Search

The magnitude of the risk of metabolic syndrome (MetS) with increased resting heart rate (RHR) has been inconsistently reported in some observational studies, and whether a dose-response relationship exists between RHR and MetS is unclear. We performed a meta-analysis including dose-response analysis to quantitatively evaluate this association in adults. We searched PubMed, Web of Knowledge, China National Knowledge Infrastructure, and WanFang databases for articles published up to April 2, 2016. A random-effects model was used to pool relative risks (RRs) and 95% confidence intervals (CIs); restricted cubic spline function was used to assess the dose-response relationship. Seven prospective cohort studies and 10 cross-sectional studies with a total of 169,786 participants were included. The pooled RR was 2.10 (95% CI 1.80-2.46, I = 79.8%, n = 13) for the highest versus reference RHR category and 1.28 (95% CI 1.23-1.34, I = 87.7%, n = 15) for each 10 beats per minute (bpm) increment in RHR. We found no evidence of a nonlinear dose-response association between RHR and MetS ( P = 0.201). The relationship was consistent in most subgroup analyses and robust on sensitivity analysis. No significant publication bias was observed. This meta-analysis suggests that risk of MetS may be increased with elevated RHR. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: Advanced glycation end products (AGEs) accumulate in diabetes and the engagement of receptor for AGE (RAGE) by AGEs contributes to the pathogenesis of diabetic cardiomyopathy. This study aims to investigate the effects of AGE/RAGE on ryanodine receptor (RyR) activity and Ca2+ handling in cardiomyocytes to elucidate the possible mechanism underlying cardiac dysfunction in diabetic cardiomypathy. Methods and Results: Confocal imaging Ca2+ spark, the elementary Ca2+ release event reflecting RyR activity in intact cell, as well as SR Ca2+ content and systolic Ca2+ transient were performed in cultured neonatal rat ventricular myocytes. The results show that 50 mg/ml AGE increased the frequency of Ca2+ sparks by 160%, while 150 mg/ml AGE increased it by 53%. AGE decreased the amplitude, width and duration of Ca2+ sparks. Blocking RAGE with anti-RAGE IgG completely abolished the alteration of Ca2+ sparks. The SR Ca2+ content indicated by the amplitude (ΔF/F0) of 20 mM caffeine-elicited Ca2+ transient was significantly decreased by 150 mg/ml AGE. In parallel, the amplitude of systolic Ca2+ transient evoked by 1 Hz-field stimulation was remarkably decreased by 150 mg/ml AGE. The anti-RAGE antibody completely restored the impaired SR load and systolic Ca2+ transient. Conclusion: AGE/RAGE signal enhanced Ca2+ spark-mediated SR Ca2+ leak, causing partial depletion of SR Ca2+ content and consequently decreasing systolic Ca2+ transient, which may contribute to contractile dysfunction in diabetic cardiomyopathy. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Tissue factor pathway inhibitor-2 (TFPI-2) is a member of the Kunitz-type family of serine protease inhibitors, which inhibits several matrix metalloproteinases activity involved in extracellular matrix degradation. Studies have shown low TFPI-2 expression in the shoulder regions of atherosclerotic plaques. But studies evaluating its role in the progression of atherosclerotic plaque are scarce. Vascular smooth muscle cells (VSMCs) are important components of atherosclerotic plaques and oxidized low density lipoprotein (ox-LDL) is an important detrimental factor of atherosclerosis. The aim of this study is to elucidate the effect of TFPI-2 on smooth muscle cell proliferation and migration induced by ox-LDL. Methods: Retroviruses expressing human TFPI-2 were constructed. Cell proliferation was determined by CCK-8 assay. Cell apoptosis was analyzed by double staining of FITC-Annexin V and propidium iodide. Cell migration was studied through a Transwell chamber and with a scratch-wound assay. The matrix metalloproteinase-2 and −9 activities were analyzed by gelatin zymography. Phosphorylation of FAK was analyzed by western blot. Results: TFPI-2 over-expression of mRNA and protein was confirmed in infected cells. CCK-8 assay showed that TFPI-2 inhibit VSMCs proliferation induced by ox-LDL while without cytotoxicity to VSMCs. Transwell and scratch wound assay confirmed TFPI-2 over-expression can inhibit VSMC migration. Zymography assay showed that TFPI-2 can inhibit MMP-2, 9 activity induced by ox-LDL. Western blot assay showed TFPI-2 can inhibit cyclinD1 expression and FAK phosphorylation. Conclusion: TFPI-2 over-expression may strongly inhibit the proliferation and migration of VSMCs and suppresses MMP-2, 9 activity induced by ox-LDL, making it a promising candidate for treatment of atherosclerotic process. [Copyright &y& Elsevier]

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 β 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. [ABSTRACT FROM AUTHOR]

The treatment options of liver fibrosis remain limited except for liver transplantation due to the complexity and slow development in its progression. Besides, liver fibrosis recurrence and intervention time have not been reported as significant indicators to affect the anti-fibrotic efficacy of tested drugs/strategies. Herein, a novel fluoropolymer is developed to achieve high drug loading of sorafenib and efficient delivery of miR155 inhibitor (anti-miR155) for dual-targeting of hepatic stellate cells (HSCs) and kupffer cells (KCs), and we report a detailed plan on the design of treatment regimen to reveal the relationship between chemogene therapy, intervention time and fibrosis recurrence. Such a combined chemo-gene therapy of sorafenib and anti-miR155 can achieve superior therapeutic efficiency by polarizing the pro-inflammatory M1 to anti-inflammatory M2 of KCs and inhibiting the proliferation of HSCs. Importantly, efficacy and recurrence prevention of chemogene therapy earlier in the liver fibrosis will be more effective than the treatment at later stage. In conclusion, this work proposes a novel strategy to improve the efficacy and prevent recurrence of liver fibrosis by dual-regulating of KCs and HSCs, and emphasizes the importance of therapy earlier in the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Introduction: Accessory pathway potential often indicates a highly effective ablation target in Wolff‐Parkinson‐White syndrome. Methods: A 27‐year‐old female presenting with palpitation underwent an electrophysiology study, who had mild pre‐excitation in surface ECG. Results: An accessory pathway with weak anterograde conduction was found. During isoproterenol infusion, the delta wave became prominent, an antidromic AV reentrant tachycardia was then induced. When the pathway was mapped, widely split double pathway potentials were observed at the 12 o'clock site of the tricuspid annulus during mild pre‐excitation, demonstrating an example of intra‐pathway conduction delay. Ablation at the site caused accelerated pathway rhythm and eliminated the pathway, rendering the tachycardia noninducible. Conclusion: Split pathway potentials can reflect slow conduction in patients with preexcitation. [ABSTRACT FROM AUTHOR]

Background and aims: Seed dormancy-break via cold stratification is of fundamental importance for plant adaptation to environmental conditions and response to climate change through timing germination, seedling emergence and consequently community dynamics. Although cold stratification requirements for dormancy break vary among species, it is not known if this variation is determined by the environmental conditions experienced by seeds or by differences among species. Methods: We determined the soil moisture content and duration of cold stratification required for seed dormancy-break of species from alpine and desert habitats (soil moisture content: 20 and 18 species from alpine and desert habitats, respectively; duration: 16 and 16 species from the alpine and desert, respectively), and examined the correlation between environmental conditions (soil moisture content and duration of cold stratification) required for dormancy-break and seed traits. Results: Seed germination increased and then decreased as soil moisture content or duration of cold stratification increased. The optimal and critical soil moisture content for seed dormancy-break were higher for alpine species than desert species. A positive correlation between optimal soil moisture content and seed shape was found. However, the duration of cold stratification required for dormancy-break was not related to habitat, seed mass or seed shape. Conclusions: Our results suggest that soil moisture content rather than duration of cold stratification resulting from climate change could affect seed germination and consequently seedling emergence and establishment, especially for desert species. [ABSTRACT FROM AUTHOR]

The distribution of forest-dominant tree species is crucial for ecosystem assessment. Remote sensing monitoring requires annual ground sample data, but consistent field surveys are challenging. This study addresses this by combining sample migration learning and machine learning for multi-year tree species classification in the Three Gorges Reservoir area in China. Using the continuous change detection and classification (CCDC) algorithm, sample data from 2023 were successfully migrated to 2018–2022, achieving high migration accuracy ( R 2 = 0.8303, RMSE = 4.64). Based on migrated samples, random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGB) algorithms classified forest tree species with overall accuracies above 70% and Kappa coefficients above 0.6. XGB. They outperformed other algorithms, with classification accuracy of over 80% and Kappa above 0.75 in almost all years. The final map indicates stable distribution from 2018 to 2023, with eucalyptus covering over 40% of the forest area, followed by horsetail pine, fir, cypress, and wetland pine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Manganese toxicity is a major obstacle to agriculture in acid soils. Dark pericarp disease (DPD) is a newly spread physiological disorder induced by excess Mn in litchi, leading to undesirable fruit appearance and substantial economic loss. In this work, broadcast of alkaline soil conditioner in winter, followed by foliar sprays of ascorbic acid and sulfur solution at fruit development, was adopted to examine the effect of these combinations on DPD alleviation in a litchi orchard, with DPD morbidities of 70~85% in recent ten years. The combination of soil conditioner broadcast and foliar water spray was used as the control. At harvest, DPD incidence was significantly decreased by sulfur spray (3.3 ± 1.0%) and slightly reduced by ascorbic acid spray (10.7 ± 8.0%) compared to the control (12.9 ± 7.6%). Soil pH and available Mn were significantly increased and reduced by the soil conditioner broadcast. Sulfur spray significantly inhibited Mn uptake but enhanced the accumulation of Mg, Ca, sugars and cyanidin-3-rutinoside in the pericarp, leading to improved fruit pigmentation. Antioxidase activities were regulated to resist Mn stress by sulfur spray. The spray of ascorbic acid could not mitigate DPD as expected, probably due to the dose used. Conclusively, this study provides a practicable approach to mitigate Mn phytoavailability in acid soils. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) is a primary threat to human health. Cisplatin is always in first‐line treatment of NSCLC; however, cisplatin resistance restricts the application in the clinic. Herein, an innovative 2D platinum delivery platform based on manganese dioxide nanosheet is presented to overcome cisplatin‐resistance and enhance theranostic efficacy in NSCLC. The photo‐induced hyperthermia of nanosheets can inhibit Pt drug efflux from the multidrug resistance‐associated protein (MRP1) repression. Then the intracellular l‐Glutathione (GSH) consumed by MnO2 nanosheets can reduce the generation of GSH‐Pt complex. Working along both lines accelerates access to the nucleus for cisplatin. Moreover, chemo‐photothermal synergistic therapy of Pt nanosheets significantly enhances therapeutic efficacy in vitro and in vivo. In addition, nanosheets can exert an on‐demand activable magnetic resonance imaging contrast effect to monitor Pt drug release. For the first time, a promising photoactivated 2D vector is provided to overcome cisplatin resistance in NSCLC therapy. [ABSTRACT FROM AUTHOR]

Platelet activation and thrombus formation is a delicate process involving a series of crosstalk between different pathways. P70 ribosomal S6 kinase1 (S6K1) is a member of serine/threonine kinases and can be phosphorylated by 3-phosphoinositide-dependent protein kinase 1 (PDK1). S6K1 is widely reported to play important roles in cancers and metabolic diseases, but the role of S6K1 and the importance of phosphorylation on Thr229 in platelet activation have not been defined. PF-4708671 is a recently synthesized highly specific inhibitor of S6K1. In this study, we tested PF-4708671 to assess the role of S6K1 in platelet. PF-4708671 facilitated mouse and human platelet aggregation and ATP secretion induced by collagen, thrombin, and adenosine diphosphate through enhanced Akt and Gsk3β phosphorylation. PF-4708671 also accelerated integrin αIIbβ3-mediated clot retraction and spreading. Intravenously given PF-4708671 shortened the occlusion time in arterial thrombosis model. Further results demonstrated that S6K1 was phosphorylated by PDK1 on Thr229 in the resting platelets and dephosphorylated in response to agonist stimulation. PDK1-deficient mice showed higher aggregation when PI3K-Akt-Gsk3β signaling was blocked by the Gsk3β-inhibitor SB216763. Thus, S6K1 Thr229 phosphorylation might function as a regulator that prevents platelets from activation. S6K1 inhibition may yield potential pro-thrombotic effects and should be used cautiously when considered as a therapy. [ABSTRACT FROM AUTHOR]

The article describes the case of focal atrial tachycardia in a 69-year-old male patient caused by fibrillatory activity in superior vena cava and multilevel exit block to right atrium, which was observed during a cryoballoon pulmonary vein isolation (PVI) procedure. Highlights include the use of a second-generation cryoballoon catheter to perform PVI, the use of a bipolar catheter for pacing ventricle or phrenic nerve, and a cranial-caudal multilevel exit block shown by electrograms.

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. [ABSTRACT FROM AUTHOR]

Aims: Soil conditions are one of the most important selection pressures driving local adaptation of plants. Unfortunately, little attention has been paid to soil-mediated local adaptation in early stages of grass species. Thus, soil-mediated local adaptation in early-life stages of Stipa breviflora was investigated in this study. Methods: Here, we collected seed and soil samples from 6 populations spanning almost the entire latitudinal range of S. breviflora in China. Then, the seeds of each population were sown in soils from 6 sites separately. Finally, we analyzed physicochemical and microbial properties of the 6 soils. Results: Home soils significantly enhanced seed germination of population A, B and C, while not for population D, E and F. For field seedling emergence, only population E and F were observed that the seedlings planted in home soils were higher than those planted in non-home soils. However, seedling survival of population A, B, C and F planted in home soils was higher than those in non-home soils. No significant difference in seedling overwintering was observed between populations planted in home soils and those planted in non-home soils. Moreover, the structural equation modeling (SEM) suggested that soil traits indirectly affected seedling survival by mainly altering soil fungal diversity and total nitrogen concentration. Conclusions: These results indicated that soil-mediated local adaptation exists in early-life stages of S. breviflora, while its strength of local adaptation varies across populations and early development stages. These findings provide new insights into the role of soil conditions in local adaption of plants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Phenotypic plasticity and genetic differentiation are the two important processes determining the leaf nutrient resorption among and within plant species, which is critical for understanding the adaptability of plants. However, relative contributions of these two processes have never been quantified at a large geographical scale.Here, we investigated intraspecific variations in nutrient resorption among 14 Stipa breviflora populations along a latitude gradient in 2018 and 2019. Furthermore, we sow seeds from these populations in two common gardens at different latitudes and examined the variations in nutrient resorption.Our results showed that nitrogen and phosphorus resorption efficiency (NRE and PRE) among S. breviflora populations in nature were positively related to latitude, while this trend disappeared in the common gardens. The heritability of NRE and PRE was 11.45% and 16.78%, respectively. These results suggested that phenotypic plasticity contributed much more than genetic variation to nutrient resorption of S. breviflora. Moreover, the structural equation modelling (SEM) suggested that latitude indirectly affected nutrient resorption mainly by altering soil nutrients. With the increasing of latitude, soil nutrients decreased while nutrient resorption increased. This phenomenon indicated that the main process regulating nutrient resorption is negative feedback to soil nutrient availability.Our study provides new insights into the role of nutrient resorption in plant adaptations to geographic variations. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this meta-analysis was to investigate the association between malnutrition assessed by the controlling nutritional status (CONUT) score and all-cause mortality in patients with heart failure. Design: Systematic review and meta-analysis. Settings: A comprehensively literature search of PubMed and Embase databases was performed until 30 November 2020. Studies reporting the utility of CONUT score in prediction of all-cause mortality among patients with heart failure were eligible. Patients with a CONUT score ≥2 are grouped as malnourished. Predictive values of the CONUT score were summarized by pooling the multivariable-adjusted risk ratios (RR) with 95 % CI for the malnourished v. normal nutritional status or per point CONUT score increase. Participants: Ten studies involving 5196 patients with heart failure. Results: Malnourished patients with heart failure conferred a higher risk of all-cause mortality (RR 1·92; 95 % CI 1·58, 2·34) compared with the normal nutritional status. Subgroup analysis showed the malnourished patients with heart failure had an increased risk of in-hospital mortality (RR 1·78; 95 % CI 1·29, 2·46) and follow-up mortality (RR 2·01; 95 % CI 1·58, 2·57). Moreover, per point increase in CONUT score significantly increased 16% risk of all-cause mortality during the follow-up. Conclusions: Malnutrition defined by the CONUT score is an independent predictor of all-cause mortality in patients with heart failure. Assessment of nutritional status using CONUT score would be helpful for improving risk stratification of heart failure. [ABSTRACT FROM AUTHOR]

• A highly biocompatible and efficient bone targeting material was synthesized to target osteosarcoma. • Collagenase can rely on a dual targeting process to target bone tumors. • Collagenase enriched in bone tumors can effectively degrade the extracellular matrix deposited in the tumor area. • The combination of collagenase and paclitaxel can basically cure osteosarcoma. Osteosarcoma is one of the commonest malignant bone tumors in children and adolescents, and its preferred treatment is chemotherapy. However, the lack of sufficient blood vessels in the bone tissue and the dense collagen fibers in osteosarcoma severely weaken the drug-directional accumulation effect and intra-tumoral penetration, leading to poor therapeutic efficacy. Herein, we reported a bone-targeted permeable nanomicelle (Co1-PTX@DSAA) composed of aspartic acid (Asp)-modified dextran (DSAA) to deliver paclitaxel (PTX) and collagenase 1 (Co1) simultaneously for highly effective osteosarcoma treatment. The prepared nanomicelle possessed excellent osteosarcoma targeting ability as Asp can combine with hydroxyapatite (HAP) in bone. More intelligently, the surface-absorbed Co1 endowed PTX@DSAA with a special function like a nano-icebreaker, which could quickly destroy the collagen fibers to promote PTX penetration deeply in the tumor. Our work suggests that Co1-PTX@DSAA nanomicelles could quickly combine with HAP and Ca2+ at an adsorption rate of ∼ 60% and ∼ 32%, respectively. Meanwhile, the penetration depth of Co1-PTX@DSAA could even reach 70 μm in the multicellular spheroids (MCSs) model. The tumor treatment efficiency of Co1-PTX@DSAA is 1.51 times that of free PTX. Overall, this unprecedented nanomicelle can simultaneously facilitate drug accumulation and deep penetration in the tumor, which will provide a promising strategy for future safe and high-efficiency clinical osteosarcoma treatment. [ABSTRACT FROM AUTHOR]

• The structural genes for anthocyanin and carotenoid biosynthesis regulate dynamically in various stages of fruit coloring. • The core genes and metabolites indicated that different characteristics of fruit color were regulated by genes and metabolites. • Coordination between color-specific metabolites and genes mediates various fruit color patterns in C. arabica. • The differential regulation of several anthocyanin pathway genes ultimately disrupts the accumulation of cyanidin-3,5-o-diglucoside, delphinidin-3-o-galactoside, delphinidin-3-o-glucoside, and pelargonidin-3,5-o-diglucoside. • The disturbance in the regulation of carotenoid encoding genes LOC113693633-LCYE, LUT1, LOC113701700-VDE, and LOC113707258-ZEP modulate the abundance of α-carotene, β-carotene, lutein, zeaxanthin, antheraxanthin, and violaxanthin. Coffee is the most popular beverage in the world with exceptional flavor and taste. Fruit color is known as the prime quality attribute that influences the nutritional quality and health benefits of coffee. The molecular mechanism underlying the diversity of fruit coloration is still unclear in C. arabica. A network of key genes and metabolites involved in coffee fruit coloration was constructed. The analysis of transcriptome and metabolic was performed by using six contrast-colored fruits. The results revealed that the differential metabolites and genes were enriched in the anthocyanin biosynthesis and carotenoid biosynthetic pathways in C. arabica fruits. In total, 31 differentially accumulated anthocyanins, 34 differentially accumulated carotenoid and 75 differentially expressed genes were identified. In addition, the difference in composition and concentration of carotenoids influenced the diversity of fruit coloration. The results of combined metabolome and transcriptome data showed a strong relationship between differentially expressed genes and accumulated metabolites. After conjoint analysis of transcriptome and metabolome, we found 13 anthocyanidins associated DEGs had a strong linkage with nine compounds and 16 carotenoids annotated DEGs displayed a strong connection with nine carotenoid compounds. This study identified the expression of key genes and the abundance of metabolites, and biosynthesis pathways, which provided the regulatory mechanism of fruit coloration in C. arabica. This study further supported the analysis for genetic control of fruit color in C. arabica. [ABSTRACT FROM AUTHOR]

An old large-scale landslide with a volume of 4.6 × 106 m3 located on the right bank of the Lancang River, Southwest China, was formed by the deep-seated toppling failure of a rock mass. The rock mass located downstream of the landslide toppled intensely with a maximum toppling depth exceeding 200 m and a volume over 1.5 × 108 m3. We studied the formation mechanism of the landslide and determined the most likely future instability range of the toppled rock mass. The results show that the toppled rock mass located downstream of the landslide could be classified into four zones, namely, highly toppled, moderately toppled, weakly toppled and normal rock mass, from the surface to the deep-seated rock mass along the slope according to three factors: the unloading intensity, variation in the occurrence of the rock layer, and toppling fracture zone. The bottom boundary of the highly toppled rock mass was limited by the depth of strong unloading of the rock mass. The landslide deposits mainly originated from the highly toppled rock mass, and the slip zone was formed based on the toppling fracture zones. The highly toppled rock mass in the rock slope located downstream of the landslide will be the most likely area of instability in the future. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Metal-based photothermal therapy has been widely used in the biomedicine field and includes gold nanoparticles, silver nanoparticles and copper sulfide nanoparticles. Furthermore, the coordination bonding-based metal nanocomplex is a new generation of photothermal agents for cancer therapy due to its high photothermal transduction efficiency, good biocompatibility, biodegradation and bioactivity. In this study, we designed a coordination bonding-based copper (Cu(II))-carboxylate ternary architecture, which consists of a conjugate dopamine-modified nontoxic hyaluronic acid, copper ions and citric acid. When the Cu(II) coordinated with the carboxyl groups, the splitting d orbitals energy gap of Cu(II) and the capability of electron transition were enhanced, which can increase the extinction ability in the near-infrared region for enhancing photothermal therapy. Moreover, the degradation of hyaluronic acid by hyaluronidase highly expressed in the tumor microenvironment led to the release of Cu-citric acid complexes, thus exhibiting an additional chemotherapeutic effect. The nanocomplexes possessed high-performance photothermal conversion, determined to be 21.3%. The solution could be easily heated to above 42 °C, which was sufficient to ablate the cancer cells. An obvious decrease in cell viability was observed in B16F10 cells incubated with the nanocomplexes under laser at the lower concentration of 20 μg/mL Cu(II). Upon near-infrared laser irradiation, the nanocomplexes showed high photothermal therapy and chemotherapeutic efficacy for breast cancer in vivo. This study demonstrated that the Cu(II)-carboxylate coordination nanocomplex is a promising new effective and facilely prepared thermochemotherapy agent for combination therapy against cancer. [ABSTRACT FROM AUTHOR]

Dynamic endocytic and exocytic trafficking of integrins is an important mechanism for cell migration, invasion, and cytokinesis. Endocytosis of integrin can be classified as clathrin dependent and clathrin independent manners. And rapid delivery of endocytic integrins back to the plasma membrane is key intracellular signals and is indispensable for cell movement. Integrin αIIbβ3 plays a critical role in thrombosis and hemostasis. Although previous studies have demonstrated that internalization of fibrinogen-bound αIIbβ3 may regulate platelet activation, the roles of endocytic and exocytic trafficking of integrin αIIbβ3 in platelet activation are unclear. In this study, we found that a selective inhibitor of clathrin-mediated endocytosis pitstop 2 inhibited human platelet spreading on immobilized fibrinogen (Fg). Mechanism studies revealed that pitstop 2 did not block the endocytosis of αIIbβ3 and Fg uptake, but inhibit the recycling of αIIbβ3 to plasma membrane during platelet or CHO cells bearing αIIbβ3 spreading on immobilized Fg. And pitstop 2 enhanced the association of αIIbβ3 with clathrin, and AP2 indicated that pitstop 2 inhibit platelet activation is probably due to disturbance of the dynamic dissociation of αIIbβ3 from clathrin and AP2. Further study demonstrated that Src/PLC/PKC was the key pathway to trigger the endocytosis of αIIbβ3 during platelet activation. Pitstop 2 also inhibited platelet aggregation and secretion. Our findings suggest integrin αIIbβ3 trafficking is clathrin dependent and plays a critical role in platelet spreading, and pitstop 2 may serve as an effective tool to address clathrin-mediated trafficking in platelets. [ABSTRACT FROM AUTHOR]

House dust mite (HDM) allergen is a major cause of allergic disease. In this study, two-dimensional immunoblot and Matrix-Assisted Laser Desorption Ionization tandem Time-of-flight mass spectrometry (MALDI-TOF-MS) were used to identify Der f 31. After Der f 31 was cloned, expressed and purified, skin prick test (SPT), Immune inhibitory assays, Western blot, ELISA and asthmatic mouse model were employed to examine the allergenicity of recombinant Der f 31. The gene of Der f 31 includes 447 bps, and encoded 148 amino acids. Positive responses of SPT to r-Der f 31 were 32.5% in 43 HDM-allergic patients. r-Der f 31 can induce allergic pulmonary inflammation in the mouse model. In conclusion, Der f 31 is a novel subtype of dust mite allergens. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of type 2 diabetes mellitus (T2DM) risk and plasma lipid levels in rural Chinese.Methods: Each lipid variable was divided into quartiles and dichotomized by clinical cutoff points. Cox proportional-hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of T2DM risk and plasma lipid levels and explore the interaction between plasma lipid levels and other risk factors.Results: 11,929 participants were included in the analysis. We documented 720 incident cases of T2DM over 70,720.84 person-years of follow-up, for an incidence of 10.18/1,000 person-years. In the multivariable-adjusted model, risk of T2DM was increased with the highest versus lowest quartiles of total cholesterol (TC) and triglycerides (TG) levels and TC/high-density lipoprotein-cholesterol (HDL-C) and TG/HDL-C ratios. The HRs (95% CIs) for the fourth quartiles, for example, were 1.34 (1.03-1.74), 2.32 (1.73-3.13), 1.66 (1.23-2.25), and 1.84 (1.38-2.45), respectively. In addition, risk of T2DM was increased with high TG level and TC/HDL-C and TG/HDL-C ratios by clinical cutoffs. The HRs (95% CIs) were 1.50 (1.25-1.80), 1.24 (1.03-1.48), and 1.44 (1.18-1.75), respectively. Risk of T2DM was associated with interactions between all lipid variables and age and BMI. TG level and TG/HDL-C ratio additionally interacted with gender (all Pinteraction < 0.0001).Conclusions: Risk of T2DM was increased with elevated serum levels of TC and TG and TC/HDL-C and TG/HDL-C ratios and also with interactions between high TC and TG levels and TC/HDL-C and TG/HDL-C ratios and age and BMI in a rural Chinese population. [ABSTRACT FROM AUTHOR]

Background Low-density lipoprotein receptor-related protein 5 ( LRP5) plays an important role in glucose and cholesterol metabolism. The present cohort study evaluated associations of LRP5 variants with the incidence of type 2 diabetes mellitus ( T2DM) in a rural adult Chinese population. Methods In all, 7751 subjects aged ≥18 years without T2DM underwent genotyping at baseline; 6326 subjects (81.62%) were followed-up, and 5511 with a clear disease outcome were eligible for analysis. The same questionnaire was administered and the same anthropometric and blood biochemical examinations were performed at baseline and follow-up. Association analysis was performed for five single nucleotide polymorphisms and haplotypes of LRP5. Results Cox proportional hazards testing of three different genetic models found no significant association between T2DM and LRP5 after adjusting for potential risk factors ( P > 0.05). However, the incidence of T2DM in subjects with LRP5 mutational genotypes was higher in the overweight/obese than normal weight population. Under the dominant model, the risk of T2DM was increased with an interaction between rs11228303 and the waist-to-height ratio adjusted for baseline age, sex, and family history of T2DM (synergy index [ SI] = 4.172; 95% confidence interval [ CI] 1.014-17.166)], and body mass index ( SI = 3.237; 95% CI 1.102-9.509). Furthermore, the A allele of rs3758644 was related to decreased fasting plasma insulin and homeostatic model assessment of β-cell function levels, whereas the T allele of rs12363572 was related to increased high-density lipoprotein cholesterol levels in new-onset diabetes patients ( P < 0.05). Conclusions The risk of T2DM may be associated with interactions between the LRP5 gene and overweight and obesity. Polymorphisms of LRP5 are related to β-cell function and lipid metabolism. [ABSTRACT FROM AUTHOR]

Background The aim of the present study was to estimate trends in the prevalence of type 2 diabetes mellitus (T2DM) in adults in China. Methods A systematic search was conducted for studies of T2DM prevalence in adults in China from 2000 to 2014. Pooled prevalence was calculated by a random-effects model. Subgroup and sensitivity analyses were performed. Chi-squared and Cochran-Mantel-Haenszel tests were used to assess differences among subgroups and pooled prevalence, respectively. Results Forty-six studies (data from 1995 to 2014; 1 463 079 adults) were included in the meta-analysis. The overall prevalence of T2DM was 7.9 %. The pooled prevalence overall and by location (urban and rural), gender (male and female), and age category (18-39, 40-59, and ≥60 years) was 4.5 %, 5.1 % and 3.0 %, 4.0 % and 4.2 %, and 1.4 %, 5.0 %, and 10.3 %, respectively, from 1995 to 1999; 6.6 %, 9.3 % and 5.6 %, 7.4 % and 7.5 %, and 1.8 %, 5.9 %, and 12.4 %, respectively, from 2000 to 2004; 10.3 %, 11.8 % and 6.8 %, 10.0 % and 8.6 %, and 2.8 %, 10.3 %, and 20.0 %, respectively, from 2005 to 2009; and 8.3 %, 12.5 % and 7.6 %, 8.6 % and 8.0 %, and 3.5 %, 8.5 %, and 15.3 %, respectively, from 2010 to 2014. The prevalence increased from 5.8 % to 11.6 % with per-capita gross domestic product and differed by diagnostic criteria. Conclusions There was a trend of increasing prevalence of T2DM in adults in China from 1995 to 2009, with a decrease in 2010-14 and a greater increase over time in urban versus rural areas, males versus females, and older versus younger adults. [ABSTRACT FROM AUTHOR]

Introduction Interleukin (IL)-37 is a newly identified member of the IL-1 family, and shows a growing role in a variety of diseases. This review aims at summarizing and discussing the role of IL-37 in cardiovascular diseases. Methods Data for this review were identified by searches of MEDLINE, Embase, and PubMed using appropriate search terms. Results IL-37 is a newly identified cytokine belonging to the IL-1 family and is expressed in inflammatory immune cells and several parenchymal cells. It has potent anti-inflammatory and immunosuppressive properties, with two mechanisms underlying this function. IL-37 is produced as a precursor and then cleaved into mature form in the cytoplasm by caspase-1, translocating to nucleus and suppressing the transcription of several pro-inflammatory genes by binding SMAD-3. Besides, IL-37 can be secreted extracellularly, and binds to IL-18Ra chain and recruits Toll/IL-1R (TIR)-8 for transducing anti-inflammatory signaling. IL-37 is upregulated in an inducible manner and negatively regulates signaling mediated by TLR agonists and pro-inflammatory cytokines. The cytokine has been shown to inhibit both innate and adaptive immunological responses, exert antitumor effects, and act as a prognostic marker in a variety of autoimmune diseases. Conclusions Recent studies have suggested that IL-37 plays a role in cardiovascular diseases. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its cardio-protective effects, and suggest guidelines for future research. [ABSTRACT FROM AUTHOR]

Objectives To examine the effect of change in body mass index (BMI) on incident hypertension by gender and age groups. Methods A total of 10,145 non-hypertensive participants 18–75 years old from rural areas in the middle of China were selected for this cohort study. Questionnaire interview and anthropometric and laboratory measurements were performed at baseline (during July to August 2007 and July to August 2008) and follow-up (during July to August 2013 and July to October 2014). Multiple logistic regression analysis was used to examine the relationship between change in BMI and incident hypertension. Results During a mean follow-up of 6.03 ± 0.69 years, hypertension developed in 794 of 3986 men and 1184 of 6159 women. Both genders who were obese (BMI ≥ 28 kg/m 2 for Chinese people) at follow-up, regardless of their obesity status at baseline, showed greater risk of hypertension than those who were non-obese (BMI < 28 kg/m 2 ) at both baseline and follow-up. We found a dose-response relationship between change in BMI and incident hypertension. Risk of hypertension was markedly greater with a BMI gain of the highest quartile or more as compared with a BMI reduction of the lowest quartile or more, except for women 60–75 years old. Conclusions Risk of hypertension was high for non-hypertensive people in rural China with stable obesity. BMI dynamic gain may be related to incident hypertension for men of all ages and young and middle-aged women. [ABSTRACT FROM AUTHOR]

Background/Aims: Mitochondrial DNA (mtDNA), acting as a newly found 'dangerassociated molecular patterns' (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. Methods: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. Results: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and upregulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. Conclusion: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether impaired fasting glucose (IFG) is an independent risk factor for incident hypertension in a rural Chinese population.Methods: We selected 9583 eligible participants 18 to 75years old, who were without hypertension and diabetes at baseline (from 2007 to 2008) and were from a rural area in the middle of China. Concentration of fasting glucose at baseline was assessed in quartiles to predict hypertension risk by gender. Odds ratios (ORs) and 95% confidence intervals (CIs) for IFG (fasting glucose of 100 to 125mg/dl) associated with hypertension were estimated by logistic regression models.Results: Risk of hypertension was increased for females with glucose levels in quartile 2 (90-96mg/dl), quartile 3 (96-102mg/dl), and quartile 4 (102-125mg/dl) versus quartile 1 (<90mg/dl): OR=1.27 (95% CI=1.01-1.60), 1.30 (1.04-1.63), and 1.55 (1.24-1.93), respectively. During the 6-year follow-up, the cumulative incidence of hypertension was greater for people with IFG than normal fasting glucose (NFG) at baseline (23.9% vs 18.4%, p<0.001 for males and 23.8% vs 16.4%, p<0.001 for females). Risk of incident hypertension was significantly increased for females with IFG versus NFG (OR=1.23 95% CI=1.05-1.45).Conclusions: IFG may be an independent risk factor for hypertension in normotensive nondiabetic Chinese females. [ABSTRACT FROM AUTHOR]

Background Tissue factor pathway inhibitor-1 ( TFPI-1 ) has multiple functions and its precise role and molecular mechanism during the development of atherosclerosis are not clear. Objectives To determine the effect and molecular mechanism of TFPI-1 deficiency in vascular smooth muscle cells (VSMCs) in atherosclerosis in the apolipoprotein E knockout ( ApoE −/− ) mouse. Methods and results A mouse model with a conditional knockout of TFPI-1 in VSMCs in an atherosclerosis-prone background ( ApoE −/− ) was generated. Mice were fed a high fat diet for 18 weeks and were then euthanized. Arterial trees and aortas were stained with Sudan IV and were labeled via immunohistochemistry. Cell proliferation and migration of VSMCs in atherosclerotic plaques were assessed. More atherosclerotic lesions and higher levels of proliferation and migration of VSMCs were observed in TFPI-1 fl/fl /Sma-Cre + ApoE −/− mice. An interaction between TFPI-1 and angiomotin (AMOT) was identified in human VSMCs by mass spectrometry, immunoprecipitation and co-localization analyses. Signal pathway changes were detected by Western blot analysis, and the expression levels of target genes were determined by real-time PCR. Decreased phosphorylation of AMOT and Yes-associated protein 1 (YAP) in TFPI-1 fl/fl / Sma-Cre + ApoE −/− mice resulted in increased expression levels of snail family zinc finger 2 ( SLUG ) and connective tissue growth factor ( CTGF ), which are target genes of the Hippo signaling pathway that have been verified as atherosclerosis candidate genes. Conclusion Deficiency in TFPI-1 in the VSMCs of ApoE −/− mice accelerated the development of atherosclerosis by promoting the proliferation and migration of VSMCs which may be caused by the decreased phosphorylation of AMOT and YAP. Significance TFPI-1 has been found to has an anticoagulant activity, induce cell apoptosis and prevent cell proliferation. For the first time, we constructed a line of conditional knockout mice in which the TPFI-1 gene is deleted in VSMCs. We found that TFPI-1 deficiency clearly promoted the development of atherosclerosis when these mice were crossed into an ApoE −/− background. One notable feature of atherosclerosis is the proliferation and migration of smooth muscle cells. Previous reports involved TFPI-1 do not completely explain the proliferation and migration of VSMCs because heterozygous TF deficient ( TF ± ) mice bred in an ApoE −/− background did not show diminished atherosclerosis compared to TF +/+ mice bred in the same background. Our results first confirmed that TFPI-1 interacts with AMOT, which led to a decrease in the phosphorylation of YAP and further increased the genes expression of the proliferation and migration involved. Our results further confirmed that atherosclerosis was a localized disease. [ABSTRACT FROM AUTHOR]

Background To examine the association of risk of incident type 2 diabetes mellitus (T2DM) with high pulse pressure (PP) by sex. Methods We performed a prospective cohort study of 12,272 eligible participants (4664 males and 7608 females) without diabetes at baseline. Participants were classified as having normal PP (20–60 mm Hg) and high PP (> 60 mm Hg) at baseline. The analysis was further stratified by sex, quartiles of age and high PP categories. Results During 6 years of follow-up, T2DM developed in 775 participants and the incidence was 10.57/1000 person-years. With PP 70 to 76 mm Hg, the multivariable adjusted hazard ratio (HR) (95% confidence interval) for incident T2DM in females was 1.722 (1.093–2.714) after adjustment for baseline age, smoking, alcohol intake, physical activity level and family history of T2DM, and 1.634 (1.037–2.575) after adjustment for the above factors and body mass index, waist circumference, blood lipid levels and fasting plasma glucose (FPG) category. After stratification by quartiles of age, for females aged 52 to 59, the multivariable adjusted HRs (95% CI) for high PP as compared to normal PP were 2.263 (1.517–3.377) and 2.140 (1.426–3.210) in different models. During follow-up, levels of FPG, fasting plasma insulin and homeostatic model assessment of insulin resistance index (HOMA-IR) were higher in females with higher than normal PP group, but β-cell function was impaired in the high PP group ( P < 0.05). Conclusion High PP may be related to incident T2DM among female in China, especially women 52 to 59 years old. [ABSTRACT FROM AUTHOR]

Aims/Introduction To clarify the association of the hypertriglyceridemic waist phenotype and type 2 diabetes mellitus among adults in China. Materials and Methods In the present case-control study, we included 1,685 patients with type 2 diabetes mellitus and 7,141 normal glucose-tolerant controls from the Henan Province of China in 2011. Elevated waist circumference ( GW) was defined as ≥90 cm for men and ≥80 cm for women. Hypertriglyceridemia ( HT) was defined as >1.7 m mol/L triglycerides ( TG) level. The association of hypertriglyceridemic waist phenotype and type 2 diabetes mellitus was investigated by sex, body mass index, physical activity, and family history of diabetes. Results Cases and controls differed in age, waist circumference ( WC), weight, TG level, fasting glucose, body mass index, smoking status, diabetic family history, physical activity and hypertriglyceridemic waist phenotype ( P < 0.05), but not alcohol drinking ( P = 0.63). In the overall sample, as compared with the phenotype of normal TG level and normal WC ( NTNW), normal TG level/enlarged WC ( NTGW), elevated TG level/normal WC ( HTNW) and elevated TG level/enlarged WC ( HTGW) were associated with type 2 diabetes mellitus (odds ratio 4.14, 2.42 and 6.23, respectively). Only HTGW was consistently associated with risk of type 2 diabetes mellitus, with or without adjustment. The strongest relationship between HTGW and type 2 diabetes mellitus was for subjects with body mass index <24.0 kg/m2 (odds ratio 6.54, 95% confidence interval 4.22-10.14) after adjustment for cofounding variables. Conclusion HTGW was stably and significantly associated with risk of type 2 diabetes mellitus in adult Chinese. [ABSTRACT FROM AUTHOR]

Two middle-aged female patients presenting with heart palpitation and electrocardiogram revealed complex cardiac arrhythmias. A review of systems was positive for dry mouth and transient arthralgia, while laboratory and instrumental tests enabled us to make the diagnosis of primary Sjögren's syndrome (pSS). Cardiac electrophysiology revealed atrioventricular node dysfunction and impaired intraventricular conduction. Prednisone therapy induced a significant improvement in symptoms and electrocardiographic readings. The diagnosis of pSS should be considered in a patient presenting with complex cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Abstract: KCNE2 plays an important role in maintaining cardiac electrical stability. Mutations in KCNE2 have been linked to long-QT syndrome (LQT6) and atrial fibrillation/short QT syndrome. It has been suggested that KCNE2 has the most promiscuity of function which can interact with multiple-subunits of voltage-dependent cation channels and modulate their functions. However, whether KCNE2 regulates voltage-dependent L-type Ca2 + channel (LCC) remains unknown. This study investigated the possible role of KCNE2 in regulating cardiac LCCs and the pathophysiological relevance of this regulation. We found that overexpression of KCNE2 in Sprague–Dawley rat cardiomyocytes decreased L-type Ca2+ current (ICa,L), whereas KCNE2 knockdown by RNA interference increased ICa,L. Upregulation of KCNE2 caused a slight positive shift of the voltage-dependent activation and a negative shift of the steady-state voltage-dependent inactivation, and slowed the recovery from inactivation of ICa,L, while knockdown of KCNE2 had the contrary effects. Similar regulation of ICa,L magnitude had been observed in transfected HEK 293 cells. Coimmunoprecipitation and colocalization assays in both cardiomyocytes and the transfected cell line suggest that Cav1.2 physically interacted with KCNE2. Deletion of the N-terminal inhibitory module (NTI) of Cav1.2 results in the large loss of KCNE2 regulation of ICa,L and interaction with Cav1.2. Furthermore, we found that the familial atrial fibrillation related KCNE2 mutation R27C enhanced the effect of KCNE2 on suppressing ICa,L. Taken together, our findings indicate that KCNE2 modulates ICa,L by regulating NTI function of Cav1.2. The KCNE2 mutation R27C may induce familial atrial fibrillation partially through enhancing the suppression of ICa,L. [Copyright &y& Elsevier]

Abstract: Our recent studies demonstrate that burn trauma induces leaky sarcoplasmic reticulum (SR) in heart due to excessively active ryanodine receptor (RyR) function. SR Ca2+ leak causes partial depletion of SR Ca2+ content and disturbances in intracellular Ca2+ homeostasis, resulting in the pathogenesis of burn-generated cardiac dysfunction. This study investigated the role of polydatin, a resveratrol glucoside, in preventing SR leak and its therapeutic effect against burn-generated cardiac dysfunction. We found that polydatin treatment improved cardiac function impaired by burn injury of 30% of total body surface area. Parallel to the alterations in cardiac function, polydatin significantly increased the defective systolic Ca2+ transient and contractility in burn-traumatized cardiomyocytes. Burn injury increased the occurrence of Ca2+ sparks. The enhancement of Ca2+ spark-mediated SR leak caused partial depletion of SR Ca2+ content in burn-traumatized cardiomyocytes. Furthermore, we found that the content of free thiols (the number of reduced cysteines) in RyR2 in cardiomyocytes determined by the monobromobimane fluorescence of RyR2 was decreased markedly in burn-traumatized hearts. Polydatin treatment decreased intracellular reactive oxygen species levels and restored the amount of free thiols in RyR2 in burns. Concomitantly, polydatin corrected Ca2+ spark-mediated SR leak and restored SR Ca2+ load. The systolic Ca2+ transient and cellular contractility were significantly increased by polydatin treatment. Taken together, the present findings provide the first evidence demonstrating that polydatin prevents enhanced Ca2+ spark-mediated SR leak by reducing oxidative stress in RyR2 in burn-traumatized heart, leading to protection of cardiac function against burn injury. [Copyright &y& Elsevier]

Stem rot caused by Sclerotinia sclerotiorum in many important dicotyledonous crops, including oilseed rape (Brassica napus), is one of the most devastating fungal diseases and imposes huge yield loss each year worldwide. Currently, breeding for Sclerotinia resistance in B. napus, as in other crops, can only rely on germplasms with quantitative resistance genes. Thus, the identification of quantitative trait locus (QTL) for S. sclerotiorum resistance/tolerance in this crop holds immediate promise for the genetic improvement of the disease resistance. In this study, ten QTLs for stem resistance (SR) at the mature plant stage and three QTLs for leaf resistance (LR) at the seedling stage in multiple environments were mapped on nine linkage groups (LGs) of a whole genome map for B. napus constructed with SSR markers. Two major QTLs, LRA9 on LG A9 and SRC6 on LG C6, were repeatedly detected across all environments and explained 8.54–15.86% and 29.01%–32.61% of the phenotypic variations, respectively. Genotypes containing resistant SRC6 or LRA9 allele showed a significant reduction in disease lesion after pathogen infection. Comparative mapping with Arabidopsis and data mining from previous gene profiling experiments identified that the Arabidopsis homologous gene of IGMT5 (At1g76790) was related to the SRC6 locus. Four copies of the IGMT5 gene in B. napus were isolated through homologous cloning, among which, only BnaC.IGMT5.a showed a polymorphism between parental lines and can be associated with the SRC6. Furthermore, two parental lines exhibited a differential expression pattern of the BnaC.IGMT5.a gene in responding to pathogen inoculation. Thus, our data suggested that BnaC.IGMT5.a was very likely a candidate gene of this major resistance QTL. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies reported that autophagy is activated in human dilated cardiomyopathy (DCM). It is still unknown whether modulating autophagy can improve cardiac function of the failing heart. Methods: We immunized rats with porcine cardiac myosin to set up a model of DCM. Rapamycin, a kind of mTOR inhibitor upregulating autophagy, was given to rats weeks after the immunization at low (1 mg/kg · day i.p.), intermediate (2 mg/kg · day i.p.) and high dose (4 mg/kg · day i.p.) for 2 weeks. Results: Compared to the control group (ejection fraction, EF = 81.3 ± 3.8%), the average EF decreased in both the DCM group (EF = 56.1 ± 3.3%) and the high-dose rapamycin group (EF = 55.9 ± 3.6%), but recovered in the low-/intermediate-dose rapamycin groups (EF = 64.9 ± 4.6/69.4 ± 4.4%). Phosphorylation of p70s6k and 4E-BP1 decreased and the expression of LC3BI/II increased in all rapamycin groups. Autophagic vacuoles were easily found in these groups. However, body weight was significantly reduced in the rapamycin groups. Furthermore, mortality was increased in the high-dose rapamycin group. Conclusions: Rapamycin could improve cardiac function of early-stage DCM, but the effect of rapamycin turned out to be biphasic and the effective range appeared narrow. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: We aimed to replicate the association of the rs290487 (IVS3C/T) and rs7903146 (IVS3C/T) polymorphisms of transcription factor 7-like 2 (TCF7L2) and type 2 diabetes mellitus (T2DM) in Han Chinese people in Henan province, China. Methods: In all, 1,842 patients with T2DM and 7,777 normal glucose-tolerant controls underwent genotyping for the T2DM-associated variants rs7903146 (IVS3C/T) and rs290487 (IVS3C/T). W performed a meta-analysis of the association of the risk alleles of rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) in TCF7L2 and T2DM in Han Chinese by combining previous studies with the present study. Results: We found that T2DM was associated with the CC genotype (1.364, 1.137–1.636, p  = 0.001), the recessive model (1.457, 1.156–1.838, p  = 0.001) of rs290487 (IVS3C/T) and haplotype CC (1.116, 1.034–1.204, p  = 0.004) in Han Chinese. Moreover, our meta-analyses supported the association of the T allele (IVS3C/T) of rs7903146 (1.36, 1.24–1.48; p  = 6.404×10−12) and T2DM but not the C allele of rs290487 (IVS3C/T) (0.99, 0.85–1.15, p  = 0.890) in Han Chinese. We found no interactions between behavioral risk factors (smoking, alcohol drinking, and physical activity) and rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) polymorphisms. Conclusions: The CC genotype and the recessive model of the variant rs290487 (IVS3C/T) and CC haplotype of rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) in TCF7L2 may be associated with T2DM in Han Chinese people in Henan province, China. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) can exacerbate asthma; however, the mechanisms are not fully understood. This study investigated the effect of LPS on antigen-stimulated mast cell degranulation and the underlying mechanisms. We found that LPS enhanced degranulation in RBL-2H3 cells and mouse peritoneal mast cells upon FcɛRI activation, in a dose- and time-dependent manner. Parallel to the alteration of degranulation, LPS increased FcɛRI-activated Ca2+ mobilization, as well as Ca2+ entry through store-operated calcium channels (SOCs) evoked by thapsigargin. Blocking Ca2+ entry through SOCs completely abolished LPS enhancement of mast cell degranulation. Consistent with functional alteration of SOCs, LPS increased mRNA and protein levels of Orai1 and STIM1, two major subunits of SOCs, in a time-dependent manner. In addition, LPS increased the mRNA level of Toll-like receptor 4 (TLR4) in a time-dependent manner. Blocking TLR4 with Cli-095 inhibited LPS, increasing transcription and expression of SOC subunits. Concomitantly, the effect of LPS enhancement of Ca2+ mobilization and mast cell degranulation was largely reduced by Cli-095. Administration of LPS (1 μg) in vivo aggravated airway hyperreactivity and inflammatory reactions in allergic asthmatic mice. Histamine levels in serum and bronchoalveolar lavage fluid were increased by LPS treatment. In addition, Ca2+ mobilization was enhanced in peritoneal mast cells isolated from LPS-treated asthmatic mice. Taken together, these results imply that LPS enhances mast cell degranulation, which potentially contributes to LPS exacerbating allergic asthma. Lipopolysaccharide increases Ca2+ entry through SOCs by upregulating transcription and expression of SOC subunits, mainly through interacting with TLR4 in mast cells, resulting in enhancement of mast cell degranulation upon antigen stimulation. [ABSTRACT FROM AUTHOR]

Background: Little is known about the plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the relationship between the severity of coronary heart disease (CHD) with NT-proBNP and multiple biomarkers in diabetic and pre-diabetic patients, compared to individuals with normal glucose levels. Methods: Four hundred and fifteen consecutive Chinese patients of both sexes were assigned to three groups on the basis of the new hemoglobin (Hb) A1c (HbA1c) cut-off points for diagnosis of diabetes and pre-diabetes. The three groups were divided into tertiles according to NT-proBNP, hs-CRP, cystatin C, and troponin T levels. Gensini scores were compared among the three groups and biomarker tertiles. Receiver operating characteristic (ROC) curves were used to obtain the angiographic CHD cut-off points for each biomarker. Stepwise multivariate linear correlation analysis was applied to examine the association between the severity of CHD and biomarker levels. Results: Gensini scores increased with increasing biomarker tertile levels and HbA1c. Gensini scores were significantly different in the middle and upper NT-proBNP tertiles of the diabetic, pre-diabetic and control groups. NT-proBNP had the highest positive and negative predictive values and area under the curve for CHD. Only NT-proBNP was identified as an independent variable for Gensini score. Conclusions: Plasma NT-proBNP may be an important biomarker to evaluate the severity of CHD and screen for CHD in diabetic or pre-diabetic patients. [ABSTRACT FROM AUTHOR]

[Display omitted] Platelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood. P2Y 12 is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y 12 in platelet hyperactivity during sepsis. We measured platelet P2Y 12 expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice. We also detected the downstream signaling of P2Y 12 in resting platelets from patients and mice with sepsis. The role of nucleotide-binding oligomerization domain 2 (NOD2)/RIP2/NF-κB/P65 pathway in sepsis-induced platelet P2Y 12 high expression was also investigated. Finally, we compared the antiplatelet and antithrombotic effects of clopidogrel, prasugrel, and ticagrelor in experimental sepsis in mice and rats. Compared to healthy subjects, platelets from septic patients exhibit P2Y 12 hyperactivity and higher P2Y 12 expression. pAkt is enhanced and pVASP is impaired in resting platelets from the patients, indicating the constitutive activation of platelet P2Y 12 receptor. Mouse sepsis model recapitulates the findings in septic patients. NOD2 deficiency attenuates sepsis-induced platelet P2Y 12 high expression, hyperactivity, and thrombosis. Prasugrel and ticagrelor are potent P2Y 12 inverse agonists, and exhibit superior antiplatelet and antithrombotic efficacy over clopidogrel in mice and rats with sepsis. NOD2 activation upregulates platelet P2Y 12 expression, which is constitutively activated and contributes to platelet hyperactivity in septic status. Compared to clopidogrel, prasugrel and ticagrelor are potent P2Y 12 inverse agonists with superior antiplatelet and antithrombotic efficacy in experimental sepsis. [ABSTRACT FROM AUTHOR]

A deep-seated flexural toppling failure of rock masses is located on the right bank upstream of the Lancang River, Southwest China. The rock masses unloaded intensely in two directions and formed intense toppled rock masses with lengths and widths of 1200 m and 950 m, respectively, and volumes over 1.5 × 108 m3. The toppled rock masses could be classified into three grades from surface to deep rock masses: strongly, moderately and weakly toppled rock masses. The strong unloading of rock masses during the rapid downcutting process of rivers was one of the main external factors that induced deep-seated toppling failure. The mechanism could be summarized as follows: intense unloading destroyed the structure of rock masses and weakened the mechanical properties of rock masses by forming many unloading cracks in rock masses; additionally, the stress field of the slope was further redistributed and a stress relaxation zone formed in the strong unloading zone. Then, the stresses of rock masses in the relaxation zone were dominated by gravity, and the deep-seated toppling failure formed in the strongly unloaded rock masses under the action of gravity. [ABSTRACT FROM AUTHOR]