Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS.

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

ALDH2 attenuates myocardial pyroptosis through breaking down Mitochondrion-NLRP3 inflammasome pathway in septic shock.

Cell survival or death is critical for cardiac function. Myocardial pyroptosis, as a newly recognized programmed cell death, remains poorly understood in sepsis. In this study, we evaluated the effect of aldehyde dehydrogenase (ALDH2) on myocardial pyroptosis and revealed the underlying mechanisms in sepsis. We established a septic shock mice model by intraperitoneal injection of Lipopolysaccharide (LPS, 15 mg/kg) 12 h before sacrifice. It was found that aldehyde dehydrogenase significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation and Caspase-1/GSDMD-dependent pyroptosis, which remarkably improved survival rate and septic shock-induced cardiac dysfunction, relative to the control group. While aldehyde dehydrogenase knockout or knockdown significantly aggravated these phenomena. Intriguingly, we found that aldehyde dehydrogenase inhibited LPS-induced deacetylation of Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex α subunit (HADHA) by suppressing the translocation of Histone deacetylase 3 (HDAC3) from nuclei to mitochondria. Acetylated HADHA is essential for mitochondrial fatty acid ß-oxidation, and its interruption can result in accumulation of toxic lipids, induce mROS and cause mtDNA and ox-mtDNA release. Our results confirmed the role of Histone deacetylase 3 and HADHA in NOD-like receptor protein 3 inflammasome activation. Hdac3 knockdown remarkedly suppressed NOD-like receptor protein 3 inflammasome and pyroptosis, but Hadha knockdown eliminated the effect. aldehyde dehydrogenase inhibited the translocation of Histone deacetylase 3, protected ac-HADHA from deacetylation, and significantly reduced the accumulation of toxic aldehyde, and inhibited mROS and ox-mtDNA, thereby avoided NOD-like receptor protein 3 inflammasome activation and pyroptosis. This study provided a novel mechanism of myocardial pyroptosis through mitochondrial Histone deacetylase 3/HADHA- NOD-like receptor protein 3 inflammasome pathway and demonstrated a significant role of aldehyde dehydrogenase as a therapeutic target for myocardial pyroptosis in sepsis.

Penalized maximum likelihood inference under the mixture cure model in sparse data.

INTRODUCTION: When a study sample includes a large proportion of long-term survivors, mixture cure (MC) models that separately assess biomarker associations with long-term recurrence-free survival and time to disease recurrence are preferred to proportional-hazards models. However, in samples with few recurrences, standard maximum likelihood can be biased. OBJECTIVE AND METHODS: We extend Firth-type penalized likelihood (FT-PL) developed for bias reduction in the exponential family to the Weibull-logistic MC, using the Jeffreys invariant prior. Via simulation studies based on a motivating cohort study, we compare parameter estimates of the FT-PL method to those by ML, as well as type 1 error (T1E) and power obtained using likelihood ratio statistics. RESULTS: In samples with relatively few events, the Firth-type penalized likelihood estimates (FT-PLEs) have mean bias closer to zero and smaller mean squared error than maximum likelihood estimates (MLEs), and can be obtained in samples where the MLEs are infinite. Under similar T1E rates, FT-PL consistently exhibits higher statistical power than ML in samples with few events. In addition, we compare FT-PL estimation with two other penalization methods (a log-F prior method and a modified Firth-type method) based on the same simulations. DISCUSSION: Consistent with findings for logistic and Cox regressions, FT-PL under MC regression yields finite estimates under stringent conditions, and better bias-and-variance balance than the other two penalizations. The practicality and strength of FT-PL for MC analysis is illustrated in a cohort study of breast cancer prognosis with long-term follow-up for recurrence-free survival.

5-Hydroxymethylfurfural induces mice frailty through cell senescence-associated sarcopenia caused by chronic inflammation.

Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty. Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting. Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised (p < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength (p < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered (p < 0.01). Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence.

Adenosine-rich extract of Ganoderma lucidum: A safe and effective lipid-lowering substance.

Ganoderma lucidum is a traditional Chinese medicine with a variety of active compounds and possesses adequate lipid-lowering and anti-atherosclerotic effects. However, its main active components and potential mechanisms still remain unclear. Here, we evaluated the anti-hyperlipidemic effect of the adenosine extract from Ganoderma lucidum (AEGL) in high-fat-diet (HFD)-induced hyperlipidemic ApoE-/- mice and explored the underlying biological mechanism by multi-omics analysis. Treatment with AEGL for 8 weeks significantly decreased the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) by 45.59%, 41.22%, and 39.02%, respectively, as well as reduced liver TC and TG by 44.15% and 76.23%, compared with the HFD-only group. We also observed significant amelioration of hepatic steatosis without liver and kidney damage after AEGL treatment. Regulating the expression and acetylation/crotonylation of proteins involved in the PPAR signaling pathway may be one of the potential mechanisms involved in the observed lipid-lowering effects of AEGL.

How Outpatient Diabetes Education Programs Can Support Local Hospitals to Reduce Emergency Department Visits for Adults With Diabetes.

OBJECTIVES: Our aim in this study was to assess the level of collaboration between a hospital-based outpatient diabetes education program (DEP) and emergency departments (EDs) for reducing number of ED revisits and hospital admissions by implementing intervention strategies to promote education services and streamlining referral and appointment intake processes. METHODS: Patients (≥18 years of age) with an ED visit for hyper- or hypoglycemia were analyzed in 2 cohorts based on their intervention exposure. We conducted a single-cohort analysis of the exposed cohort (exposure to the intervention strategies) and compared 2-year outcomes with those of the unexposed cohort. Primary outcomes were hyper- or hypoglycemia-related ED revisit and hospitalization rates. Process outcomes included DEP referrals and DEP attendance. RESULTS: There were no significant differences in ED revisits and hospital admissions between the exposed and unexposed cohorts. However, patients were more likely to be referred to a DEP by ED physicians (odds ratio [OR], 1.76; p=0.02) and to attend a DEP appointment (OR, 1.96; p<0.01) after intervention exposure. DEP attendees from both cohorts became less likely to revisit an ED (exposed: OR, 0.41; 95% confidence interval [CI], 0.23 to 0.71; unexposed: OR, 0.4; 95% CI, 0.15 to 1.15) at 12-month follow up; however, this reduction was sustained only among the exposed cohort (OR, 0.5; 95% CI, 0.31 to 0.81) and not the unexposed cohort (OR, 1.32; 95% CI, 0.60 to 2.91) at 24 months (p=0.04 when comparing the 2 cohorts). CONCLUSIONS: Collaboration between outpatient DEPs with local EDs could effectively reduce diabetes-related ED revisits by increasing diabetes program utilization.

Hydrochemical Evolution Mechanisms of Shallow Groundwater and Its Quality Assessment in the Estuarine Coastal Zone: A Case Study of Qidong, China.

Identification of geochemical characters and the influence of river and seawater on coastal areas are of significant impact on water resources management in coastal areas globally. Thus, it requires careful investigation of the hydrochemical evolution mechanisms and assessment of the quality of shallow groundwater. The study specifically focused on the estuarine coastal zone of Qidong, China, a city located on the Yangtze estuary. Thirty shallow groundwater samples and five surface water samples were collected during a field investigation, and 25 water quality indexes were analyzed. Methods including mathematical statistics, Gibbs figure, Piper diagram, and ionic rations were used to analyze the hydrochemical characteristics and evolution mechanisms. The spatial distribution of key parameters was assessed using a GIS-based spatial gridding technique. Results showed that the shallow groundwater in this estuarine coastal zone is weakly alkaline. The major hydrochemical parameters, including total dissolved solids (TDS), Na+ and Cl-, Mg2+, and SO42-, displayed similar spatial distributions; the distributions of Ca2+ and Mg2+ were irregular ; the distributions of SO42- and HCO3- shared a similar trend, increasing gradually from the southern to northern regions of the study zone; and the values of NO3- and NH4+ were generally low in the study area. The hydrochemistry of the groundwater consists of HCO3-CaMg type and HCO3-Na, with HCO3·Cl-Na type and Cl-Na being the dominant constituents toward the coastal strip. The coastal aquifers are subjected to the ongoing influence of seawater intrusion, ion exchange processes, freshwater infiltration, and mineral (carbonate and silicate) dissolution, which impact groundwater evolution. Most of the groundwater samples are unsuitable for drinking purposes, but more than 90% of samples have irrigation suitability, based on the WHO standards and the classifications of sodium absorption ratio (SAR), soluble-sodium percentage (SSP).

Evaluating the impact of onsite diabetes education teams in primary care on clinical outcomes.

BACKGROUND: To evaluate the impact of integrating diabetes education teams in primary care on glycemic control, lipid, and blood-pressure management in type 2 diabetes patients. METHODS: A historical cohort design was used to assess the integration of teams comprising nurse and dietitian educators in 11 Ontario primary-care sites, which delivered individualized self-management education. Of the 771 adult patients with A1C ≥ 7% recruited, 487 patients attended appointments with the diabetes teams, while the remaining 284 patients did not. The intervention's primary goal was to increase the proportion of patients with A1C ≤7%. Secondary goals were to reduce mean A1C, low-density lipoprotein, total cholesterol-high density lipoprotein, and diastolic and systolic blood pressure, as recommended by clinical-practice guidelines. RESULTS: After 12 months, a higher proportion of intervention-group patients reached the target for A1C, compared with the control group. Mean A1C levels fell significantly among all patients, but the mean reduction was larger for the intervention group than the control group. Although more intervention-group patients reached targets for all clinical outcomes, the between-group differences were not statistically significant, except for A1C. CONCLUSIONS: Nurse and dietitian diabetes-education teams can have a clinically meaningful impact on patients' ability to meet recommended A1C targets. Given the study's historical cohort design, results are generalizable and applicable to day-to-day primary-care practice. Longer follow-up studies are needed to investigate whether the positive outcomes of the intervention are sustainable.

Current Evidence of Interleukin-6 Signaling Inhibitors in Patients With COVID-19: A Systematic Review and Meta-Analysis.

Background: Interleukin-6 (IL-6) is known to be detrimental in coronavirus disease 2019 (COVID-19) because of its involvement in driving cytokine storm. This systematic review and meta-analysis aimed to assess the safety and efficacy of anti-IL-6 signaling (anti-IL6/IL-6R/JAK) agents on COVID-19 based on the current evidence. Methods: Studies were identified through systematic searches of PubMed, EMBASE, ISI Web of Science, Cochrane library, ongoing clinical trial registries (clinicaltrials.gov), and preprint servers (medRxiv, ChinaXiv) on August 10, 2020, as well as eligibility checks according to predefined selection criteria. Statistical analysis was performed using Review Manager (version 5.3) and STATA 12.0. Results: Thirty-one studies were included in the pooled analysis of mortality, and 12 studies were identified for the analysis of risk of secondary infections. For mortality analysis, 5630 COVID-19 cases including 2,132 treated patients and 3,498 controls were analyzed. Anti-IL-6 signaling agents plus standard of care (SOC) significantly decreased the mortality rate compared to SOC alone (pooled OR = 0.61, 95% CI 0.45-0.84, p = 0.002). For the analysis of secondary infection risk, 1,624 patients with COVID-19 including 639 treated patients and 985 controls were included, showing that anti-IL-6 signaling agents did not increase the rate of secondary infections (pooled OR = 1.21, 95% CI 0.70-2.08, p = 0.50). By contrast, for patients with critical COVID-19 disease, anti-IL-6 signaling agents failed to reduce mortality compared to SOC alone (pooled OR = 0.75, 95% CI 0.42-1.33, p = 0.33), but they tended to increase the risk of secondary infections (pooled OR = 1.85, 95% CI 0.95-3.61, p = 0.07). A blockade of IL-6 signaling failed to reduce the mechanical ventilation rate, ICU admission rate, or elevate the clinical improvement rate. Conclusion: IL-6 signaling inhibitors reduced the mortality rate without increasing secondary infections in patients with COVID-19 based on current studies. For patients with critical disease, IL-6 signaling inhibitors did not exhibit any benefit.

Impact of diabetes education teams in primary care on processes of care indicators.

AIMS: To evaluate the impact of the integration of onsite diabetes education teams in primary care on processes of care indicators according to practice guidelines. METHODS: Teams of nurse and dietitian educators delivered individualized self-management education counseling in 11 Ontario primary care sites. Of the 771 adult patients with HbA1c ≥7% who were recruited in a prospective cohort study, 487 patients attended appointments with the education teams, while the remaining 284 patients did not (usual care group). Baseline demographic, clinical information, and patient care processes (diabetes medical visit, HbA1c test, lipid profile, estimated glomerular filtration rate, and albumin-to-creatinine ratio, measuring blood pressure, performing foot exams, provision of flu vaccine, and referral for dilated retinal exam) were collected from patient charts one year before (pre period) and after (post period) the integration began. A multi-level random effects model was used to analyze the effect of group and period on whether the process indicators were met based on practice guidelines. RESULTS: Compared to the usual care group, patients seen by the education teams had significant improvements on indicators for semi-annual medical visit and annual foot exam. No significant improvements were found for other process of care indicators. CONCLUSIONS: Onsite education teams in primary care settings can potentially improve diabetes management as shown in two process of care indicators: medical visits and foot exams. The results support the benefits of having education teams in primary care settings to increase adherence to practice guidelines.

Synthesis of size-controlled Ag@Co@Ni/graphene core-shell nanoparticles for the catalytic hydrolysis of ammonia borane.

Size-controlled Ag0.04@Co0.48@Ni0.48 core-shell nanoparticles (NPs) were synthesized by employing graphene (rGO) with different reduction degrees as supports. The number of C=O and C=O functional groups on the surface of rGO might play a major role in controlling the particle size. The strong steric-hindrance effect of C=O resulted in the growth of large particles, whereas C=O contributed to the formation of small particles. The particle size of Ag0.04@Co0.48@Ni0.48 NPs supported on rGO with different reduction degrees decreased as the number of C=O functional groups decreased. The decrease in the particle size probably led to the increase in the catalytic activity towards the hydrolysis of ammonia borane (AB). The enhanced catalytic activity largely stemmed from the increasing active sites on the surface of catalysts owing to the decreasing particle size.

Synthesis of triple-layered Ag@Co@Ni core-shell nanoparticles for the catalytic dehydrogenation of ammonia borane.

Triple-layered Ag@Co@Ni core-shell nanoparticles (NPs) containing a silver core, a cobalt inner shell, and a nickel outer shell were formed by an in situ chemical reduction method. The thickness of the double shells varied with different cobalt and nickel contents. Ag0.04 @Co0.48 @Ni0.48 showed the most distinct core-shell structure. Compared with its bimetallic core-shell counterparts, this catalyst showed higher catalytic activity for the hydrolysis of NH3 BH3 (AB). The synergetic interaction between Co and Ni in Ag0.04 @Co0.48 @Ni0.48 NPs may play a critical role in the enhanced catalytic activity. Furthermore, cobalt-nickel double shells surrounding the silver core in the special triple-layered core-shell structure provided increasing amounts of active sites on the surface to facilitate the catalytic reaction. These promising catalysts may lead to applications for AB in the field of fuel cells.

Excellent catalytic effects of highly crumpled graphene nanosheets on hydrogenation/dehydrogenation of magnesium hydride.

Highly crumpled graphene nanosheets (GNS) with a BET surface area as high as 1159 m(2) g(-1) was fabricated by a thermal exfoliation method. A systematic investigation was performed on the hydrogen sorption properties of MgH(2)-5 wt% GNS nanocomposites acquired by ball-milling. It was found that the as-synthesized GNS exhibited a superior catalytic effect on hydrogenation/dehydrogenation of MgH(2). Differential Scanning Calorimetry (DSC) and isothermal hydrogenation/dehydrogenation measurements indicated that both hydrogen sorption capacity and dehydrogenation/hydrogenation kinetics of the composites improved with increasing milling time. The composites MgH(2)-GNS milled for 20 h can absorb 6.6 wt% H(2) within 1 min at 300 °C and 6.3 wt% within 40 min at 200 °C, even at 150 °C, it can also absorb 6.0 wt% H(2) within 180 min. It was also demonstrated that MgH(2)-GNS-20 h could release 6.1 wt% H(2) at 300 °C within 40 min. In addition, microstructure measurements based on XRD, SEM, TEM as well as Raman spectra revealed that the grain size of thus-prepared MgH(2)-GNS nanocomposites decreased with increasing milling time, moreover, the graphene layers were broken into smaller graphene nanosheets in a disordered and irregular manner during milling. It was confirmed that these smaller graphene nanosheets on the composite surface, providing more edge sites and hydrogen diffusion channels, prevented the nanograins from sintering and agglomerating, thus, leading to promotion of the hydrogenation/dehydrogenation kinetics of MgH(2).

Biochemical characterization of UDP-Gal:GlcNAc-pyrophosphate-lipid ß-1,4-Galactosyltransferase WfeD, a new enzyme from Shigella boydii type 14 that catalyzes the second step in O-antigen repeating-unit synthesis.

The O antigen is the outer part of the lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria and contains many repeats of an oligosaccharide unit. It contributes to antigenic variability and is essential to the full function and virulence of bacteria. Shigella is a Gram-negative human pathogen that causes diarrhea in humans. The O antigen of Shigella boydii type 14 consists of repeating oligosaccharide units with the structure [→6-d-Galpα1→4-d-GlcpAß1→6-d-Galpß1→4-d-Galpß1→4-d-GlcpNAcß1→]n. The wfeD gene in the O-antigen gene cluster of Shigella boydii type 14 was proposed to encode a galactosyltransferase (GalT) involved in O-antigen synthesis. We confirmed here that the wfeD gene product is a ß4-GalT that synthesizes the Galß1-4GlcNAcα-R linkage. WfeD was expressed in Escherichia coli, and the activity was characterized by using UDP-[³H]Gal as the donor substrate as well as the synthetic acceptor substrate GlcNAcα-pyrophosphate-(CH2)11-O-phenyl. The enzyme product was analyzed by liquid chromatography-mass spectrometry (LC-MS), high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and galactosidase digestion. The enzyme was shown to be specific for the UDP-Gal donor substrate and required pyrophosphate in the acceptor substrate. Divalent metal ions such as Mn²(+), Ni²(+), and, surprisingly, also Pb²(+) enhanced the enzyme activity. Mutational analysis showed that the Glu101 residue within a DxD motif is essential for activity, possibly by forming the catalytic nucleophile. The Lys211 residue was also shown to be required for activity and may be involved in the binding of the negatively charged acceptor substrate. Our study revealed that the ß4-GalT WfeD is a novel enzyme that has virtually no sequence similarity to mammalian ß4-GalT, although it catalyzes a similar reaction.

Synthesis of acceptor substrate analogs for the study of glycosyltransferases involved in the second step of the biosynthesis of O-antigen repeating units.

O-antigens of Gram negative bacteria are polysaccharides covalently attached to lipopolysaccharides (LPS) that have roles as virulence factors. Due to the lack of defined substrates for in vitro assays only a few of the enzymes involved in the biosynthesis of O-antigens have been studied. Many O-antigens have GlcNAc at the reducing end of the oligosaccharide chain linked to pyrophosphate-lipid. We therefore designed and synthesized a series of GlcNAc-pyrophosphate-lipid analogs of the natural GlcNAc-pyrophosphate-undecaprenol acceptor substrate for studies of the acceptor specificities of O-antigen biosynthetic enzymes. We synthesized analogs with modifications of the pyrophosphate bond as well as the lipid chain. These compounds will be useful for the specificity studies of many bacterial glycosyltransferases. Knowledge of the substrate specificities is the basis for the development of specific glycosyltransferase inhibitors that could block O-antigen biosynthesis.

Functional immobilization of interferon-gamma induces neuronal differentiation of neural stem cells.

Stem cell transplantation provides significant promise to regenerative strategies after injury in the central nervous system. Neural stem/progenitor cells (NSPCs) have been studied in terms of their regenerative capacity and their ability to differentiate into neurons when exposed to various soluble factors. In this study, interferon-gamma (IFN-gamma) was compared with brain-derived neurotrophic factor (BDNF) and erythropoietin and was shown to be the best single growth factor for inducing neuronal differentiation from adult rat brain-derived NSPCs. Next, IFN-gamma was surface immobilized to a methacrylamide chitosan (MAC) scaffold that was specifically designed to match the modulus of brain tissue and neuronal differentiation of NSPCs was examined in vitro by immunohistochemistry. Bioactive IFN-gamma was successfully immobilized and quantified by ELISA. Both soluble and immobilized IFN-gamma on MAC surfaces showed dose dependent neuronal differentiation with soluble saturation occurring at 100 ng/mL and the most effective immobilized IFN-gamma dose at 37.5 ng/cm(2), where significantly more neurons resulted compared with controls including soluble IFN-gamma.