Trend in prevalence, associated risk factors, and longitudinal outcomes of sarcopenia in China: A national cohort study.

AIMS: To estimate the contemporary trend in the prevalence of sarcopenia and evaluate its risk factors and the longitudinal associations with multiple chronic conditions and mortality among Chinese middle-aged and older adults. METHODS: This was a nationwide, prospective cohort study using data from the China Health and Retirement Longitudinal Study. The definition of sarcopenia was based on the Asian Working Group for Sarcopenia 2019 algorithm. In the cross-sectional analysis, we estimated the trend in the weighted prevalence of sarcopenia from 2011 to 2015 and examined the associated risk factors for sarcopenia severity in 2011. In the longitudinal analysis, we assessed the longitudinal associations between sarcopenia and 14 chronic conditions and mortality during a 9-year follow-up. RESULTS: The weighted prevalence of sarcopenia remained consistently high in the overall population from 2011 (15.9%, 95% confidence intervals [CI]: 15.1, 16.6) to 2015 (15.0%, 95% CI: 14.3, 15.6; p for trend = 0.075). A range of risk factors were independently associated with the severity of sarcopenia, including older age, female sex, lower socioeconomic status, smoking status, malnutrition, and several chronic conditions. Possible sarcopenic and sarcopenic individuals had higher odds of several chronic conditions (i.e., heart disease, chronic lung disease, and memory-related disease) and increased risks of mortality (possible sarcopenia: odds ratios (OR): 1.66, 95% CI: 1.37, 2.00; sarcopenia: OR: 1.69, 95% CI: 1.36, 2.11) in 9 years of follow-up. CONCLUSIONS: The prevalence of sarcopenia remained consistently high in the investigated population. Various risk factors were significantly associated with a higher prevalence of sarcopenia. Sarcopenic individuals had higher odds of several chronic conditions and increased risks of mortality, highlighting that the urgent need for dedicated efforts to improve the management of sarcopenic patients.

Systolic blood pressure status modifies the associations between the triglyceride-glucose index and incident cardiovascular disease: a national cohort study in China.

BACKGROUND: The triglyceride-glucose (TyG) index and blood pressure (BP) are correlated and serve as risk factors for cardiovascular disease (CVD). The potential impact of BP status on the association between the TyG index and CVD risk remains uncertain. This study aims to investigate the relationships between the TyG index and incident CVD in Chinese middle-aged and elderly adults, considering variations in BP status among participants. METHODS: 6558 participants (mean age: 58.3 (± 8.7) years; 46.0% were men) without prevalent CVD were recruited from the China Health and Retirement Longitudinal Study. Participants were divided into three groups according to their systolic blood pressure (SBP) levels (< 120mmHg, 120 ∼ 129mmHg, ≥ 130mmHg). The TyG index was computed as ln[triglyceride (mg/dl) * fasting blood glucose (mg/dl)/2]. The primary outcome was CVD (heart disease and stroke), and the secondary outcomes were individual CVD components. Cox regression models and restricted cubic splines were performed to investigate the associations between continuous and categorical TyG with CVD. RESULTS: 1599 cases of CVD were captured during 58,333 person-years of follow-up. Per 1-SD higher TyG index was associated with a 19% (HR: 1.19; 95% CI: 1.12, 1.27) higher risk for incident CVD, and the participants with the highest quartile of TyG index had a 54% (HR: 1.54; 95% CI: 1.29, 1.84) higher risk of CVD compared to those in the lowest quartile. SBP significantly modifies the association between the TyG index and CVD, with higher HRs for CVD observed in those with optimal and normal SBP. SBP partially mediated the associations between the TyG index with CVD. The results were generally consistent among participants with varying pulse pressure statuses rather than diastolic BP statuses. CONCLUSIONS: The associations between the TyG index and CVD were modified by BP status, with greater HRs for CVD observed among those who had SBP < 130mmHg. SBP can partially mediate the association between the TyG index with CVD, highlighting the importance of early screening for the TyG index to identify at risk of hypertension and CVD.

The association between TyG and all-cause/non-cardiovascular mortality in general patients with type 2 diabetes mellitus is modified by age: results from the cohort study of NHANES 1999-2018.

BACKGROUND: The prognostic value of triglyceride-glucose (TyG) index in general type 2 diabetes mellitus (T2DM) patients is still unclear. Therefore, we aimed to determine the associations between TyG and all-cause/cause-specific death in a T2DM cohort and explore whether such associations would be modified by age. METHODS: A total of 3,376 patients with T2DM from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were selected and divided into the younger group (< 65 yrs) and the older group (≥ 65 yrs). Baseline TyG was calculated and cause-specific mortality status [cardiovascular (CV), cancer, and non-CV] was determined by the NHANES Public-Use Linked Mortality Files through 31 December 2019. Multivariate Cox and restricted cubic spline (RCS) regression models were used to evaluate the association between TyG and all-cause/cause-specific mortality. Interaction between TyG and age to mortality was also evaluated. Sensitivity analyses were performed in patients without cardiovascular disease, chronic kidney disease, or insulin treatment. RESULTS: During a median follow-up of 107 months, 805 all-cause deaths occurred, of which 250 and 144 were attributed to CV and cancer deaths. There was a significant age interaction to the association between TyG and all-cause/non-CV mortality. After fully adjusting for potential confounding factors, higher TyG was associated with an increased risk of all-cause [TyG per unit increase Hazard Ratio (HR) 1.33, 95% Confidence Interval (CI) 1.06-1.66, p = 0.014] and non-CV mortality (TyG per unit increase HR 1.54, 95% CI 1.18-2.01, p = 0.002) only in the younger group, but not in the older group. There was no significant association between TyG and CV/cancer death in the total cohort and two age subgroups. Similar results were found in RCS and sensitivity analyses. CONCLUSION: In a national sample of patients with T2DM in the United States, we found that the association between TyG and all-cause/non-CV death was modified by age. Higher TyG was only associated with an increased risk of all-cause/non-CV only in T2DM patients younger than 65 years old, but not in older patients.

Anionic oxyl radical formed on CrVI-oxo anchored on the defect site of the UiO-66 node facilitates methane to methanol conversion.

The direct conversion of methane to methanol has attracted increasing interest due to abundant and low-cost natural gas resources. Herein, by anchoring Cr-oxo/-oxyhydroxides on UiO-66 metal-organic frameworks, we demonstrate that reactive anionic oxyl radicals can be formed by controlling the coordination environment based on the results of density functional theory calculations. The anionic oxyl radicals produced at the completely oxidized CrVI site acted as the active species for facile methane activation. The thermodynamically stable CrVI-oxo/-oxyhydroxides with the anionic oxyl radicals catalyze the activation of the methane C-H bond through a homolytic mechanism. An analysis of the results showed that the catalytic performance of the active oxyl species correlates with the reaction energy of methane activation and H adsorption energies. Following methanol formation, N2O can regenerate the active sites on the most stable CrVI oxyhydroxides, i.e., the Cr(O)4Hf species. The present study demonstrated that the anionic oxyl radicals formed on the anchored CrVI oxyhydroxides by tuning the coordination environment enabled facile methane activation and facilitated methanol production.

Resolving Temperature-Dependent Hydrate Nucleation Pathway: The Role of "Transition Layer".

Understanding the nucleation of natural gas hydrate (NGH) at different conditions has important implications to NGH recovery and other industrial applications, such as gas storage and separation. Herein, vast numbers of hydrate nucleation events are traced via molecular dynamics (MD) simulations at different degrees of supercooling (or driving forces). Specifically, to precisely characterize a hydrate nucleus from an aqueous system during the MD simulation, we develop an evolutionary order parameter (OP) to recognize the nucleus size and shape. Subsequently, the free energy landscapes of hydrate during nucleation are explored by using the newly developed OP. The results suggest that at 270 K (or 0.92 Tm supercooling, where Tm is the melting point), the near-rounded nucleus prevails during the nucleation, as described from the classical nucleation theory. In contrast, at relatively strong driving forces of 0.85 and 0.88 Tm, nonclassical nucleation events arise. Specifically, the pathway toward an elongated nucleus becomes as important as the pathway toward a near-rounded nucleus. To explain the distinct nucleation phenomena at different supercoolings, a notion of a "transition layer" (or liquid-blob-like layer) is proposed. Here, the transition layer is to describe the interfacial region between the nucleus and aqueous solution, and this layer entails two functionalities: (1) it tends to retain CH4 depending on the degrees of supercooling and (2) it facilitates collision among CH4, which thus promote the incorporation of CH4 into nucleus. Our simulation indicates that compared to the near-rounded nucleus, the transition layer surrounding the elongated nucleus is more evident with the higher collision rate among CH4 molecules. As such, the transition layer tends to promote the elongated nucleus pathway, while offsetting the cost of larger surface free energy associated with the elongated nucleus. At 0.92 Tm, however, the transition layer gradually disappears, and classical nucleation events dominate. Overall, the notion of "transition layer" offers deeper insight into the NGH nucleation at different degrees of supercooling and could be extended to describe other types of hydrate nucleation.

Chemical Implications of Rapid Reactive Absorption of I2O4 at the Air-Water Interface.

Marine aerosol formation involving iodine-bearing species significantly affects the global climate and radiation balance. Although recent studies outline the critical role of iodine oxide in nucleation, much less is known about its contribution to aerosol growth. This paper presents molecular-level evidence that the air-water interfacial reaction of I2O4 mediated by potent atmospheric chemicals, such as sulfuric acid (H2SO4) and amines [e.g., dimethylamine (DMA) and trimethylamine (TMA)], can occur rapidly on a picosecond time scale by Born-Oppenheimer molecular dynamics simulations. The interfacial water bridges the reactants while facilitating the DMA-mediated proton transfer and stabilizing the ionic products of H2SO4-involved reactions. The identified heterogeneous mechanisms exhibit the dual contribution to aerosol growth: (i) the ionic products (e.g., IO3-, DMAH+, TMAH+, and HSO4-) formed by reactive adsorption possess less volatility than the reactants and (ii) these ions, such as alkylammonium salts (e.g., DMAH+), are also highly hydrophilic, further facilitating hygroscopic growth. This investigation enhances not only our understanding of heterogeneous iodine chemistry but also the impact of iodine oxide on aerosol growth. Also, these findings can bridge the gap between the abundance of I2O4 in the laboratory and its absence in field-collected aerosols and provide an explanation for the missing source of IO3-, HSO4-, and DMAH+ in marine aerosols.

Distinctive Heterogeneous Reaction Mechanism of ClNO2 on the Air-Water Surface Containing Cl.

The heterogeneous reaction of nitryl chloride (ClNO2) on the air-water surface plays a significant role in the chloride lifecycle. The air-water surface is ubiquitous on ice surfaces under supercooled conditions, affecting the uptake and heterogeneous reaction processes of trace gases. Previous studies suggest that ClNO2 is formed on Cl-doped ice surfaces following the N2O5 uptake. Herein, a distinctive heterogeneous reaction mechanism of ClNO2 is suggested on an air-water surface containing Cl under supercooled conditions using combined classic molecular dynamics (MD) and Born-Oppenheimer MD simulations. It is found that N2O5 dissociates into a NO2+ and NO3- ionic pair on the top air-water surface. In the top layer of the surface containing barely any Cl-, NO2+ proceeds through hydrolysis and produces H3O+ and HNO3. Thus, surface acidification appears because of H3O+ yields. With NO2+ diffusion to the deep layer of the surface, NO2+ reacts with Cl- and forms ClNO2. Note that ClNO2 formation competes with NO2+ hydrolysis, and the rate of ClNO2 formation is 27.7[Cl-] larger than that of NO2+ hydrolysis. Afterward, the reaction of ClNO2 with Cl- becomes barrierless with the catalysis by H3O+, which is not feasible on a neutral surface. Cl2 is thus generated and escapes into the atmosphere (low solubility of Cl2), contributing to the Cl radical. The proposed mechanism bolsters the current understanding of ClNO2's fate and its role in Cl chemistry in extremely cold environments like the Arctic and other high-latitude regions in wintertime.

A histidine-rich fusion tag enables real-time monitoring of recombinant protein expression by Pauly reaction-based colorimetric assay.

Commercially available recombinant expression systems always use fusion tags to facilitate target protein purification and SDS-PAGE analysis followed by Coomassie Brilliant Blue (CBB) staining is the classical method to validate the expression level of target protein, which is time-consuming, although not very laborious. Previously, we found that a histidine-rich elastin-like polypeptide (HRELP) tag could make its fusion proteins being quickly and specifically stained with Pauly's reagent. In this study, we designed a Pauly reaction-based colorimetric assay to real-time monitoring of the expression level of recombinant protein tagged HRELP and found that the absorption value of post-induction E. coli cells stained with Pauly's reagent correlated well with both the band intensity of the target protein from Pauly's reagent-stained and CBB-stained gels. Moreover, we found the colorimetric assay could also be helpful to roughly estimate the expression efficiency by using a poly-histidine-tagged protein, which has only 1.17% histidine residue. In our opinion, Pauly reaction-based colorimetric assay could significantly shorten the time to validate the over-expression of recombinant protein tagged with either HRELP or poly-histidine. And HRELP seemed to be an ideal fusion tag for it can not only facilitate protein purification but also simplify protein detection.

Correlation between the Properties of Surface Lattice Oxygen on NiO and Its Reactivity and Selectivity towards the Oxidative Dehydrogenation of Propane.

Modified NiO catalysts with controllable vacancies and dopants are promising for alkene production from oxidative dehydrogenation (ODH) of light alkanes, and a molecular understanding of the modification on elementary reaction steps would facilitate the design of highly efficient catalysts and catalytic processes. In this study, density functional theory (DFT) calculations was used to map out the complete reaction pathways of propane ODH on the NiO (100) surfaces with different modifiers. The results demonstrated that the presence of vacancies (O and Ni) and dopants (Li and Al) alters the electrophilicity of surface oxygen species, which in turn affects the reactivity towards C-H bond activation and the overall catalytic activity and selectivity. The strongly electrophilic O favors a radical mechanism for the first C-H activation on O followed by the second C-H activation on O-O site, whereas weak electrophilic O favors concerted C-H bond breaking over Ni-O site. The C-H bond activation proceeds through a late transition state, characterized by the almost completion of the O-H bond formation. Consequently, the adsorption energy of H adatom on O rather than p-band center or Bader charge of O has been identified to be an accurate descriptor to predict the activation barrier for C-H breaking (activity) as well as the difference between the activation barriers of propene and CH3 CCH3 (selectivity) of ODH.

Alveolar Macrophages Inherently Express Programmed Death-1 Ligand 1 for Optimal Protective Immunity and Tolerance.

Macrophages play a central role in lung physiology and pathology. In this study, we show in mice that alveolar macrophages (AMs), unlike other macrophage types (interstitial, peritoneal, and splenic macrophages), constitutively express programmed death-1 ligand 1 (PD-L1), thereby possessing a superior phagocytic ability and the capacity to repress CTLs by cis- and trans-interacting with CD80 and programmed death-1 (PD-1), respectively. This extraordinary ability of AMs assures optimal protective immunity and tolerance within the lung. These findings uncover a unique characteristic of AMs and an innate immune function of PD-L1 and CD80 and therefore help in the understanding of lung physiology, diseases, and PD-L1/PD-1-based immunotherapy.

Dietary interventions for pediatric patients with functional abdominal pain disorders: a systematic review and network meta-analysis.

Dietary therapies are recommended for the treatment of pediatrics with functional abdominal pain disorders (FAPDs), but the comparative effectiveness among them is unclear. Therefore, the main aim of this systematic review and meta-analysis was to compare the effectiveness of differential dietary therapies in pediatrics with functional abdominal pain disorders. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases from inception to February 28, 2023. Randomized clinical trials of dietary treatments for pediatric patients with functional abdominal pain disorders were included. The primary outcome was the improvement in abdominal pain. The secondary outcomes were changes in pain intensity and pain frequency. Thirty-one studies after screening 8695 retrieved articles were included, and 29 studies were available for network meta-analysis. Compared with placebo, fiber (RR, 4.86; 95%CI, 1.77 to 13.32; P-score = 0.84), synbiotics (RR, 3.92; 95%CI, 1.65 to 9.28; P-score = 0.75), and probiotics (RR, 2.18; 95%CI, 1.46 to 3.26; P-score = 0.46) had significantly larger effect on the improvement in abdominal pain, the three treatments had larger effect than placebo but statistically insignificant in difference in improving pain frequency and intensity. Similarly, there were no significant differences between the dietary treatments after indirect comparisons of the three outcomes.  Conclusion: Fiber supplements, synbiotics, and probiotics were efficacious in improving abdominal pain of FAPDs in children, suggested by very low or low evidence. The evidence of the efficacy of probiotics is more convincing than fiber and synbiotics when sample size and statistical power were considered. No difference in the efficacy of the three treatments. High-quality trials are needed to further investigate the efficacy of dietary interventions. What is Known: • Multiple dietary treatment options are available for functional abdominal pain disorders in the pediatric population, of which the most beneficial one is currently unknown. What is New: • This NMA found very low to low certainty of the evidence suggesting that fiber, synbiotics, and probiotics might be more efficacious in improving abdominal pain of FAPDs in children than the other dietary treatments. • There were no significant differences between active dietary treatments for changes in abdominal pain intensity.

Coupled oxygen desorption and structural reconstruction accompanying reduction of copper oxide.

Understanding structural transformation and phase transition accompanying reactions in a solid as a catalyst or oxygen carrier is important to the design and optimization of many catalytic or chemical looping reaction processes. Herein, we combined density functional theory calculation with the stochastic surface walking global optimization approach to track the structural transformation accompanying the reduction of CuO upon releasing oxygen. We then used machine learning (ML) methods to correlate the structural properties of CuOx with varying x. By decomposing a reduction step into oxygen detachment and structural reconstruction, we identified two types of pathways: (1) uniform reduction with minimal structural changes; (2) segregated reduction with significant reconstruction. The results of ML analysis showed that the most important feature is the radial distribution functions of Cu-O at a percentage of oxygen vacancy [C(OV)] < 50% and Cu-Cu at C(OV) > 50% for CuOx formation. These features reflect the underlying physicochemical origin, i.e., Cu-O breaking and Cu-Cu formation in the respective stage of reduction. Phase diagram analysis indicates that CuO will be reduced to Cu2O under a typical oxygen uncoupling condition. This work demonstrates the complexity of solid structural transformation and the potential of ML methods in studying solid state materials involved in many chemical processes.

Unraveling nucleation pathway in methane clathrate formation.

Methane clathrates are widespread on the ocean floor of the Earth. A better understanding of methane clathrate formation has important implications for natural-gas exploitation, storage, and transportation. A key step toward understanding clathrate formation is hydrate nucleation, which has been suggested to involve multiple evolution pathways. Herein, a unique nucleation/growth pathway for methane clathrate formation has been identified by analyzing the trajectories of large-scale molecular dynamics (MD) simulations. In particular, ternary water-ring aggregations (TWRAs) have been identified as fundamental structures for characterizing the nucleation pathway. Based on this nucleation pathway, the critical nucleus size and nucleation timescale can be quantitatively determined. Specifically, a methane hydration layer compression/shedding process is observed to be the critical step in (and driving) the nucleation/growth pathway, which is manifested through overlapping/compression of the surrounding hydration layers of the methane molecules, followed by detachment (shedding) of the hydration layer. As such, an effective way to control methane hydrate nucleation is to alter the hydration layer compression/shedding process during the course of nucleation.

Solvation and Hydrolysis Reaction of Isocyanic Acid at the Air-Water Interface: A Computational Study.

Isocyanic acid (HNCO) is known to be inert to strong oxidants and photolysis in the atmosphere but often appears in different forms of smoke; therefore, it is linked to various smoke-related illnesses due to tobacco usage or wildfire events. To date, the major loss pathway of HNCO is believed to be through its uptake on aerosol droplets. However, the molecular mechanisms underlying such an uptake process are still incompletely understood. Herein, we use the Born-Oppenheimer molecular dynamics (BOMD) simulations to study solvation and hydrolysis reactions of HNCO on water droplets at ambient temperature. The BOMD simulations indicate that the scavenging of HNCO by water droplets is largely attributed to the preferential adsorption of HNCO at the air-water interface, rather than inside bulk water. Specifically, the H atom of HNCO interacts with the O atom of interfacial water, leading to the formation of a hydrogen bond (H-bond) of (HNCO)H···O(H2O), which prevents HNCO from evaporating. Moreover, the interfacial water can act as H-bond acceptors/donors to promote the proton transfer during the HNCO hydrolysis reaction. Compared to the gas phase, the activation barrier is lowered from 45 to 14 kcal·mol-1 on the water surface, which facilitates the formation of the key intermediate of NH2COOH. This intermediate eventually decomposes into NH3 and CO2, consistent with the previous study [ Atmos. Chem. Phys. 2016, 16, 703-714]. The new molecular insight into HNCO solvation and reaction on the water surface improves our understanding of the uptake of HNCO on aerosols.

The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice.

Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre -mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre ;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis.

The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source.

BACKGROUND & AIMS: Calcineurin is a ubiquitously expressed central Ca2+-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation. METHODS: We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1UBC△/△) and in the corresponding controls for each deletion of CNB1. Acute pancreatitis was induced in mice by administration of caerulein or high-pressure infusion of radiocontrast into biliopancreatic ducts; some mice were also given intraductal infusions of an adeno-associated virus vector that expressed nuclear factor of activated T -cells (NFAT)-luciferase into pancreas. Pancreas, bone marrow, liver, kidney, heart, and lung were collected and analyzed by histopathology, immunohistochemistry, and immunoblots; levels of cytokines were measured in serum. Mouse and human primary pancreatic acinar cells were transfected with a vector that expressed NFAT-luciferase and incubated with an agent that blocks interaction of NFAT with calcineurin; cells were analyzed by immunofluorescence. Calcineurin-mediated neutrophil chemotaxis and reactive oxygen species production were measured in neutrophils from mice. RESULTS: Mice with hematopoietic-specific deletion of CNB1 developed the same level of local pancreatic inflammation as control mice after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts. Cnb1UBC△/△ mice or mice with pancreas-specific deletion of CNB1 developed less severe pancreatitis and reduced pancreatic inflammation after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts compared with control mice. NFAT was activated in pancreas of Swiss Webster mice given caerulein or infusions of radiocontrast into biliopancreatic ducts. Blocking the interaction between calcineurin and NFAT did not reduce pancreatic acinar cell necrosis in response to caerulein or infusions of radiocontrast. Mice with hematopoietic-specific deletion of CNB1 (but not mice with pancreas-specific deletion of CNB1) had reduced infiltration of lung tissues by neutrophils. Neutrophil chemotaxis and production of reactive oxygen species were decreased after incubation with a calcineurin inhibitor. CONCLUSIONS: Hematopoietic and neutrophil expression of calcineurin promotes pancreatitis-associated lung inflammation, whereas pancreatic calcineurin promotes local pancreatic inflammation. The findings indicate that the protective effects of blocking or deleting calcineurin on pancreatitis are mediated by the source of its expression. This information should be used in the development of strategies to inhibit calcineurin for the prevention of pancreatitis and pancreatitis-associated lung inflammation.

Genetic analysis using targeted next-generation sequencing of sporadic Chinese patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Inherited dilated cardiomyopathy (DCM) contributes to approximately 25% of idiopathic DCM cases, and the proportion is even higher in familial DCM patients. Most studies have focused on familial DCM, whereas the genetic profile of sporadic DCM in Chinese patients remains unknown. METHODS: Between June 2018 and September 2019, 24 patients diagnosed with idiopathic DCM without a family history were included in the present study. All patients underwent genetic screening for 80 DCM-related genes using targeted next-generation sequencing. RESULTS: By in silico analysis, 10 of 99 detected variants were considered pathogenic or likely-pathogenic, including seven TTN truncating variants (TTNtv), one in-frame deletion in TNNT2, one missense mutation in RBM20, and one frameshift deletion variant in FLNC. Of these variants, eight are reported for the first time. CONCLUSIONS: Using targeted next-generation sequencing, potential genetic causes of idiopathic DCM were identified. Sarcomere mutations remained the most common genetic cause of inherited DCM in this cohort of sporadic Chinese DCM.

The association of lipoprotein(a) and intraplaque neovascularization in patients with carotid stenosis: a retrospective study.

BACKGROUND: Lipoprotein(a) is genetically determined and increasingly recognized as a major risk factor for arteriosclerotic cardiovascular disease. We examined whether plasma lipoprotein(a) concentrations were associated with intraplaque neovascularization (IPN) grade in patients with carotid stenosis and in terms of increasing plaque susceptibility to haemorrhage and rupture. METHODS: We included 85 patients diagnosed with carotid stenosis as confirmed using carotid ultrasound who were treated at Guangdong General Hospital. Baseline data, including demographics, comorbid conditions and carotid ultrasonography, were recorded. The IPN grade was determined using contrast-enhanced ultrasound through the movement of the microbubbles. Univariate and multivariate binary logistic regression analyses were used to evaluate the association between lipoprotein(a) and IPN grade, with stepwise adjustment for covariates including age, sex, comorbid conditions and statin therapy (model 1), total cholesterol, triglyceride, low-density lipoprotein cholesterol calculated by Friedwald's formula, high-density lipoprotein cholesterol, apolipoprotein A and apolipoprotein B (model 2), maximum plaque thickness and total carotid maximum plaque thickness, degree of carotid stenosis and internal carotid artery (ICA) occlusion (model 3). RESULTS: Lipoprotein(a) was a significant predictor of higher IPN grade in binary logistic regression before adjusting for other risk factors (odds ratio [OR] 1.238, 95% confidence interval [CI] (1.020, 1.503), P = 0.031). After adjusting for other risk factors, lipoprotein(a) still remained statistically significant in predicting IPN grade in all model. (Model 1: OR 1.333, 95% CI 1.074, 1.655, P = 0.009; Model 2: OR 1.321, 95% CI 1.059, 1.648, P = 0.014; Model 3: OR 1.305, 95% CI 1.045, 1.628, P = 0.019). Lp(a) ≥ 300 mg/L is also significantly related to IPN compare to < 300 mg/L (OR 2.828, 95% CI 1.055, 7.580, P = 0.039) as well as in model 1, while in model 2 and model 3 there are not significant difference. CONCLUSIONS: Plasma lipoprotein(a) concentrations were found to be independently associated with higher IPN grade in patients with carotid stenosis. Lowering plasma lipoprotein(a) levels may result in plaque stabilization by avoiding IPN formation.

The role of the plasma glycosylated hemoglobin A1c/Apolipoprotein A-l ratio in predicting cardiovascular outcomes in acute coronary syndrome.

BACKGROUND AND AIMS: Glucose and lipid metabolism are major prognostic indicators of coronary heart disease. The ratio of plasma glycosylated hemoglobin A1c (HbA1c) to apolipoprotein A-l (ApoA-l) is an indirect measure of insulin resistance. The study aimed to evaluate whether the HbA1c/ApoA-1 ratio can predict the prognosis in patients with the acute coronary syndrome (ACS). METHODS AND RESULTS: A total of 476 ACS patients diagnosed by coronary angiography were enrolled in this longitudinal, observational, retrospective study. Plasma HbA1c, fasting blood glucose and lipid profile were measured. Patients were stratified according to the tertiles of HbA1c/ApoA-l levels. Cox proportional hazard model was used to examine the predictive value of HbA1c/ApoA-l for study endpoints. The association between the Log HbA1c/ApoA-l ratio and major adverse cardiovascular events (MACEs) was estimated using multiple logistic regression. Baseline characteristics showed a mean age of 66 ± 8 years, and 52.5% were hypertensive, 26.8% diabetic, and 54.5% current or prior smokers. During a mean follow-up period of 22.3 ± 1.7 months, 59 deaths occurred. After adjusting for age, gender, smoking, hypertension, diabetes, and coronary artery disease severity, patients in the highest HbA1c/ApoA-l ratio tertile had a 4.36-fold increased risk of mortality compared with those in the lowest tertile. The multivariate logistic regression showed that the Log HbA1c/ApoA-l ratio was associated with MACEs (Odds ratio 2.95, p = 0.013). CONCLUSION: After adjusting for traditional cardiovascular risk factors and ACS severity scores, the HbA1c/ApoA-1 ratio remained an independent predictor of all-cause mortality and MACEs in the ACS patients undergoing angiography.

Picroside II alleviates liver injury induced by alpha-naphthylisothiocyanate through AMPK-FXR pathway.

Alpha-naphthylisothiocyanate (ANIT) is a typical hepatotoxicant that causes cholestasis, which causes toxic bile acid accumulation in the liver and leads to liver injury. Picroside II (PIC), one of the dominant effective components extracted from Picrorhiza scrophulariiflora Pennell, exhibits many pharmacological effects. However, the role of AMP-activated protein kinase (AMPK)-Farnesoid X receptor (FXR) pathway in the hepatoprotective effect of PIC against ANIT-induced cholestasis remains largely unknown. This study aimed to investigate the mechanisms of PIC on ANIT-induced cholestasis in vivo and in vitro. Our results showed that PIC protected against ANIT-induced liver injury in primary mouse hepatocytes, and decreased serum biochemical markers and lessened histological injuries in mice. ANIT inhibited FXR and its target genes of bile acid synthesis enzymes sterol-12α-hydroxylase (CYP8B1), and increase bile acid uptake transporter Na + -dependent taurocholate transporter (NTCP), efflux transporter bile salt export pump (BSEP) and bile acid metabolizing enzymes UDP-glucuronosyltransferase 1a1 (UGT1A1) expressions. PIC prevented its downregulation of FXR, NTCP, BSEP and UGT1A1, and further reduced CYP8B1 by ANIT. Furthermore, ANIT activated AMPK via ERK1/2-LKB1 pathway. PIC inhibited ERK1/2, LKB1 and AMPK phosphorylation in ANIT-induced cholestasis in vivo and in vitro. AICAR, an AMPK agonist, blocked PIC-mediated changes in FXR, CYP8B1 and BSEP expression in vitro. Meanwhile, U0126, an ERK1/2 inhibitor, further repressed ERK1/2-LKB1-AMPK pathway phosphorylation. In conclusion, PIC regulated bile acid-related transporters and enzymes to protect against ANIT-induced liver injury, which related to ERK1/2-LKB1-AMPK pathway. Thus, this study extends the understanding of the anti-cholestasis effect of PIC and provides new therapeutic targets for cholestasis treatment.