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A series of Mo-containing MFI zeolites with different Mo loadings (Mo-MFI-n, n represent the initial Si/Mo molar ratio) was hydrothermally synthesized by using tetrapropylammonium hydroxide as the template and Mo-EDTA complex as the Mo source. Various characterization results demonstrated that the use of the Mo-EDTA complex is beneficial for the incorporation of more Mo species into the MFI-type zeolites. The special complexing capability of EDTA2– plays a critical role in adjusting the release rate of the Mo species to combine with the Si tetrahedron species during the zeolite growth process, thus leading to a uniform distribution of Mo in the MFI framework. In addition, a small portion of extra-framework Mo clusters may be distributed inside the channels or near the pore window of the zeolites. The catalytic properties of these Mo-containing MFI zeolites were evaluated for the epoxidation of cyclohexene with H2O2 as the oxidant. The composition-optimized catalyst, Mo-MFI-50, efficiently converted cyclohexene to the corresponding epoxide with a relatively high conversion (93%) and epoxide selectivity (82%) at 75 °C after 9 h of reaction. Moreover, the resultant Mo-containing MFI catalyst exhibited excellent structural stability and recoverability and was easily recycled by simple filtration without the need for calcination treatment.

Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.

Background: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell–cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression. Methods: We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell–cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody. Results: The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor–β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo. Conclusions: We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor–β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Background. Uterine fibroids are most common in women aged 30-50 and are the most common benign gynecological tumors. Relevant data suggest that about 25% of patients with uterine fibroids are at childbearing age. Uterine fibroids not only cause the discomfort symptoms, and affect the pregnancy, but also have certain malignant transformation risk, thus needed to be treated positively and promptly. Aim. This study is aimed at exploring the effect of laparoscopic myomectomy and comprehensive rehabilitation nursing on patients with uterine fibroids. Methods. The clinical data of 110 cases of uterine fibroids admitted to our hospital from August 2019 to December 2021 were analyzed retrospectively, and they were divided into two groups according to postoperative rehabilitation strategies. Both groups were treated with laparoscopic myomectomy. The A group was treated with routine rehabilitation strategy, while the B group was treated with comprehensive rehabilitation nursing strategy. The differences in operation-related indicators, stress factors, inflammatory factors, nutritional indicators, knowledge mastery, occurrence of adverse symptoms and pain scores, negative emotion scores, nursing satisfaction, and simplified comfort status scale (GCQ) scores between the two groups under nursing strategies were compared. Results. The postoperative exhaust time ( 13.14 ± 2.03 ) h, bed time ( 9.86 ± 1.94 ) h, postoperative hospital stay ( 4.37 ± 1.31 ) d, and total hospital stay ( 6.78 ± 1.69 ) d in the B group were shorter than those in the A group, and the hospitalization expenses ( 0.74 ± 0.25 ) million were less than those in the A group ( P < 0.05 ). Before operation, stress factors, inflammatory factors, and nutritional indexes were compared between the two groups ( P > 0.05 ). On the 3rd day after operation, tumor necrosis factor-α (TNF-α), cortisol (Cor), norepinephrine (NE), and interleukin-1β (IL-1β) in the two groups showed a significantly upward trend compared with those before operation, and albumin and transferrin were significantly fell compared with those before operation. However, the values of stress factor and inflammatory factor in the B group were significantly lower than those in the A group, and the values after the decrease of nutritional index were significantly higher than those in the A group ( P < 0.05 ). The pain scores at 24 h, 48 h, and 72 h after operation in the B group were significantly lower than those in the A group ( P < 0.05 ). Negative emotions, nursing satisfaction, and GCQ scores were compared between the two groups before intervention ( P > 0.05 ). After the intervention, the scores of Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) in the two groups were significantly lower than those before the intervention, and the scores of nursing satisfaction and GCQ were higher than those before the intervention. The values of negative emotions in the B group after the decline were significantly lower than those in the A group, while the values of nursing satisfaction and GCQ after the increase were higher than those in the A group ( P < 0.05 ). The excellent and good rate of knowledge acquisition in the B group was 94.55% (52/55), which was significantly higher than 78.18% (43/55) in the A group ( P < 0.05 ). The incidence of adverse symptoms in the B group was 9.09% (5/55), which was lower than 21.82% (12/55) in the A group, while the difference was not statistically significant ( P > 0.05 ). Conclusion. Laparoscopic myomectomy combined with comprehensive rehabilitation nursing can reduce the postoperative stress state of patients with uterine fibroids, improve patient satisfaction, reduce adverse emotions, and promote rehabilitation.

Although photocatalytic water splitting has excellent potential for converting solar energy into chemical energy, the challenging charge separation process and sluggish surface catalytic reactions significantly limit progress in solar energy conversion using semiconductor photocatalysts. Herein, we demonstrate a feasible strategy involving the surface assembly of cobalt oxide species (CoOx) on a visible-light-responsive Cd0.9Zn0.1S (CZS) photocatalyst to fabricate a hierarchical CZS@CoOx heterostructure. The unique hierarchical structure effectively accelerates the directional transfer of photogenerated charges, reducing charge recombination through the smooth interfacial heterojunction between CZS and CoOx, as evidenced by photoluminescence (PL) spectroscopy and various electrochemical characterizations. The surface cobalt species on the CZS material also act as efficient cocatalysts for photocatalytic hydrogen production, with activity even higher than that of noble metals. The well-defined CZS@CoOx heterostructure not only enhances the interfacial separation of photoinduced charges, but also improves surface catalytic reactions. This leads to superior photocatalytic performances, with an apparent quantum efficiency of 20% at 420 nm for visible-light-driven hydrogen generation, which is one of the highest quantum efficiencies measured among noble-metal-free photocatalysts. Our work presents a potential pathway for controlling complex charge separation and catalytic reaction processes in photocatalysis, guiding the practical development of artificial photocatalysts for successful transformation of solar to chemical energy.

BackgroundArrhythmogenic Cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty replacement, systolic dysfunction and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. So far, treatment options are only symptomatic. Here, we investigate the relevance of defective desmosomal adhesion for ACM development and progression.MethodsWe mutated the binding site of desmoglein-2 (DSG2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 based on structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. We next generated a DSG2-W2A knock-in mouse model, which was analyzed by echocardiography and histological and bio-molecular techniques including RNA sequencing, transmission electron and super-resolution microscopy. The results were compared to ACM patient samples and their relevance was confirmed in cardiac slice cultures.ResultsThe DSG2-W2A mutation induced impaired binding and desmosomal adhesion dysfunction on cellular and molecular level. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent TGF-β signaling as driver of cardiac fibrosis. Accordingly, blocking antibodies targeting integrin-αVβ6 or inhibition of TGF-β receptor signaling both led to reduced expression of pro-fibrotic markers in cardiac slice cultures.ConclusionsHere, we show that disruption of desmosomal adhesion is sufficient to induce ACM, which confirms the dysfunctional adhesion hypothesis. Mechanistically, deregulation of integrin-αVβ6 signaling was identified as a central step towards fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Clinical translation of ultrasound molecular imaging will depend on the development of binders that can easily be generated, manufactured and coupled, and that are compatible with in vivo use. We describe targeted microbubbles (MBs) using designed ankyrin repeat proteins (DARPins) as a novel class of such translatable binders. Candidate DARPin binders for vascular cell adhesion molecule 1, an endothelial cell adhesion molecule involved in inflammatory processes, were selected using ribosome display and coupled to MBs. Flow-chamber assays of five MBs carrying high-affinity binders showed selective retention on endothelial cells activated by tumor necrosis factor-α for two binders compared with a MB carrying a control DARPin. In vivo ultrasound molecular imaging in a murine hind-limb inflammation model demonstrated up to a fourfold signal enhancement for three of the five MBs versus control. However, there was no correlation between results from flow-chamber assays and in vivo imaging. Thus, we conclude that ultrasound molecular imaging of inflammation using DARPin binders is feasible per se, but that screening of candidates cannot be accomplished with flow-chamber assays as used in our study.

AIMS: Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood.METHODS AND RESULTS: NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1β- and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts, but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to LPS in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD.CONCLUSIONS: NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodeling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.TRANSLATIONAL PERSPECTIVE: In their multifactorial pathogenesis, diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) still remain poorly understood. They frequently occur in patients with obesity and metabolic syndrome. Microvascular inflammation and dysfunction have recently been recognized as major driving forces. We show that genetic deletion of Nox1 prevents cardiac inflammation, remodeling and dysfunction in metabolic disease in mice and find NOX1 upregulated in peripheral monocytes of patients with DD. These findings add to our understanding how obesity, inflammation and heart disease are linked, which is a prerequisite to find therapeutic strategies beyond the control of co-morbidities in HFpEF.

Objective: Contrast-enhanced ultrasound molecular imaging (CEUMI) of endothelial expression of VCAM (vascular cell adhesion molecule)-1 could improve risk stratification for atherosclerosis. The microbubble contrast agents developed for preclinical studies are not suitable for clinical translation. Our aim was to characterize and validate a microbubble contrast agent using a clinically translatable single-variable domain immunoglobulin (nanobody) ligand. Approach and Results: Microbubble with a nanobody targeting VCAM-1 (MB cAbVcam1-5 ) and microbubble with a control nanobody (MB VHH2E7 ) were prepared and characterized in vitro. Attachment efficiency to VCAM-1 under continuous and pulsatile flow was investigated using activated murine endothelial cells. In vivo CEUMI of the aorta was performed in atherosclerotic double knockout and wild-type mice after injection of MB cAbVcam1-5 and MB VHH2E7 . Ex vivo CEUMI of human endarterectomy specimens was performed in a closed-loop circulation model. The surface density of the nanobody ligand was 3.5×10 5 per microbubble. Compared with MB VHH2E7 , MB cAbVcam1-5 showed increased attachment under continuous flow with increasing shear stress of 1-8 dynes/cm 2 while under pulsatile flow attachment occurred at higher shear stress. CEUMI in double knockout mice showed signal enhancement for MB cAbVcam1-5 in early ( P =0.0003 versus MB VHH2E7 ) and late atherosclerosis ( P =0.007 versus MB VHH2E7 ); in wild-type mice, there were no differences between MB cAbVcam1-5 and MB VHH2E7 . CEUMI in human endarterectomy specimens showed a 100% increase in signal for MB cAbVcam1-5 versus MB VHH2E7 (20.6±27.7 versus 9.6±14.7, P =0.0156). Conclusions: CEUMI of the expression of VCAM-1 is feasible in murine models of atherosclerosis and on human tissue using a clinically translatable microbubble bearing a VCAM-1 targeted nanobody.

After the model training and simulation, the data accuracy reaches the expected requirements, which proves that the BP neural network is effective and convenient for the risk evaluation of online loan platform, and proves the effectiveness of the modern evaluation methods such as BP neural network applied to the evaluation of online loan platform, which provides a broader research prospect for the future research. In addition, from the perspective of national regulators, platform itself and investors, this paper describes the use scenarios of the risk assessment method in this paper, and puts forward corresponding suggestions for the control and risk identification of online lending platform.

Mammalian target of rapamycin (mTOR) is an evolutionary conserved kinase that senses the nutrient and energy status of cells, the availability of growth factors, stress stimuli and other cellular and environmental cues. It responds by regulating a range of cellular processes related to metabolism and growth in accordance with the available resources and intracellular needs. mTOR has distinct functions depending on its assembly in the structurally distinct multiprotein complexes mTORC1 or mTORC2. Active mTORC1 enhances processes including glycolysis, protein, lipid and nucleotide biosynthesis, and it inhibits autophagy. Reported functions for mTORC2 after growth factor stimulation are very diverse, are tissue and cell-type specific, and include insulin-stimulated glucose transport and enhanced glycogen synthesis. In accordance with its cellular functions, mTOR has been demonstrated to regulate cardiac growth in response to pressure overload and is also known to regulate cells of the immune system. The present manuscript presents recently obtained insights into mechanisms whereby mTOR may change anabolic, catabolic and stress response pathways in cardiomocytes and discusses how mTOR may affect inflammatory cells in the heart during hemodynamic stress. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

During stress conditions such as pressure overload and acute ischemia, the myocardial endothelium releases neuregulin-1β (NRG-1), which acts as a cardioprotective factor and supports recovery of the heart. Recently, we demonstrated that recombinant human (rh)NRG-1 enhances glucose uptake in neonatal rat ventricular myocytes via the ErbB2/ErbB4 heterodimer and PI3Kα. The present study aimed to further elucidate the mechanism whereby rhNRG-1 activates glucose uptake in comparison to the well-established insulin and to extend the findings to adult models. Combinations of rhNRG-1 with increasing doses of insulin did not yield any additive effect on glucose uptake measured as 3H-deoxy-d-glucose incorporation, indicating that the mechanisms of the two stimuli are similar. In c-Myc-GLUT4-mCherry-transfected neonatal rat cardiomyocytes, rhNRG-1 increased sarcolemmal GLUT4 by 16-fold, similar to insulin. In contrast to insulin, rhNRG-1 did not phosphorylate IRS-1 at Tyr612, indicating that IRS-1 is not implicated in the signal transmission. Treatment of neonatal rats with rhNRG-1 induced a signaling response comparable with that observed in vitro, including increased ErbB4-pTyr1284, Akt-pThr308 and Erk1/2-pThr202/Tyr204. In contrast, in adult cardiomyocytes rhNRG-1 only increased the phosphorylation of Erk1/2 without having any significant effect on Akt and AS160 phosphorylation and glucose uptake, suggesting that rhNRG-1 function in neonatal cardiomyocytes differs from that in adult cardiomyocytes. In conclusion, our results show that similar to insulin, rhNRG-1 can induce glucose uptake by activating the PI3Kα-Akt-AS160 pathway and GLUT4 translocation. Unlike insulin, the rhNRG-1-induced effect is not mediated by IRS proteins and is observed in neonatal, but not in adult rat cardiomyocytes.

Using China as a case study, this paper explores the integrated regional ecological risk assessment of multiple stressors and multiple receptors on a large spatial scale. The objective is to provide scientific data to support ecological risk identification and prevention. To carry out this assessment, ten natural disasters were chosen as risk sources, and twenty-two ecosystems were chosen as risk receptors. The vulnerability of environment where these ecosystems existed was taken into consideration. Using the software platform GIS, the ecological risk of each disaster was evaluated, the integrated assessment for all disasters was compiled, and the integrated risk of different ecosystems was obtained. All results were shown in assessment maps. The results show that forty-five percent of the ecosystems’ areas in China face high or medium ecological risks. This result indicates that the establishment of ecosystem protection and ecological risk prevention mechanisms in China is still a long-term, difficult task, requiring the rational use and conservation of forests, meadows, farmland, wetlands, and other ecosystems alike is of great necessity. The uncertainty analysis of risk assessment using the Monte Carlo Simulation method demonstrated the results to be reliable and credible.

The association between abdominal obesity (as measured by waist circumference (WC) and waist-to-hip ratio (WHR)) and colorectal cancer (CRC) has not been fully quantified, and the magnitude of CRC risk associated with abdominal obesity is still unclear. A meta-analysis of prospective studies was performed to elucidate the CRC risk associated with abdominal obesity. Pubmed and Embase were searched for studies assessing the association between abdominal obesity and CRC risk. Relative risks (RRs) with 95% confidence intervals (95% CIs) were pooled using random-effects model of meta-analysis. Nineteen prospective cohort studies from eighteen publications were included in this meta-analysis. A total of 12,837 CRC cases were identified among 1,343,560 participants. Greater WC and WHR were significantly associated with increased risk of total colorectal cancer (WC: RR 1.42, 95% CI 1.30, 1.55; WHR: RR 1.39, 95% CI 1.25, 1.53), colon cancer (WC: RR 1.53, 95% CI 1.36, 1.72; WHR: 1.39, 95% CI 1.18, 1.63), and rectal cancer (WC: RR 1.20, 95% CI 1.03, 1.39; WHR: RR 1.22, 95% CI 1.05, 1.42). Subgroup analyses further identified the robustness of the association above. No obvious risk of publication bias was observed. In summary, abdominal obesity may play an important role in the development of CRC.

Background: Neuregulin (Nrg)1β is a growth factor that activates PI3K/Akt and Src/FAK via the ErbB2/ErbB4 receptors. Although it is currently in clinical trial to treat haert failure, it remains unclear which cellular mechanisms are responsible for its cardioprotective actions. Here we tested if Nrg1β regulates glucose uptake in cardiomyocytes and analyzed the underlying signaling mechanisms. Methods: Neonatal rat ventricular myocytes were treated with Nrg1β (10ng/ml) in combination with the mTOR inhibitors PP242 (2mM) and rapamycin (20ng/ml), the ErbB2 inhibitor lapatinib (1mM), the Src inhibitor PP2 (5mM), the Akt inhibitor VIII (20mM), or vehicle. Cells were pre-incubated for 30 min with the inhibitors and proteins extracted 30 min after the addition of Nrg1β for analysis by Western blot. Glucose uptake was assessed by measuring the incorporation of 3H-D-glucose for 30 min. ErbB2 or ErbB4 receptors were knocked down with siRNA for 48h before Nrg1β treatment. Results: Similar to IGF-I and Insulin, Nrg1β caused a 1.9 fold increase in 3H-D-glucose incorporation (P< 0.01). Nrg1β induced phosphorylation of mTOR (S2448), Akt (S308) and FAK (Y861), as well as of the mTORC1 targets 4E-BP1, p70-S6K1 and ULK and the mTORC2 target Akt (S473). Lapatinib, PP242 and Akt inhibitor VIII blocked the Nrg1β-induced Akt-, mTOR-, p70-S6K1-, ULK-, and 4E-BP1-phosphorylation, indicating that these effects require ErbB2 and are mediated by Akt and mTOR. However, only lapatinib and Akt inhibitor VIII fully blocked the Nrg1β-induced glucose uptake; PP242 partially blocked it and rapamycin did not block it at all. These results suggest that Akt is required for Nrg1β-induced glucose uptake, and that mTORC2-dependent Akt phosphorylation mediates, at least in part, this response. PP2 blocked phosphorylation of FAK as expected, and it also partially blocked phosphorylation of Akt (S473) and p70-S6K1. PP2 also decreased general glucose uptake (0.6-fold of Ctl, p

Arenaviruses such as Lassa virus (LASV) cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. Here we used HLA-A2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (LCMV-WE), a close relative of LASV, to investigate the pathophysiology of arenavirus hemorrhagic fever (AHF). AHF manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic shock. A characteristic cytokine storm included numerous pro-inflammatory cytokines and nitric oxide (NO) metabolites. Edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), although the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and interferon-γ (IFN-γ)-dependent fashion. Accordingly, blockade of IFN-γ or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia. We identify the IFN-γ-iNOS axis as an essential and potentially druggable molecular pathway to AHF-induced shock.

Most catastrophic disasters are triggered by multi-hazards that occur simultaneously or sequentially rather than singly; this can result in more severe consequences. Therefore, it is necessary to understand the occurrence, development, and transformation of hazard chains and comprehend their rules in order to predict secondary hazards. An effective action for reducing potential losses can be taken to block a hazard chain before it expands and transforms. Many studies have been conducted on hazard chains, some of which are of great significance. This article is a comprehensive literature review on hazard chains. First, an introduction to the definition, classification, and recognition of hazard chains is given. Then, some typical researches on mechanical studies of geological hazard chains, meteorological hazard, chains and geological–meteorological hazard chains are presented. On the basis of case studies on hazard chains, the following comprehensive methodologies are summarized: (1) engineering geology methodology, (2) integrated geographical assessment methodology, (3) system dynamics methodology, and (4) methodology of disaster physics. Reconstruction as a part of the disaster process is also reviewed. However, the research presented is still in the beginning stage; neither the mechanics nor the methodology is finalized. Research on hazard chains still has a long way to go.

Objective— Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation Approach and Results— Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MB V ), to platelet glycoprotein Ibα (MB Pl ), and control microbubbles (MB Ctr ). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MB V (1.3±0.3 AU) and MB Pl (1.5±0.5 AU) was higher than for MB Ctr (0.5±0.2 AU; P P V : 0.3±0.1; MB Pl : 0.4±0.1; MB Ctr : 0.3±0.2 AU; P =0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% ( P Conclusions— Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden.

Risk assessment of soil erosion addresses the likelihood of the occurrence of erosion as well as its consequences. This in turn can provide precautionary and relevant suggestions to assist with disaster reduction. In light of the great threat of soil erosion to global soil resources, it is necessary to implement this type of risk assessment. This study aims to appraise the risk of soil erosion caused by water along the Bohai Sea region during the rainy season. A new method, namely the RUSLE–IDM coupled model, which embeds the IDM (Information Diffusion Model) into the RUSLE(Revised Universal Soil Loss Equation)model, is applied to reveal soil erosion risk in different scenarios, with rainfall exceeding the probability of 0.1 and 0.02 respectively. From this case study, three conclusions can be drawn as follows: (i) This coupled method can effectively examine soil erosion risk and show comparable results of different scenarios, which cannot only calculate the erosion amount, but also identify the likelihood; (ii) Soil erosion caused by water is serious from July to September, but comparatively speaking, the greatest amount of attention should be paid to the prevention of soil erosion in July, as the erosion amount at this time is times larger than during September; (iii) Vegetation coverage and soil erosion control practices are controllable and important factors for the future soil conservation in this area.

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2β-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2β-Ph2COCH2-3β-4-Cl-Ph analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2β compounds increased locomotion, only the 2β-(4-ClPh)PhCOCH2-3β-4-Cl-Ph analog had cocaine-like efficacy. None of the 2α-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)- compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2β- and 2α-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine.

Background— Cardiac tests for diagnosing myocarditis lack sensitivity or specificity. We hypothesized that contrast-enhanced ultrasound molecular imaging could detect myocardial inflammation and the recruitment of specific cellular subsets of the inflammatory response in murine myocarditis. Methods and Results— Microbubbles (MB) bearing antibodies targeting lymphocyte CD4 (MB CD4 ), endothelial P-selectin (MB PSel ), or isotype control antibody (MB Iso ) and MB with a negative electric charge for targeting of leukocytes (MB Lc ) were prepared. Attachment of MB CD4 was validated in vitro using murine spleen CD4+ T cells. Twenty-eight mice were studied after the induction of autoimmune myocarditis by immunization with α-myosin-peptide; 20 mice served as controls. Contrast-enhanced ultrasound molecular imaging of the heart was performed. Left ventricular function was assessed by conventional and deformation echocardiography, and myocarditis severity graded on histology. Animals were grouped into no myocarditis, moderate myocarditis, and severe myocarditis. In vitro, attachment of MB CD4 to CD4+ T cells was significantly greater than of MB Iso . Of the left ventricular ejection fraction or strain and strain rate readouts, only longitudinal strain was significantly different from control animals in severe myocarditis. In contrast, contrast-enhanced ultrasound molecular imaging showed increased signals for all targeted MB versus MB Iso both in moderate and severe myocarditis, and MB CD4 signal correlated with CD4+ T-lymphocyte infiltration in the myocardium. Conclusions— Contrast-enhanced ultrasound molecular imaging can detect endothelial inflammation and leukocyte infiltration in myocarditis in the absence of a detectable decline in left ventricular performance by functional imaging. In particular, imaging of CD4+ T cells involved in autoimmune responses could be helpful in diagnosing myocarditis.

Aims Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart. Methods and results Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)βII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCβII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts. Conclusion Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart.

Item does not contain fulltext Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1Y522S) had longer bleeding times than their wild-type littermates. Primary vascular smooth muscle cells from RYR1Y522S knock-in mice exhibited a higher frequency of subplasmalemmal Ca(2+) sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1Y522S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca(2+) sparks in primary vascular smooth muscle cells from the MHS RYR1Y522S mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.

Research on changes of land use in natural reserves is a critical issue and discussion of land use policies relevant to them is needed for their preservation in face of pressures of local socio-economic development. This study examined Tianjin Palaeocoast and Wetland National Natural Reserve (TJPW) and reviewed its development processes, status of adjustments and evolutionary mechanisms. Land use/cover change (LUCC), driving forces, adjustment schemes, and land use policy changes were also investigated. Land use changes were studied by supervised classification of Landsat TM remote sensing images of 1988, 1998, and 2008, respectively. Local economic development is the main driving force of LUCC. As such, it is critical to lay out a scientific, integrated development plan for adjustment that pays more attention to changes in natural reserve land properties and establishes ecological protection networks. In addition, the ecological integrity of natural reserves needs to be preserved and sustained instead of randomly modifying their boundaries to meet the demand of key infrastructure projects. Therefore, the results described in the study provides a detailed reference model that can lead to adopt boundary adjustment strategy to balance coastal wetland protection and a sustainable development of resource’s management.

In the last decade, 1D semiconductor nanostructures attracted much attention due to their potential applications in electronics, optoelectronics, sensor, and biotechnology. Among various synthetic strategies, the electrochemical method is a relatively simple and effective way to prepare 1D semiconductor nanostructures. Moreover, electrochemical methods can afford precise processes for controlling the compositions and morphologies of the nanostructured materials. In this review, we present a systematic description of the electrochemical synthesis of oriented and hierarchical quasi-1D semiconducting nanostructures. The main contents containing: (1) electrodeposition of materials in hard porous membranes templates with 1D pore geometry or under assistance of the capping reagents for oriented nanowires/nanorods film; (2) multi-step template replication methods, two-step synthetic strategy and anodization methods for uniform nanotube arrays; (3) electrochemical synthetic strategies for complex hierarchical nanostructured films. Additionally, we give a brief introduction about the applications of these quasi-1D semiconducting nanostructures.

Herein, we developed a novel anodic electrodeposition route to prepare shape-controlled α-FeOOH thin films on indium tin oxide (ITO) substrates in aqueous (NH4)2Fe(SO4)2 solutions. Different morphologies of α-FeOOH products, including platelets, rhombohedral rods, square rods, six-fold snowflakes, and hexagonal particles were obtained by controlling the growth rates of various facets of the deposit with appropriate capping agents. Furthermore, we demonstrated that α-FeOOH films can be transferred into α-Fe2O3 nanostructures with the same morphologies through a thermal annealing process.

We present a facile route to preparing nonspherical half-shells of copper sulfide in which the octahedral mesocages of copper sulfide were grown on the substrate by a two-step electrochemical method first and then were cleaved into tetrahedral half-shells by ultrasonic vibration in water. The obtained half-shells are 1−3 μm in lengths, and the shell thickness is uniform in ∼100 nm. It is found that only centrosymmetric octahedral and six-pod shells can be equally split into two similar half-shells. Furthermore, a finite element analysis has been used to model the stress distribution in the octahedral CuS shell structure during ultrasonic vibration.

We present a two-step electrochemical deposition process to produce hierarchical ZnO nanostructures that involves the electrodeposition of ZnO crystals with different morphologies, followed by the electrochemical epitaxial growth of oriented nanorods on the surfaces of the primary ZnO nanostructures. A variety of hierarchical ZnO nanostructures, including 2-fold nanorod arrays on nanosheets, 6-fold nanorods on nanorods, and 6-fold nanoneedles on nanoneedles, were synthesized on a large scale. The hierarchical nanostructures obtained by this technique are pure and uniform in morphology. Furthermore, we demonstrate that the hierarchical ZnO nanostructure of nanorods on nanosheets provides a good candidate for photoanodes in dye-sensitized solar cells.

Large-scale and highly oriented single-crystalline ZnO nanotubes on conductive glass substrates have been realized by a two-step solution approach, which involves the electrodeposition of oriented ZnO nanorods and subsequently coordination-assisted selective dissolution along the c-axis to form tubular structure caused by preferential adsorption of ethylenediamine (EDA) and OH- on different crystal faces. After dissolution in aqueous EDA solution for 10−15 h, the inner/outer wall surfaces of the obtained ZnO nanotubes are quite smooth and the wall thickness is uniform in ∼10−30 nm. Furthermore, a strong near-band gap ultraviolet stimulated emission at a wavelength of 389 nm with a half-maximum of 3 nm is observed at room temperature.

Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473but does not modify AS160-p-Thr642or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

Previous structure-activity studies indicated that a series of cocaine analogs (3s-aryltropanes with various 2s-diarylmethoxy substitutions) selectively bind the dopamine transporter (DAT) with nM ...

As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency. Di-substitution at the 7,8-positions, in general, was found to result in potent compounds. 7-NMe2, 7-NHEt, 7-OMe, and 7,8-di-NH2 analogs were found to have similar SAR for the 4-aryl group, and several 7-substituted and 7,8-di-substituted analogs were found to have similar potencies as the lead compound MX58151 (2a) both as caspase activators and inhibitors of cell proliferation.

3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT. These SAR studies provide further evidence for the varied binding requirements of structurally diverse tropane-based ligands and support future studies to elucidate DAT binding requirements in relation to cocaine-like behavioral endpoints.

A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2beta-(R)-alcohol 10 over the 2beta-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse.

Delivery of genetically modified cells overexpressing Vascular Endothelial Growth Factor (VEGF) is a promising approach to induce therapeutic angiogenesis in ischemic tissues. The effect of the protein is strictly modulated by its interaction with the components of the extracellular matrix. Its therapeutic potential depends on a sustained but controlled release at the microenvironmental level in order to avoid the formation of abnormal blood vessels. In this study, it is hypothesized that the composition of the scaffold plays a key role in modulating the binding, hence the therapeutic effect, of the VEGF released by 3D-cell constructs. It is found that collagen sponges, which poorly bind VEGF, prevent the formation of localized hot spots of excessive concentration, therefore, precluding the development of aberrant angiogenesis despite uncontrolled expression by a genetically engineered population of adipose tissue-derived stromal cells. On the contrary, after seeding on VEGF-binding egg-white scaffolds, the same cell population caused aberrantly enlarged vascular structures after 14 d. Collagen-based engineered tissues also induced a safe and efficient angiogenesis in both the patch itself and the underlying myocardium in rat models. These findings open new perspectives on the control and the delivery of proangiogenic stimuli, and are fundamental for the vascularization of engineered tissues/organs.

China is one of the most severely affected countries by coastal erosion. About 70% of the sandy beaches and most of muddy tidal flat in open water regions are erode. Coastal erosion results in the width of beach being narrowed, bathing beach destruction, coast-protection facilities and roads collapse, and wetland deterioration. These destructions bring many losses to the local people. However, previous coastal erosion studies focused on the hazard of erosion and paid less attention to the risk of erosion. Therefore, it’s necessary to study the mechanism of coastal erosion and build the coastal erosion risk assessment system for the effective coastal management. On the basis of the existed researches, this paper builds the coastal erosion risk assessment index system which contains hazard index system and vulnerability index system. The index system is expected to provide a practical theoretical basis for coastal erosion risk assessment.

Objectives The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart. Background FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure. Methods Myocardial infarction was induced in mice by permanent ligation of the left anterior descending coronary artery followed by intramyocardial injection of FLT3 ligand (FL) or vehicle into the infarct border zone. Cardiac morphology and function were assessed by echocardiography and histological analysis 1 week after infarction. In addition, FLT3 expression and regulation, as well as molecular mechanisms of FLT3 action, were examined in cardiomyocytes in vitro. Results The intramyocardial injection of FL into the infarct border zone decreased infarct size and ameliorated post-myocardial infarction remodeling and function in mice. This beneficial effect was associated with reduced apoptosis, including myocytes in the infarct border zone. Cardiomyocytes expressed functional FLT3, and FLT3 messenger ribonucleic acid and protein were up-regulated under oxidative stress, identifying cardiomyocytes as FL target cells. FLT3 activation with FL protected cardiomyocytes from oxidative stress–induced apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway. Conclusions FLT3 is a cytoprotective system in the heart and a potential therapeutic target in ischemic cardiac injury. The protective mechanisms uncovered here may be further explored in view of potential cardiotoxic effects of FLT3-targeting anticancer therapy, particularly in patients with ischemic heart disease.