hybribio Medical Laboratory (n = 266,035) and the mobile medical shelter at a Shanghai airport (n = 114,658). These participants underwent SARS-CoV-2 RT-PCR from March 28 to April 10, 2022. All RT-PCR results were interpreted by laboratorians and by using AGS simultaneously. Considering the manual interpretation as gold standard, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were applied to evaluate the diagnostic value of the AGS on the interpretation of RT-PCR results. Results: Among the 266,035 samples in Hong Kong, there were 16,356 (6.15%) positive, 231,073 (86.86%) negative, 18,606 (6.99%) indefinite, 231,073 (86.86%, negative) no retest required and 34,962 (13.14%, positive and indefinite) retest required; the 114,658 samples in Shanghai consisted of 76 (0.07%) positive, 109,956 (95.90%) negative, 4626 (4.03%) indefinite, 109,956 (95.90%, negative) no retest required and 4702 (4.10%, positive and indefinite) retest required. Compared to the fashioned manual interpretation, the AGS is a procedure of high accuracy [99.96% (95%CI, 99.95–99.97%) in Hong Kong and 100% (95%CI, 100–100%) in Shanghai] with perfect sensitivity [99.98% (95%CI, 99.97–99.98%) in Hong Kong and 100% (95%CI, 100–100%) in Shanghai], specificity [99.87% (95%CI, 99.82–99.90%) in Hong Kong and 100% (95%CI, 99.92–100%) in Shanghai], PPV [99.98% (95%CI, 99.97–99.99%) in Hong Kong and 100% (95%CI, 99.99–100%) in Shanghai] and NPV [99.85% (95%CI, 99.80–99.88%) in Hong Kong and 100% (95%CI, 99.90–100%) in Shanghai]. The need for manual interpretation of total samples was dramatically reduced from 100% to 13.1% and the interpretation time fell from 53 h to 26 min in Hong Kong; while the manual interpretation of total samples was decreased from 100% to 4.1% and the interpretation time dropped from 20 h to 16 min at Shanghai. Conclusions: The AGS is a procedure of high accuracy and significantly relieves both labour and time from the challenge of large-scale screening of SARS-CoV-2 using RT-PCR. It should be recommended as a powerful screening, diagnostic and predictive system for SARS-CoV-2 to contribute timely the ending of the COVID-19 pandemic following the concept of PPPM

Organelle-specific anchored delivery system stretching a reversal of tumor hypoxia microenvironment to a combinational chemo-photothermal therapy

Direct delivery to an organelle-specific point can boost the efficacy of therapy procedures to new heights. Among other subcellular organelles, mitochondria generate ATP as intracellular powerhouse, and are associated with multiple aspects of tumorigenesis and tumor development. Here, a mitochondrial anchored biomimetic nanoplatform (CZACN) is designed and its reversal of tumor hypoxia microenvironment underlying the mitochondria-located chemo-photothermal therapy is studied. After shuttling into cancer cells, therapeutic payloads including cisplatin (CDDP) and Au nanozymes are controllably released in the ATP-overexpressed mitochondria. CDDP generates O2â ¢â , forms H2O2 for a chemical fuel in the next reaction, and damages mitochondrial DNA. Meanwhile, the catalase-like Au nanozymes catalyze the produced hydrogen peroxide for oxygen supply to relieve hypoxic tumor microenvironment, offering cytotoxic singlet oxygen against cancer cells under NIR treatment. As a result of cancer-cell self-recognition, mitochondria-targeted therapy, and photothermal conversion ability, the fabricated CZACNs obtained 89.2 ± 3.70% of tumor growth inhibition under NIR irradiation and constrained the dose-limiting toxicity of CDDP, as well. These findings reinforce the synergistic effect of organelle-specific navigation and in situ oxygen self-sufficiency for combinational chemo-photothermal therapy.X.C., X.Y., and L.Z. contributed equally to this work. This work has been supported by the National Natural Science Foundation of China (22003038, 81922037, and 11575107), the Shanghai University-Universal Medical Imaging Diagnostic Research Foundation (19H00100), Shanghai Biomedical Science and Technology Support Project (19441903600), the Program for Changjiang Scholars and Innovative Research Team in University (IRT13078). The authors would like to thank the workers from Shiyanjia Lab (www.shiyanjia.com) for the ICP-OES analysis

Psychological symptoms in Chinese nurses may be associated with predisposition to chronic disease: A cross-sectional study of suboptimal health status

© 2020, The Author(s). Background: Suboptimal health status (SHS) is a reversible state between ideal health and illness and it can be effectively reversed by risk prediction, disease prevention, and personalized medicine under the global background of predictive, preventive, and personalized medicine (PPPM) concepts. More and more Chinese nurses have been troubled by psychological symptoms (PS). The correlation between PS and SHS is unclear in nurses. The purpose of current study is to investigate the prevalence of SHS and PS in Chinese nurses and the relationship between SHS and PS along with predisposing factors as well as to discuss the feasibility of improving health status and preventing diseases according to PPPM concepts in Chinese nurses. Methods: A cross-sectional study was conducted with the cluster sampling method among 9793 registered nurses in Foshan city, China. SHS was evaluated with the Suboptimal Health Status Questionnaire-25 (SHSQ-25). Meanwhile, the PS of depression and anxiety were evaluated with Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) self-assessment questionnaires. The relationship between PS and SHS in Chinese nurses was subsequently analyzed. Results: Among the 9793 participants, 6107 nurses were included in the final analysis. The prevalence of SHS in the participants was 74.21% (4532/6107) while the symptoms of depression and anxiety were 47.62% (2908/6107) and 24.59% (1502/6107) respectively. The prevalence of SHS in the participants with depression and anxiety was significantly higher than those without the symptoms of depression (83.3% vs 16.7%, P \u3c 0.001) and anxiety (94.2% vs 5.8%, P \u3c 0.0001). The ratio of exercise habit was significantly lower than that of non-exercise habit (68.8% vs 78.4%, P \u3c 0.001) in SHS group. Conclusions: There is a high prevalence of SHS and PS in Chinese nurses. PS in Chinese nurses are associated with SHS. Physical exercise is a protective factor for SHS and PS so that the exercise should be strongly recommended as a valuable preventive measure well in the agreement with PPPM philosophy. Along with SDS and SAS, SHSQ-25 should also be highly recommended and applied as a novel predictive/preventive tool for the health measures from the perspectives of PPPM in view of susceptible population and individual screening, the predisposition to chronic disease preventing, personalization of intervention, and the ideal health state restoring

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk