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.
The mammalian target of rapamycin (mTOR) activates the biosynthesis of macromolecules needed for cardiomyocyte and immune cell growth.•By modulating immunoproteasomal degradation, mTOR may modify inflammatory responses and hypertrophy of the heart.•mTORC1 and mTORC2 regulate cardiac metabolism, hypertrophy and contractility.
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.
► We assess soil erosion risk using a newly coupled method, namely RUSLE–IDM. ► We examine differences of soil erosion risk among July, August and September at two rainfall scenarios respectively. ► The RUSLE–IDM method is effective, facilitating rainfall uncertainty in soil erosion risk. ► The greatest amount of attention should be paid to the prevention of soil erosion in July.
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.
Myocarditis can lead to myocyte loss and myocardial fibrosis resulting in dilated cardiomyopathy (DCMP). Currently employed methods for assessing the risk for development of DCMP are inaccurate or ...rely on invasive myocardial biopsies. We hypothesized that molecular imaging of tissue inflammation with contrast enhanced ultrasound during peak inflammation in myocarditis could predict development of fibrosis and impaired left ventricular function.
Experimental autoimmune myocarditis (EAM) was induced in Balbc mice by injection of the α-myosin heavy chain peptide. Contrast enhanced ultrasound (CEU) using microbubbles targeted to leukocytes (MBLc), to CD4+ lymphocytes (MBCD4), and to the endothelial cell adhesion molecule P-selectin (MBPSel) was performed during the expected EAM peak inflammatory activity 21 days after induction. High resolution ultrasound, invasive hemodynamic measurements and fibrosis quantification were done 63 days after EAM assessment. All tested microbubbles correlated to fibrosis (MBLc spearman r 0.28, p 0.047, MBCD4 r 0.44, p 0.01, MBPSel r 0.73, p 0.02), however, correlations were weak overall and the spread of data was considerable. Also, targeted CEU data on day 21 did not correlate to hemodynamic and functional data on day 63.
Ultrasound molecular imaging using targeted microbubbles during the peak inflammatory activity of myocarditis correlates weakly with later development of fibrosis but not with hemodynamic or left ventricular functional parameters.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
Inflammatory changes on the endothelium are responsible for leukocyte recruitment to plaques in atherosclerosis. Noninvasive assessment of treatment-effects on endothelial inflammation may be of use ...for managing medical therapy and developing novel therapies. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) with contrast enhanced ultrasound (CEU) could assess treatment effects on endothelial phenotype in early atherosclerosis.
Mice with atherosclerosis produced by gene deletion of the LDL-receptor and Apobec-1-editing protein were studied. At 12 weeks of age, mice received 8 weeks of regular chow or atorvastatin-enriched chow (10 mg/kg/day). At 20 weeks, CEU molecular imaging for aortic endothelial VCAM-1 expression was performed with VCAM-1-targeted (MB(VCAM)) and control microbubbles (MB(Ctr)). Aortic wall thickness was assessed with high frequency ultrasound. Histology, immunohistology and Western blot were used to assess plaque burden and VCAM-1 expression.
Plaque burden was reduced on histology, and VCAM-1 was reduced on Western blot by atorvastatin, which corresponded to less endothelial expression of VCAM-1 on immunohistology. High frequency ultrasound did not detect differences in aortic wall thickness between groups. In contrast, CEU molecular imaging demonstrated selective signal enhancement for MB(VCAM) in non-treated animals (MB(VCAM) 2±0.3 vs MB(Ctr) 0.7±0.2, p<0.01), but not in statin-treated animals (MB(VCAM) 0.8±0.2 vs MB(Ctr) 1.0±0.2, p = ns; p<0.01 for the effect of statin on MB(VCAM) signal).
Non-invasive CEU molecular imaging detects the effects of anti-inflammatory treatment on endothelial inflammation in early atherosclerosis. This easily accessible, low-cost technique may be useful in assessing treatment effects in preclinical research and in patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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