Genome-wide identification of bZIP transcription factors in 12 Rosaceae species and modeling of novel mechanisms of EjbZIPs response to salt stress.

In plantae, basic leucine zipper (bZIP) transcription factors (TFs) are widespread and regulate a variety of biological processes under abiotic stress. However, it has not been extensively studied in Rosaceae, and the functional effects of bZIP on Eriobotrya japonica under salt stress are still unknown. Therefore, in this study, the bZIP TF family of 12 species of Rosaceae was analyzed by bioinformatics method, and the expression profile and quantitative real-time polymerase chain reaction of E. japonica under salt stress were analyzed. The results showed that a total of 869 bZIP TFs were identified in 12 species of Rosaceae and divided into nine subfamilies. Differences in promoter cis-elements between subfamilies vary depending on their role. Species belonging to the same subfamily have a similar number of chromosomes and the number of genes contained on each chromosome. Gene duplication analysis has found segmental duplication to be a prime force in the evolution of Rosaceae species. In addition, nine EjbZIPs were significantly different, including seven up-regulated and two down-regulated in E. japonica under salt stress. Especially, EjbZIP13 was involved in the expression of SA-responsive proteins by binding to the NPR1 gene. EjbZIP27, EjbZIP30, and EjbZIP38 were highly expressed in E. japonica under salt stress, thus improving the salt tolerance capacity of the plants. These results can provide a theoretical basis for exploring the characteristics and functions of the bZIP TF family in more species and breeding salt-tolerant E. japonica varieties. It also provides a reference for resolving the response mechanism of bZIP TF in 12 Rosaceae species under salt stress.

Genome-wide identification and expression analysis of the Eriobotrya japonica TIFY gene family reveals its functional diversity under abiotic stress conditions.

BACKGROUND: Plant-specific TIFY proteins are widely found in terrestrial plants and play important roles in plant adversity responses. Although the genome of loquat at the chromosome level has been published, studies on the TIFY family in loquat are lacking. Therefore, the EjTIFY gene family was bioinformatically analyzed by constructing a phylogenetic tree, chromosomal localization, gene structure, and adversity expression profiling in this study. RESULTS: Twenty-six EjTIFY genes were identified and categorized into four subfamilies (ZML, JAZ, PPD, and TIFY) based on their structural domains. Twenty-four EjTIFY genes were irregularly distributed on 11 of the 17 chromosomes, and the remaining two genes were distributed in fragments. We identified 15 covariate TIFY gene pairs in the loquat genome, 13 of which were involved in large-scale interchromosomal segmental duplication events, and two of which were involved in tandem duplication events. Many abiotic stress cis-elements were widely present in the promoter region. Analysis of the Ka/Ks ratio showed that the paralogous homologs of the EjTIFY family were mainly subjected to purifying selection. Analysis of the RNA-seq data revealed that a total of five differentially expressed genes (DEGs) were expressed in the shoots under gibberellin treatment, whereas only one gene was significantly differentially expressed in the leaves; under both low-temperature and high-temperature stresses, there were significantly differentially expressed genes, and the EjJAZ15 gene was significantly upregulated under both low- and high-temperature stress. RNA-seq and qRT-PCR expression analysis under salt stress conditions revealed that EjJAZ2, EjJAZ4, and EjJAZ9 responded to salt stress in loquat plants, which promoted resistance to salt stress through the JA pathway. The response model of the TIFY genes in the jasmonic acid pathway under salt stress in loquat was systematically summarized. CONCLUSIONS: These results provide a theoretical basis for exploring the characteristics and functions of additional EjTIFY genes in the future. This study also provides a theoretical basis for further research on breeding for salt stress resistance in loquat. RT-qPCR analysis revealed that the expression of one of the three EjTIFY genes increased and the expression of two decreased under salt stress conditions, suggesting that EjTIFY exhibited different expression patterns under salt stress conditions.

IL-37 ameliorates myocardial fibrosis by regulating mtDNA-enriched vesicle release in diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.

Characteristics, predictors and outcomes of new-onset QT prolongation in sepsis: a multicenter retrospective study.

BACKGROUND: Sepsis-induced myocardial injury is a serious complication of sepsis. QT prolongation is a proarrhythmic state which reflects myocardial injury in a group of heterogeneous disorders. However, the study on the clinical value of QT prolongation in sepsis is limited. METHODS: We aimed to investigate the clinical characteristics and predictors of new-onset QT prolongation in sepsis and its impact on the outcome in a multicenter retrospective cohort study. Electrocardiographic and clinical data were collected from patients with sepsis from the wards and intensive care units of four centers after exclusion of QT-influencing medications and electrolyte abnormalities. Clinical outcomes were compared between patients with and without QT prolongation (QTc > 450 ms). Multivariate analysis was performed to ascertain whether QT prolongation was an independent predictor for 30-day mortality. The factors predicting QT prolongation in sepsis were also analyzed. RESULTS: New-onset QT prolongation occurred in 235/1024 (22.9%) patients. The majority demonstrated similar pattern as type 1 long QT syndrome. Patients with QT prolongation had a higher 30-day in-hospital mortality (P < 0.001), which was also associated with increased tachyarrhythmias including paroxysmal atrial fibrillation or tachycardia (P < 0.001) and ventricular arrhythmia (P < 0.001) during hospitalization. QT prolongation independently predicted 30-day mortality (P = 0.044) after multivariate analysis. History of coronary artery disease (P = 0.001), septic shock (P = 0.008), acute respiratory (P < 0.001), heart (P = 0.021) and renal dysfunction (P = 0.013) were independent predictors of QT prolongation in sepsis. CONCLUSIONS: New-onset QT prolongation in sepsis was associated with increased mortality as well as atrial and ventricular arrhythmias, which was predicted by disease severity and organ dysfunction.

Orthodromic Reciprocating Tachycardia Relying on Aberrant Conduction: The Need for a Larger Circuit.

Aberrant conduction during orthodromic reciprocating tachycardia (ORT) prolongs the ventriculoatrial conduction time, which can be essential for the maintenance of tachycardia in specific cases. We searched for ORT relying on aberrancy among 220 cases in our center. Three patients showed the phenomenon of aberrancy-dependent ORT. All accessory pathways were located at the lateral regions of the atrioventricular annulus. None of them had a baseline bundle branch block (BBB). Creating a functional BBB was necessary to induce the tachycardias. In two cases, termination of tachycardias was directly associated with resolution of the aberration. In the other case, re-entry required both BBB and slow pathway conduction. We conclude that extra transseptal time caused by aberrancy can be an integral part of the ORT circuit, which explains the infrequent and unsustainable episodes of ORT in certain patients and is useful in understanding the circuit and localizing the pathway.

Acute epicardial pulmonary vein reconnection: Nondurable transmural lesion or late manifestation of conduction through intercaval bundle.

INTRODUCTION: Acute pulmonary vein reconnection (PVR) via epicardial fibers can be found during observation period after PV isolation, the characteristics and related factors have not been fully studied. We aimed to investigate the prevalence, locations, electrogram characteristics, and ablation parameters related to acute epicardial pulmonary vein reconnection (AEPVR). METHODS: Acute PVR was monitored during observation period after PV isolation. AEPVRs were mapped and distinguished from endocardial conduction gaps. The clinical, electrophysiological characteristics and lesion set parameters were compared between patients with and without PVR. They were also compared among AEPVR, gap-related reconnection, and epicardial PVR in repeat procedures. RESULTS: A total of 56.1% acute PVR were AEPVR, which required a longer waiting period (p < .001) than endocardial gap. The majority of AEPVR were connections from the posterior PV carina to the left atrial posterior wall, followed by late manifestation of intercaval bundle conduction from the right anterior carina to right atrium. AEPVR was similar to epicardial PVR in redo procedures in distribution and electrogram characteristics. Smaller atrium (p < .001), lower impedance drop (p = .039), and ablation index (p = .028) on the posterior wall were independently associated with presence of AEPVR, while lower interlesion distance (p = .043) was the only predictor for AEPVR in acute PVR. An integrated model containing multiple lesion set parameters had the highest predictive ability for AEPVR in receiver operating characteristics analysis. CONCLUSIONS: Epicardial reconduction accounted for the majority of acute PVR. AEPVR was associated with anatomic characteristics and multiple ablation-related parameters, which could be explained by nondurable transmural lesion or late manifestation of conduction through intercaval bundle.

Analysis of spatiotemporal variations and influencing factors of soil erosion in the Jiangnan Hills red soil zone, China.

Soil erosion is an important environmental problem in China. The hilly region of Jiangnan is characterized by severe soil erosion due to its unique climate and intensive human activities. Therefore, assessing soil erosion in this area is of great significance for achieving regional sustainable development. Based on the spatial zoning of natural resources and the spatial differences in precipitation, land cover, topographic features, and soil texture, we estimated soil erosion from 2000 to 2020 using the Revised Universal Soil Loss Equation (RUSLE) model. The study showed that micro-erosion dominates spatially in the subtropical forest subzone of the eastern hills, accounting for more than 60% of the total erosion area. Intense erosion was found in woodlands and grasslands and the erosion intensity tended to be lower in the plains. Erosion occurred mainly in areas with slopes >8°. The areas with significantly lower erosion were mainly distributed at the boundaries between forests, arable land, and artificial land surfaces. The areas where soil erosion significantly increased over the study period were mainly found in farmland areas (31.70%). Soil erosion occurred because of a combination of factors, among which vegetation cover played a prominent role. Elevation and slope were correlated with soil erosion intensity. Severe erosion in different parts of the study area showed two trends of spatial aggregation and discrete distribution. This analysis of soil erosion in the study area by the RUSLE model provides reference data for the eastern subtropical forest subregion including the Jiangnan Hills.

Sugar intake and risk of hypertension: a systematic review and dose-response meta-analysis of cohort and cross-sectional studies.

Several epidemiological studies have investigated the association between sugar intake, the levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the risk of hypertension, but findings have been inconsistent. We carried out a systematic review and meta-analysis of observational studies to examine the associations between sugar intake, hypertension risk, and BP levels. Articles published up to February 2, 2021 were sourced through PubMed, EMBASE and Web of Science. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a fixed- or random-effects model. Restricted cubic splines were used to evaluate dose-response associations. Overall, 35 studies were included in the present meta-analysis (23 for hypertension and 12 for BP). Sugar-sweetened beverages (SSBs) and artificially sweetened beverages (ASBs) were positively associated with hypertension risk: 1.26 (95% CI, 1.15-1.37) and 1.10 (1.07-1.13) per 250-g/day increment, respectively. For SBP, only SSBs were significant with a pooled ß value of 0.24 mmHg (95% CI, 0.12-0.36) per 250 g increase. Fructose, sucrose, and added sugar, however, were shown to be associated with elevated DBP with 0.83 mmHg (0.07-1.59), 1.10 mmHg (0.12-2.08), and 5.15 mmHg (0.09-10.21), respectively. Current evidence supports the harmful effects of sugar intake for hypertension and BP level, especially SSBs, ASBs, and total sugar intake.

IL-37 Attenuates Platelet Activation and Thrombosis Through IL-1R8 Pathway.

BACKGROUND: IL-37 (interleukin-37), a natural suppressor of innate inflammatory and immune responses, is increased in patients with myocardial infarction. Platelets play an important role in the progress of myocardial infarction, but the direct effects of IL-37 on platelet activation and thrombosis, as well as the underlying mechanisms, still remain unclear. METHODS: We evaluated the direct effects of IL-37 on agonists-induced platelet activation and thrombus formation, as well as revealed the underlying mechanisms using platelet-specific IL-1R8 (IL-1 receptor 8)-deficient mice. Using myocardial infarct model, we explored the effects of IL-37 on microvascular obstruction and myocardial injury. RESULTS: IL-37 directly inhibited agonists-induced platelet aggregation, dense granule ATP release, P-selectin exposure, integrin αIIbß3 activation, platelet spreading, and clot retraction. IL-37 inhibited thrombus formation in vivo in a FeCl3-injured mesenteric arteriole thrombosis mouse model and ex vivo in a microfluidic whole-blood perfusion assay. Mechanistic studies using platelet-specific IL-1R8-deficient mice revealed that IL-37 bound to platelet IL-1R8 and IL-18Rα, and IL-1R8 deficiency impaired the inhibitory effects of IL-37 on platelet activation. Using PTEN (phosphatase and tensin homolog)-specific inhibitor and PTEN-deficient platelets, we found that IL-37 combined with IL-1R8 to enhance PTEN activity, inhibit Akt (protein kinase B), mitogen-activated protein kinases, and spleen tyrosine kinase pathways, as well as decrease the generation of reactive oxygen species to regulate platelet activation. Exogenous IL-37 injection suppressed microvascular thrombosis to protect against myocardial injury in wild-type mice but not in platelet-specific IL-1R8-deficient mice after permanent ligation of the left anterior descending coronary. Finally, a negative correlation between plasma IL-37 concentration and platelet aggregation was observed in patients with myocardial infarction. CONCLUSIONS: IL-37 directly attenuated platelet activation, thrombus formation, and myocardial injury via IL-1R8 receptor. Accumulated IL-37 in plasma inhibited platelet activation to ameliorate atherothrombosis and infarction expansion, and thus may have therapeutic advantages as potential antiplatelet drugs.

Subclinical cardiac involvement present as electrocardiographic abnormalities in various neuromuscular diseases.

Background: Cardiac involvement is commonly present in various neuromuscular diseases which may develop life-threatening consequences. The early manifestation is often asymptomatic which however has been insufficiently studied. Objectives: We aim to characterize electrocardiographic (ECG) changes in neuromuscular diseases without cardiac symptoms. Methods: Adults having genetically and/or pathologically confirmed type 1 myotonic dystrophy (DM1), Becker muscular dystrophy (BMD), limb girdle muscular dystrophies (LGMDs) and mitochondrial diseases (MtDs) but without history of heart diseases and cardiovascular symptoms were enrolled. The 12-lead ECG characteristics and other test results at diagnosis were retrieved and analyzed. Results: 196 patients with neuromuscular diseases (44 DM1, 25 BMD, 82 LGMDs, 45 MtDs) were consecutively enrolled. ECG abnormalities were identified in 107 (54.6%) patients with a prevalence of 59.1% in DM1, 76.0% in BMD, 40.2% in LGMDs and 64.4% in MtDs. Conduction block was more commonly present in DM1 than the other groups (P < 0.01), which had a longest PR interval and QRS duration of 186.1 ± 38.3 ms and 104.2 [90.0-108.0]ms, respectively. QT prolongation was most frequently seen in DM1 (P < 0.001). Left ventricular hypertrophy features were found in BMD, LGMDs and MtDs (P < 0.05) without intergroup difference, while a significantly higher right ventricular amplitude is observed in BMD than in other groups (P < 0.001). Conclusions: Subclinical cardiac involvement is commonly present as ECG abnormalities in multiple adult neuromuscular diseases before associated symptoms occur and show diversity in different groups.

All-cause mortality risk with different metabolic abdominal obesity phenotypes: the Rural Chinese Cohort Study.

We aimed to investigate the association of metabolic obesity phenotypes with all-cause mortality risk in a rural Chinese population. This prospective cohort study enrolled 15 704 Chinese adults (38·86 % men) with a median age of 51·00 (interquartile range: 41·00-60·00) at baseline (2007-2008) and followed up during 2013-2014. Obesity was defined by waist circumference (WC: ≥ 90 cm for men and ≥ 80 cm for women) or waist-to-height ratio (WHtR: ≥ 0·5). The hazard ratio (HR) and 95 % CI for the risk of all-cause mortality related to metabolic obesity phenotypes were calculated using the Cox hazards regression model. During a median follow-up of 6·01 years, 864 deaths were identified. When obesity was defined by WC, the prevalence of participants with metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO) and metabolically unhealthy obesity (MUO) at baseline was 12·12 %, 2·80 %, 41·93 % and 43·15 %, respectively. After adjusting for age, sex, alcohol drinking, smoking, physical activity and education, the risk of all-cause mortality was higher with both MUNO (HR = 1·20, 95 % CI 1·14, 1·26) and MUO (HR = 1·20, 95 % CI 1·13, 1·27) v. MHNO, but the risk was not statistically significant with MHO (HR = 0·99, 95 % CI 0·89, 1·10). This result remained consistent when stratified by sex. Defining obesity by WHtR gave similar results. MHO does not suggest a greater risk of all-cause mortality compared to MHNO, but participants with metabolic abnormality, with or without obesity, have a higher risk of all-cause mortality. These results should be cautiously interpreted as the representation of MHO is small.

Air pollution exposure and heart failure: A systematic review and meta-analysis.

While the literature strongly supports a positive association between particulate matter with diameter ≤ 2.5 µm (PM2.5) exposure and heart failure (HF), there is uncertainty regarding the other pollutants and the dose and duration of exposure that triggers an adverse response. To comprehensively assess and quantify the association of air pollution exposure with HF incidence and mortality, we performed separate meta-analyses according to pollutant types [PM2.5, PM10, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3)], and exposure duration (short- and long-term). We systematically searched PubMed, EMBASE, and Web of Science for relevant articles with publication dates up to July 12, 2022, identifying 35 eligible studies. Random-effects models were used to summarize the pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs). For long-term exposure, the growing risk of HF was significantly associated with each 10 µg/m3 increase in PM2.5 (OR = 1.196, 95 % CI: 1.079-1.326; I2 = 76.8 %), PM10 (1.190, 1.045-1.356; I2 = 76.2 %), and NO2 (1.072, 1.028-1.118; I2 = 78.3 %). For short-term exposure, PM2.5, PM10, NO2, and O3 (per 10 µg/m3 increment) increased the risk of HF, with estimated ORs of 1.019 (1.008-1.030; I2 = 39.9 %), 1.012 (1.007-1.017; I2 = 28.3 %), 1.016 (1.005-1.026; I2 = 53.7 %), and 1.006 (1.002-1.010; I2 = 0.0 %), respectively. No significant effects of SO2 and CO exposure on the risk of HF were observed. In summary, our study powerfully highlights the deleterious impact of PM2.5, PM10, and NO2 exposure (either short- or long-term) on HF risk. Serious efforts should be made to improve air quality through legislation and interdisciplinary cooperation.

A Bio-Liposome Activating Natural Killer Cell by Illuminating Tumor Homogenization Antigen Properties.

Natural killer (NK) cell therapies, primarily based on chimeric antigen receptor NK cells (CAR-NK), have been developed and applied clinically for therapeutic treatment of patients with mid-to-late-stage tumors. However, NK cell therapy has limited efficacy due to insufficient antigen expression on the tumor cell surface. Here, a universal "illuminate tumor homogenization antigen properties" (ITHAP) strategy to achieve stable and controlled antigen expression on the surface of tumor cells using nanomedicine, thus significantly enhancing the immune recognizability of tumor cells, is described. The ITHAP strategy is used to generate bio-liposomes (Pt@PL-IgG) composed of intermingled platelet membranes and liposomes with NK-activatable target antigen (IgG antibodies) and cisplatin pre-drug. It is demonstrated that Pt@PL-IgG successfully targets tumor cells using the autonomous drive of platelet membranes and achieves IgG implantation on tumor cells by utilizing membrane fusion properties. Moreover, it is shown that the Pt-DNA complex combined with NK cell-induced pyroptosis causes substantial interferon (IFN) secretion, thus providing a synthase-stimulator of interferon genes (STING)-IFN-mediated positive immune microenvironment to further potentiate NK therapy. These results show that anchoring cancer cells with NK-activatable target antigens is a promising translational strategy for addressing therapeutic challenges in tumor heterogeneity.

Identifying the culprit artery via 12-lead electrocardiogram in inferior wall ST-segment elevation myocardial infarction: A meta-analysis.

BACKGROUND: Inferior wall ST-segment elevation myocardial infarction (STEMI) is mostly caused by acute occlusion of right coronary artery (RCA) and left circumflex artery (LCX). Several methods and algorithms using 12-lead ECG were developed to localize the lesion in inferior wall STEMI. However, the diagnostic properties of these methods remain under-recognized. AIMS: The aim of this meta-analysis is to compare the diagnostic properties among the methods of identifying culprit artery in inferior wall STEMI using 12-lead ECG. METHODS: We performed a meta-analysis to calculate the pooled sensitive, specificity, area under the curve (AUC) and diagnostic odds ratio (DOR) of each method. RESULTS: Thirty-three studies with 4414 participants were included in the analysis. Methods using double leads had better diagnostic properties, especially ST-segment elevation (STE) in III > II [with pooled sensitivity 0.89 (0.84-0.93), specificity 0.68 (0.57-0.79), DOR 17 (9-32), AUC 0.88 (0.85-0.91)], ST-segment depression (STD) in aVL > I [with pooled sensitivity 0.82 (0.72-0.90), specificity 0.69 (0.48-0.86), DOR 11 (4-29), AUC 0.85 (0.81-0.88)], and STD V3/STE III ≤1.2 [with pooled sensitivity 0.88 (0.78-0.95), specificity 0.59 (0.42-0.75), DOR 12 (5-27), AUC 0.82 (0.78-0.85)]. Diagnostic algorithms, including Jim score[pooled sensitivity 0.70 (0.55-0.85), specificity 0.88 (0.75-0.96)], Fiol's algorithm [pooled sensitivity 0.54 (0.44-0.62), specificity 0.92 (0.88-0.96)] and Tierala's algorithm [pooled sensitivity 0.60 (0.49-0.71), specificity 0.91 (0.86-0.96)], were not superior to these simple methods. CONCLUSIONS: Our meta-analysis indicated that diagnostic methods using double leads had better properties. STE in III > II together with STD in aVL > I may be the most ideal method, for its accuracy and convenience.

Consumption of Dairy Products and the Risk of Overweight or Obesity, Hypertension, and Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis and Systematic Review of Cohort Studies.

Dairy products have been suggested to be related to the prevention of overweight or obesity, hypertension, and type 2 diabetes mellitus (T2DM). These associations are currently controversial, however, and a systematic quantitative meta-analysis is lacking. In this study, we examined the associations between dairy products and the risk of overweight or obesity, hypertension, and T2DM and tested for dose-response relations. We comprehensively searched PubMed, Embase, and Web of Science up to April 2021. Cohort studies were included if dairy food consumption was reported at a minimum of 3 levels or as continuous variables, and the associations were assessed with overweight or obesity, hypertension, and T2DM. Summary RRs and 95% CIs were estimated for the dose-response association. Restricted cubic splines were used to evaluate the linear or nonlinear relations. Among the 9887 articles retrieved, 42 articles were included. For overweight or obesity, a linear association was observed for total dairy, milk, and yogurt. The risk decreased by 25%, 7%, and 12% per 200-g/d increase for total dairy, high-fat dairy, and milk, respectively, and by 13% per 50-g/d increment of yogurt. For hypertension, a nonlinear association was observed with total dairy, whereas significant inverse associations were found for low-fat dairy (RR: 0.94; 95% CI: 0.90, 0.98) and milk (RR: 0.94; 95% CI: 0.92, 0.97) per 200-g/d intake increase. For T2DM, all types of dairy food consumption except for milk and low-fat dairy products showed nonlinear associations, with total dairy and yogurt intake associated with 3% and 7% lower risk per 200-g/d and 50-g/d intake increase, respectively. In conclusion, our study suggests that total dairy is associated with a low risk of overweight or obesity, hypertension, and T2DM, especially milk and yogurt for overweight or obesity, low-fat dairy and milk for hypertension, and yogurt for T2DM.

Nr2f2 Overexpression Aggravates Ferroptosis and Mitochondrial Dysfunction by Regulating the PGC-1α Signaling in Diabetes-Induced Heart Failure Mice.

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.

Anatomy-based characteristics of far-field SVC electrograms in right superior pulmonary veins after isolation.

Background. Far-field electrograms from superior vena cava (SVC) can be present in right superior pulmonary vein (RSPV) after pulmonary vein (PV) isolation. Objectives. To analyze the characteristics of far-field SVC potentials in RSPV after PV isolation and the local anatomy difference between patients with and without the potentials. Methods. Patients undergoing PV isolation were retrospectively reviewed, contrast-enhanced computed tomography (CT) was performed before procedure for observing the anatomical relationship between RSPV and SVC. The prevalence and characteristics of far-field SVC electrograms were described and compared to far-field left atrial potentials at the nearest point along the linear ablation lesion. The anatomical proximity of RSPV and SVC on a 2-dimensional horizontal CT view was compared between patients with and without far-field SVC potentials. Results. Far-field SVC electrograms were observed in 35/92(38%) patients with an amplitude of 0.24 ± 0.11 mV and a major deflection slope of 0.051 ± 0.036 mV, both significantly higher than far-field left atrial electrograms (p < .001). In patients with far-field SVC electrograms, 83% had connected RSPV-SVC, defined as distance between RSPV and SVC endocardium less than 3 mm at the layer of RSPV ostium roof, while in patients without far-field SVC electrograms, 70% had disconnected RSPV-SVC. Conclusions. Far-field SVC electrograms appeared in RSPV had a prevalence higher than previously reported and a sharper major deflection compared to far-field left atrial electrograms. Connected RSPV-SVC on CT was associated with the presence of far-field SVC electrograms.

Transcriptome and carotenoid profiling of different varieties of Coffea arabica provides insights into fruit color formation.

The processability and ultimate quality of coffee (C offea arabica) are determined by the composition of the matured fruits. The basis of genetic variation in coffee fruit quality could be explained by studying color formation during fruit maturation. Transcriptome profiling was conducted on matured fruits of four C. arabica varieties (orange colored fruits (ORF); purple colored fruits (PF); red colored fruits (RF) and yellow colored fruits (YF)) to identify key color-regulating genes, biosynthesis pathways and transcription factors implicated in fruit color formation. A total of 39,938 genes were identified in the transcriptomes of the four C. arabica varieties. In all, 2745, 781 and 1224 differentially expressed genes (DEGs) were detected in YF_vs_PF, YF_vs_RF and YF_vs_ORF, respectively, with 1732 DEGs conserved among the three pairwise groups. Functional annotation of the DEGs led to the detection of 28 and 82 key genes involved in the biosynthesis of carotenoids and anthocyanins, respectively. Key transcription factors bHLH, MYB, NAC, MADS, and WRKY implicated in fruit color regulation were detected. The high expression levels of gene-LOC113688784 (PSY), gene-LOC113730013 (ß-CHY), gene-LOC113728842 (CCD7), gene-LOC113689681 (NCED) and gene-LOC113729473 (ABA2) in YF may have accounted for the yellow coloration. The differential expression of several anthocyanin and carotenoid-specific genes in the fruits substantially account for the purple (PF), red (RF), and orange (ORF) colorations. This study provides important insights into fruit color formation and variations in C. arabica and will help to develop coffee varieties with specific color and quality traits.

Synergetic regulation of kupffer cells, extracellular matrix and hepatic stellate cells with versatile CXCR4-inhibiting nanocomplex for magnified therapy in liver fibrosis.

Hepatic stellate cell (HSC)-targeted delivery is an attractive strategy for liver fibrosis therapy, but the efficacy is hampered by poor delivery of nanomaterials and complicated microenvironments of the fibrotic liver. Here, we report a versatile CXCR4-inhibiting nanocomplex composed of polymeric CXCR4 antagonism (PAMD, PA), CLD (clodronate) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) that surmounts multiple barriers to improve the outcome by co-regulating Kupffer cells (KCs), extracellular matrix (ECM) and HSCs. Upon encountering biological barriers, the nanocomplex exerted penetrating and targeting functions, efficiently overcoming KCs capture, ECM trapping and nonspecific recognition of HSCs, finally contributing to the enhanced HSCs uptake. Moreover, an enlarged antifibrotic activity is realized through synergetic regulation of KCs apoptosis, ECM degradation and HSCs inactivation. Overall, such a versatile nanocomplex provides a framework for designing HSC-targeted delivery system and has valuable potential as a novel antifibrotic strategy.

Cilostazol combined with P2Y12 receptor inhibitors: A substitute antiplatelet regimen for aspirin-intolerant patients undergoing percutaneous coronary stent implantation.

BACKGROUND: Cilostazol combined with P2Y12 receptor inhibitor has been used as a substitute regimen for aspirin-intolerant patients undergoing percutaneous coronary stent implantation on a small scale. Its exact impact on platelet functions and clinical benefits of aspirin-intolerant patients is unknown. HYPOTHESIS: Cilostazol combined with P2Y12 receptor inhibitors could be used as a substitute antiplatelet regimen for aspirin-intolerant patients undergoing percutaneous coronary stent implantation. METHODS: In this multicenter prospective cohort trial, patients undergoing elective percutaneous coronary stent implantation were assigned to the cilostazol group (cilostazol plus P2Y12 receptor inhibitors), based on aspirin intolerance criteria, or the aspirin group (aspirin plus P2Y12 receptor inhibitors). Platelet PAC-1, CD62p, and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) were detected by flow cytometry. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) including all-cause death, acute myocardial infarction, emerging arrhythmia, nonfatal stroke, and heart failure. The secondary endpoints were the Bleeding Academic Research Consortium (BARC) bleeding events. RESULTS: One hundred and fifty-four aspirin-intolerant percutaneous coronary stent implantation patients and 154 matched aspirin-tolerant patients from a total of 2059 percutaneous coronary stent implantation patients were enrolled. The relative activation level of PAC-1, CD62p, and platelet reaction index reflected by the VASP-P test were similar in the two groups (p > .05). After 12 months of follow-up, the incidence of all-cause death was 1.9% in the cilostazol group and 1.3% in the aspirin group (risk ratio [RR], 1.500; 95% confidence interval [CI], 0.254-8.852; p = 1.000); the incidence of acute myocardial infarction was 0.6% in the cilostazol group and 1.3% in the aspirin group (RR, 0.500; 95% CI, 0.046-5.457; p = 1.000). No significant difference was seen in other MACCE events, or in any types of BARC bleeding events. CONCLUSIONS: Cilostazol combined with P2Y12 inhibitors was not inferior to aspirin-based standard therapy and could be used as a reasonable substitute antiplatelet regimen for aspirin-intolerant patients undergoing percutaneous coronary stent implantation, but again with limitations, which required a larger sample and longer follow-up to confirm its efficacy.