The Association Between Late Gadolinium Enhancement by Cardiac Magnetic Resonance and Ventricular Arrhythmia in Patients With Mitral Valve Prolapse: A Systematic Review and Meta-Analysis.

INTRODUCTION: Malignant ventricular arrhythmia (VA) and sudden cardiac death (SCD) have been reported in patients with mitral valve prolapse (MVP); however, effective risk stratification methods are still lacking. Myocardial fibrosis is thought to play an important role in the development of VA; however, observational studies have produced contradictory findings regarding the relationship between VA and late gadolinium enhancement (LGE) in MVP patients. The aim of this meta-analysis and systematic review of observational studies was to investigate the association between left ventricular LGE and VA in patients with MVP. METHODS: We searched the PubMed, Embase, and Web of Science databases from 1993 to 2023 to identify case-control, cross-sectional, and cohort studies that compared the incidence of VA in patients with MVP who had left ventricular LGE and those without left ventricular LGE. RESULTS: A total of 1464 subjects with MVP from 12 observational studies met the eligibility criteria. Among them, VA episodes were reported in 221 individuals (15.1%). Meta-analysis demonstrated that the presence of left ventricular LGE was significantly associated with an increased risk of VA (pooled risk ratio 2.96, 95% CI: 2.26-3.88, p for heterogeneity = 0.07, I2 = 40%). However, a meta-regression analysis of the prevalence of mitral regurgitation (MR) showed that the severity of MR did not significantly affect the association between the occurrence of LGE and VA (p = 0.079). CONCLUSION: The detection of LGE could be helpful for stratifying the risk of VA in patients with MVP.

Metabolic dysfunction-associated liver disease and diabetes: Matrix remodeling, fibrosis, and therapeutic implications.

Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.

Symptom-BERT: Enhancing Cancer Symptom Detection in EHR Clinical Notes.

CONTEXT: Extracting cancer symptom documentation allows clinicians to develop highly individualized symptom prediction algorithms to deliver symptom management care. Leveraging advanced language models to detect symptom data in clinical narratives can significantly enhance this process. OBJECTIVE: This study uses a pretrained large language model to detect and extract cancer symptoms in clinical notes. METHODS: We developed a pretrained language model to identify cancer symptoms in clinical notes based on a clinical corpus from the Enterprise Data Warehouse for Research at a healthcare system in the Midwestern United States. This study was conducted in 4 phases:1 pretraining a Bio-Clinical BERT model on one million unlabeled clinical documents,2 fine-tuning Symptom-BERT for detecting 13 cancer symptom groups within 1112 annotated clinical notes,3 generating 180 synthetic clinical notes using ChatGPT-4 for external validation, and4 comparing the internal and external performance of Symptom-BERT against a non-pretrained version and six other BERT implementations. RESULTS: The Symptom-BERT model effectively detected cancer symptoms in clinical notes. It achieved results with a micro-averaged F1-score of 0.933, an AUC of 0.929 internally, and 0.831 and 0.834 externally. Our analysis shows that physical symptoms, like Pruritus, are typically identified with higher performance than psychological symptoms, such as anxiety. CONCLUSION: This study underscores the transformative potential of specialized pretraining on domain-specific data in boosting the performance of language models for medical applications. The Symptom-BERT model's exceptional efficacy in detecting cancer symptoms heralds a groundbreaking stride in patient-centered AI technologies, offering a promising path to elevate symptom management and cultivate superior patient self-care outcomes.

Associations of total homocysteine and kidney function with all-cause and cause-specific mortality in hypertensive patients: a mediation and joint analysis.

Plasma total homocysteine (tHcy) and kidney function are both associated with mortality risk, but the degree to which kidney function modifies the impact of tHcy on mortality remains unknown. This prospective cohort study included a total of 14,225 hypertensive adults. Cox proportional hazard regression was used to analyze the separate and combined association of tHcy and estimated glomerular filtration rate (eGFR) with all-cause and cause-specific mortality. Mediation analysis was conducted to explore the mediating effect of eGFR. During a median follow-up of 4.0 years, 805 deaths were identified, including 397 deaths from cardiovascular disease (CVD). There were significant, positive relationships of tHcy with all-cause mortality (per 5 µmol/L; HR: 1.09; 95% CI: 1.07, 1.11), CVD mortality (HR: 1.11; 95% CI: 1.08, 1.13), and non-CVD mortality (HR: 1.07; 95% CI: 1.04, 1.10). The proportions of eGFR mediating these relationships were 39.1%, 35.7%, and 49.7%, respectively. There were additive interactions between tHcy and eGFR. Compared with those with low tHcy (<15 µmol/L) and high eGFR (≥90 mL·min-1·1.73 m-2), participants with high tHcy (≥20 µmol/L) and low eGFR (<60 mL·min-1·1.73 m-2) had the highest risk of all-cause mortality (HR: 4.89; 95% CI: 3.81, 6.28), CVD mortality (HR: 5.80; 95% CI: 4.01, 8.40), and non-CVD mortality (HR: 4.25; 95% CI: 3.02, 5.97). In conclusion, among Chinese hypertensive adults, high tHcy and impaired kidney function were independently and jointly associated with higher risks of all-cause and cause-specific mortality. Importantly, kidney function explained most (nearly 40%) of the increased risk of mortality conferred by high tHcy.

Machine Learning Approaches to Predict Symptoms in People With Cancer: Systematic Review.

BACKGROUND: People with cancer frequently experience severe and distressing symptoms associated with cancer and its treatments. Predicting symptoms in patients with cancer continues to be a significant challenge for both clinicians and researchers. The rapid evolution of machine learning (ML) highlights the need for a current systematic review to improve cancer symptom prediction. OBJECTIVE: This systematic review aims to synthesize the literature that has used ML algorithms to predict the development of cancer symptoms and to identify the predictors of these symptoms. This is essential for integrating new developments and identifying gaps in existing literature. METHODS: We conducted this systematic review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We conducted a systematic search of CINAHL, Embase, and PubMed for English records published from 1984 to August 11, 2023, using the following search terms: cancer, neoplasm, specific symptoms, neural networks, machine learning, specific algorithm names, and deep learning. All records that met the eligibility criteria were individually reviewed by 2 coauthors, and key findings were extracted and synthesized. We focused on studies using ML algorithms to predict cancer symptoms, excluding nonhuman research, technical reports, reviews, book chapters, conference proceedings, and inaccessible full texts. RESULTS: A total of 42 studies were included, the majority of which were published after 2017. Most studies were conducted in North America (18/42, 43%) and Asia (16/42, 38%). The sample sizes in most studies (27/42, 64%) typically ranged from 100 to 1000 participants. The most prevalent category of algorithms was supervised ML, accounting for 39 (93%) of the 42 studies. Each of the methods-deep learning, ensemble classifiers, and unsupervised ML-constituted 3 (3%) of the 42 studies. The ML algorithms with the best performance were logistic regression (9/42, 17%), random forest (7/42, 13%), artificial neural networks (5/42, 9%), and decision trees (5/42, 9%). The most commonly included primary cancer sites were the head and neck (9/42, 22%) and breast (8/42, 19%), with 17 (41%) of the 42 studies not specifying the site. The most frequently studied symptoms were xerostomia (9/42, 14%), depression (8/42, 13%), pain (8/42, 13%), and fatigue (6/42, 10%). The significant predictors were age, gender, treatment type, treatment number, cancer site, cancer stage, chemotherapy, radiotherapy, chronic diseases, comorbidities, physical factors, and psychological factors. CONCLUSIONS: This review outlines the algorithms used for predicting symptoms in individuals with cancer. Given the diversity of symptoms people with cancer experience, analytic approaches that can handle complex and nonlinear relationships are critical. This knowledge can pave the way for crafting algorithms tailored to a specific symptom. In addition, to improve prediction precision, future research should compare cutting-edge ML strategies such as deep learning and ensemble methods with traditional statistical models.

Stress hyperglycemia is associated with poor outcome in critically ill patients with pulmonary hypertension.

Background and objective: Stress hyperglycemia is common in critically ill patients and is associated with poor prognosis. Whether this association exists in pulmonary hypertension (PH) patients is unknown. The present cohort study investigated the association of stress hyperglycemia with 90-day all-cause mortality in intensive care unit (ICU) patients with PH. Methods: Data of the study population were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. A new index, the ratio of admission glucose to HbA1c (GAR), was used to evaluate stress hyperglycemia. The study population was divided into groups according to GAR quartiles (Q1-Q4). The outcome of interest was all-cause mortality within 90 days, which was considered a short-term prognosis. Result: A total of 53,569 patients were screened. Ultimately, 414 PH patients were enrolled; 44.2% were male, and 23.2% were admitted to the cardiac ICU. As the GAR increased from Q2 to Q4, the groups had lower creatinine levels, longer ICU stays, and a higher proportion of renal disease. After adjusting for confounding factors such as demographics, vital signs, and comorbidities, an elevated GAR was associated with an increased risk of 90-day mortality. Conclusion: Stress hyperglycemia assessed by the GAR was associated with increased 90-day mortality in ICU patients with PH.

Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis.

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Glycemic variability and in-hospital death of critically ill patients and the role of ventricular arrhythmias.

BACKGROUND: Abnormal glycemic variability is common in the intensive care unit (ICU) and is associated with increased in-hospital mortality and major adverse cardiovascular events, but little is known about whether adverse outcomes are partly mediated by ventricular arrhythmias (VA). We aimed to explore the association between glycemic variability and VA in the ICU and whether VA related to glycemic variability mediate the increased risk of in-hospital death. METHODS: We extracted all measurements of blood glucose during the ICU stay from The Medical Information Mart for Intensive Care IV (MIMIC-IV) database version 2.0. Glycemic variability was expressed by the coefficient of variation (CV), which was calculated by the ratio of standard deviation (SD) and average blood glucose values. The outcomes included the incidence of VA and in-hospital death. The KHB (Karlson, KB & Holm, A) is a method to analyze the mediation effect for nonlinear models, which was used to decompose the total effect of glycemic variability on in-hospital death into a direct and VA-mediated indirect effect. RESULTS: Finally, 17,756 ICU patients with a median age of 64 years were enrolled; 47.2% of them were male, 64.0% were white, and 17.8% were admitted to the cardiac ICU. The total incidence of VA and in-hospital death were 10.6% and 12.8%, respectively. In the adjusted logistic model, each unit increase in log-transformed CV was associated with a 21% increased risk of VA (OR 1.21, 95% CI: 1.11-1.31) and a 30% increased risk (OR 1.30, 95% CI: 1.20-1.41) of in-hospital death. A total of 3.85% of the effect of glycemic variability on in-hospital death was related to the increased risk of VA. CONCLUSION: High glycemic variability was an independent risk factor for in-hospital death in ICU patients, and the effect was caused in part by an increased risk of VA.

A comparison of the effects of NOAC and VKA therapy on the incidence of dementia in patients with atrial fibrillation: A systematic review and meta-analysis.

Atrial fibrillation (AF) patients are more susceptible to dementia, but the results about the effect of oral anticoagulants (OACs) on the risk of dementia are not consistent. We hypothesize that OAC is associated with a reduced risk of dementia with AF and that nonvitamin K antagonist oral anticoagulants (NOAC) are superior to vitamin K antagonists (VKA). Four databases were systematically searched until July 1, 2022. Two reviewers independently selected literature, evaluated quality, and extracted data. Data were examined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Fourteen research studies involving 910 patients were enrolled. The findings indicated that OACs were associated with a decreased risk of dementia (pooled HR: 0.68, 95% CI: 0.55-0.82, I2 = 87.7%), and NOACs had a stronger effect than VKAs (pooled HR: 0.87, 95% CI: 0.79-0.95, I2 = 72%), especially in participants with a CHA2DS2VASc score ≥ 2 (pooled HR: 0.85, 95% CI: 0.72-0.99). Subgroup analysis demonstrated no statistical significance among patients aged <65 years old (pooled HR: 0.83, 95% CI: 0.64-1.07), patients in "based on treatment" studies (pooled HR: 0.89, 95% CI: 0.75-1.06), or people with no stroke background (pooled HR: 0.90, 95% CI: 0.71-1.15). This analysis revealed that OACs were related to the reduction of dementia incidence in AF individuals, and NOACs were better than VKAs, remarkably in people with a CHA2DS2VASc score ≥ 2. The results should be confirmed by further prospective studies, particularly in patients in "based on treatment" studies aged <65 years old with a CHA2DS2VASc score < 2 or without a stroke background.

Effects of walnut/Rosa roxburghii compound planting on growth, fruit yield, quality of Rosa roxburghii and soil properties.

Walnut and Rosa roxburghii are important arbor and shrub fruit trees cultivated in the southwest mountainous area of China. Furthermore, those two species are compound cultivated in this area. In this study, we investigated the growth, yield, fruit quality, photosynthesis, and soil fertility of R. roxburghii in a 7-year typical 'Qianhe 7'/ 'Guinong 5' compound planting pattern in Guizhou. The results showed that compared with the monoculture, photosynthetic pigment content and photosynthetic rate of R. roxburghii leaves were significantly lower in the compound plantation. The growth and yield of R. roxburghii decreased significantly, with a 77.7% reduction of yield. Fruit quality of R. roxburghii was improved. The content of ascorbic acid (Vc), total phenol, carbohydrate, K, Ca, Mg, Fe, Mn, Zn, and other substances increased significantly. Fruit Vc and Mn content increased by 34.1% and 64.1%, respectively. The contents of total N, available N and K in the soil increased by 45.8%, 34.8% and 67.8%, respectively. The abundance of soil microorganisms and functional bacteria increased significantly, with the increase of bacteria and fungi being more than 36.0%. The increase of potassium bacteria and nitrogen fixing bacteria was 71.3% and 124.8%, respectively. However, the contents of organic matter, carbon-nitrogen ratio, total P, total K, available mineral nutrient (P, Ca, Mg, Fe, Mn, Cu, Zn) contents decreased. While the activities of soil urease and catalase were increased, the activities of other soil enzymes (sucrase, cellulase, protease, phosphatase) were significantly reduced. In summary, with continuous growth of walnuts in the walnut/R. roxburghii compound plantation, there was obvious shade and soil fertility competition for R. roxburghii, which affected its yield, but had a improvement effect on fruit quality.

Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis.

BACKGROUND: Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients. METHODS: We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used. RESULTS: Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46-1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17-2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34-2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92-2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80-1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results. CONCLUSION: ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation.

Group 2 innate lymphoid cells (ILC2s) are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13, which mediate the type 2 immune response. However, specific drug targets on lung ILC2s have rarely been reported. Previous studies have shown that type 2 cytokines, such as IL-5 and IL-13, are related to depression. Here, we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression. Interestingly, serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation. Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs. Furthermore, an HTR2A selective agonist (DOI) impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro. Mice with ILC2-specific depletion of HTR2A (Il5cre/+·Htr2aflox/flox mice) abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation. In conclusion, serotonin and DOI could restrict the type 2 lung immune response, indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ ILC2s.

The Association of Proton Pump Inhibitors and QT Interval Prolongation in Critically Ill Patients.

INTRODUCTION: Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. METHODS: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. RESULTS: This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. CONCLUSION: In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.

Mental toll on working women during the COVID-19 pandemic: An exploratory study using Reddit data.

COVID-19 has led to an unprecedented surge in unemployment associated with increased anxiety, stress, and loneliness impacting the well-being of various groups of people (based on gender and age). Given the increased unemployment rate, this study intends to understand if the different dimensions of well-being change across age and gender. By quantifying sentiment, stress, and loneliness with natural language processing tools and one-way, between-group multivariate analysis of variance (MANOVA) using Reddit data, we assessed the differences in well-being characteristics for age groups and gender. We see a noticeable increase in the number of mental health-related subreddits for younger women since March 2020 and the trigger words used by them indicate poor mental health caused by relationship and career challenges posed by the pandemic. The MANOVA results show that women under 30 have significantly (p = 0.05) higher negative sentiment, stress, and loneliness levels than other age and gender groups. The results suggest that younger women express their vulnerability on social media more strongly than older women or men. The huge disruption of job routines caused by COVID-19 alongside inadequate relief and benefit programs has wrecked the economy and forced millions of women and families to the edge of bankruptcy. Women had to choose between being home managers and financial providers due to the countrywide shutdown of schools and day-cares. These findings open opportunities to reconsider how policy supports women's responsibilities.

Shc Is Implicated in Calreticulin-Mediated Sterile Inflammation in Alcoholic Hepatitis.

BACKGROUND & AIMS: Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells. METHODS: Liver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice. RESULTS: Shc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1ß, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury. CONCLUSIONS: Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.

Non-alcoholic Fatty Liver Disease and Liver Fibrosis during Aging.

Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease-related mortality. The prevalence of NAFLD/NASH is expected to increase given the epidemics of obesity and type 2 diabetes mellitus. Older patients are disproportionally affected by NASH and related complications such as progressive fibrosis, cirrhosis and hepatocellular carcinoma; however, they are often ineligible for liver transplantation due to their frailty and comorbidities, and effective medical treatments are still lacking. In this review we focused on pathways that are key to the aging process in the liver and perpetuate NAFLD/NASH, leading to fibrosis. In addition, we highlighted recent findings and cross-talks of normal and/or senescent liver cells, dysregulated nutrient sensing, proteostasis and mitochondrial dysfunction in the framework of changing metabolic milieu. Better understanding these pathways during preclinical and clinical studies will be essential to design novel and specific therapeutic strategies to treat NASH in the elderly.

Regulation effects of carbonized apple branches on absorption, distribution, and utilization of 15N single-labeled ammonium nitrate (15NH4NO3 or NH415NO3) in Malus hupehensis.

To improve the utilization of nitrogen fertilizer and orchard waste, the apple branches were separated and pyrolyzed into carbonized wood and carbonized bark, and then applied to root-zone soil of potted Malus hupehensis. The physiological characteristics of leaves and roots were detected, and the absorption, utilization, and distribution of 15NH4NO3 and NH415NO3 in plants were analyzed using the 15N isotope tracer technique. The results indicated that the net photosynthetic rate and water use efficiency of leaves, the root growth, and the activity of nitrate reductase and glutamine synthetase were greatest increased by 1.0% (w:w) carbonized bark and carbonized wood, and the effect of carbonized bark was more effective. The carbonized bark more effectively increased nitrogen derived from fertilizer (Ndff) value in all organs, the distribution of 15N in roots, and utilization of the 15NH4NO3 and NH415NO3 of Malus hupehensis compared with carbonized wood at the same application ratio, and 1.0% ratio performed better than other ratios in these terms. The Malus hupehensis treated with carbonized bark had the highest utilization ratio of 15NH4NO3 (10.54%) when the application ratio was 1.0%, and the corresponding parameter of NH415NO3 was 12.98%. The soil immobilization capacity of 15N was improved, and carbonized bark resulted in the greatest decrease in the loss ratios of 15NH4NO3 and NH415NO3 under 1.0% ratio, which decreased by 27.33% and 30.08%, respectively. For reducing nitrogen loss and improving nitrogen utilization, carbonized bark was more effective than carbonized wood, mainly because bark contained more cellulose and less lignin than wood.

3D Imaging of the Liver Extracellular Matrix in a Mouse Model of Non-Alcoholic Steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease in the United States, affecting more than 70 million Americans. NASH can progress to fibrosis and eventually to cirrhosis, a significant risk factor for hepatocellular carcinoma. The extracellular matrix (ECM) provides structural support and maintains liver homeostasis via matricellular signals. Liver fibrosis results from an imbalance in the dynamic ECM remodeling process and is characterized by excessive accumulation of structural elements and associated changes in glycosaminoglycans. The typical fibrosis pattern of NASH is called "chicken wire," which usually consists of zone 3 perisinusoidal/pericellular fibrosis, based on features observed by Masson's trichrome stain and Picrosirius Red stains. However, these traditional thin two-dimensional (2D) tissue slide-based imaging techniques cannot demonstrate the detailed three-dimensional (3D) ECM structural changes, limiting the understanding of the dynamic ECM remodeling in liver fibrosis. The current work optimized a fast and efficient protocol to image the native ECM structure in the liver via decellularization to address the above challenges. Mice were fed either with chow or fast-food diet for 14 weeks. Decellularization was performed after in situ portal vein perfusion, and the two-photon microscopy techniques were applied to image and analyze changes in the native ECM. The 3D images of the normal and NASH livers were reconstituted and analyzed. Performing in situ perfusion decellularization and analyzing the scaffold by two-photon microscopy provided a practical and reliable platform to visualize the dynamic ECM remodeling in the liver.