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Vascular endothelial growth factor (VEGF)- driven increase in vascular permeability is a key feature of many disease states associated with inflammation and ischemic injury, contributing significantly to morbidity and mortality in these settings. Despite its importance, no specific regulators that preferentially control VEGF-dependent increase in permeability versus its other biological activities, have been identified. Here we report that a proteoglycan Syndecan-2 (Sdc2) regulates the interaction between a transmembrane phosphatase DEP1 and VEGFR2 by controlling cell surface levels of DEP1. In the absence of Sdc2 or the presence of an antibody that blocks Sdc2-DEP1 interaction, increased plasma membrane DEP1 levels promote selective dephosphorylation of the VEGFR2 Y951 site that is involved in permeability control. Either an endothelial-specific Sdc2 deletion or a treatment with an anti-Sdc2 antibody result in a highly significant reduction in stroke size due to a decrease in intracerebral edema.

Understanding how plants adjust their requirements for different N forms can help elucidate plant coexistence strategies in N-limited desert ecosystems. To understand the mechanisms involved, we investigated whether two desert herbs can directly absorb dissolved organic nitrogen (N) and tested whether the patterns changed over different growth stages. Two dominant herbaceous species, Astragalus arpilobus and Arnebia decumbens, from the southern edge of the Gurbantunggut desert, China, were selected. Short-term (24 h)

Vascular complications are a major cause of illness and death in type 1 diabetes (T1D). Diabetic vascular basement membranes are enriched in fibronectin (FN), an extracellular matrix protein that amplifies inflammatory signaling in endothelial cells through its main receptor, integrin α5β1. Binding of the integrin α5 cytoplasmic domain to phosphodiesterase 4D5 (PDE4D5), which increases PDE catalytic activity and inhibits anti-inflammatory cAMP signaling, was found to mediate these effects. Here, we examined mice in which the integrin α5 cytoplasmic domain is replaced by that of α2 (integrin α5/2) or the integrin α5 binding site in PDE4D is mutated (PDE4Dmut). T1D was induced via injection of streptozotocin and hyperlipidemia induced via injection of PCSK9 virus and high fat diet. We found that in T1D and hyperlipidemia, the integrin α5/2 mutation reduced atherosclerosis plaque size by ~50%, with reduced inflammatory cell invasion and metalloproteinase expression. Integrin α5/2 T1D mice also showed improved blood flow recovery from hindlimb ischemia and improved biomechanical properties of the carotid artery. By contrast, the PDE4Dmut had no beneficial effects in T1D. FN signaling through integrin α5 is thus a major contributor to diabetic vascular disease but not through its interaction with PDE4D.

Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3–MEK5–ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK–MEK5–ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.

Epigenomic-wide DNA methylation profiling holds the potential to reflect both electronic cigarette exposure-associated risks and individual poor health outcomes. However, a systemic study in animals or humans is still lacking. Using the Infinium Mouse Methylation BeadChip, we examined the DNA methylation status of white blood cells in male ApoE-/- mice after 14 weeks of electronic cigarette exposure with the InExpose system (2 hr/day, 5 days/week, 50% PG and 50% VG) with low (6 mg/ml) and high (36 mg/ml) nicotine concentrations. Our results indicate that electronic cigarette aerosol inhalation induces significant alteration of 8,985 CpGs in a dose-dependent manner (FDR

Arterial remodeling is an important adaptive mechanism that maintains normal fluid shear stress in a variety of physiologic and pathologic conditions. Inward remodeling, a process that leads to reduction in arterial diameter, plays a critical role in progression of such common diseases as hypertension and atherosclerosis. Yet despite its pathogenic importance, molecular mechanisms controlling inward remodeling remain undefined. Mitogen-activated protein kinases (MAPKs) perform a number of functions ranging from control of proliferation to migration and cell fate transitions. While the MAPK ERK1/2 signaling pathway has been extensively examined in the endothelium, less is known about the role of the MEKK3/ERK5 pathway in vascular remodeling. To better define the role played by this signaling cascade, we studied the effect of endothelial-specific deletion of its key upstream MAP3K, MEKK3, in adult mice. The gene’s deletion resulted in a gradual inward remodeling of both pulmonary and systematic arteries leading to spontaneous hypertension in both vascular circuits and accelerated progression of atherosclerosis in hyperlipidemic mice. Molecular analysis revealed activation of TGFβ signaling both in vitro and in vivo. Endothelial-specific TGFβR1 knockout prevented inward arterial remodeling in MEKK3 endothelial knockout mice. These data point to the unexpected participation of endothelial MEKK3 in regulation of TGFβR1-Smad2/3 signaling and inward arterial remodeling in artery diseases.SignificanceInward remodeling of arteries to reduce lumen diameter is a major factor in disease progression and morbidity in multiple vascular diseases, including hypertension and atherosclerosis. However, molecular mechanisms controlling inward arterial remodeling remain largely undefined. In this study, we identify endothelial MEKK3 as an unexpected regulator of inward remodeling via inhibition of TGFβ-Smad2/3 signaling. Genetic deletion of MEKK3 in adult endothelium results in induction of TGFβ-Smad2/3 signaling, endothelial-to-mesenchymal transition and inward remodeling in both pulmonary and arterial circuits. The latter process results in pulmonary and systemic hypertension and accelerates atherosclerosis. These results provide a new basis for understanding the inward artery remodeling that leads to reduced blood flow to affected tissues and exacerbates hypertension in vascular disease.

Vascular complications are a major cause of illness and death in patients with type 1 diabetes (T1D). Diabetic vascular basement membranes are enriched in fibronectin (FN), an extracellular matrix protein that amplifies inflammatory signaling in endothelial cells through its main receptor, integrin α5β1. Binding of the integrin α5 cytoplasmic domain to phosphodiesterase 4D5 (PDE4D5), which increases phosphodiesterase catalytic activity and inhibits antiinflammatory cAMP signaling, was found to mediate these effects. Here, we examined mice in which the integrin α5 cytoplasmic domain is replaced by that of α2 (integrin α5/2) or the integrin α5 binding site in PDE4D is mutated (PDE4Dmut). T1D was induced via injection of streptozotocin and hyperlipidemia induced via injection of PCSK9 virus and provision of a high-fat diet. We found that in T1D and hyperlipidemia, the integrin α5/2 mutation reduced atherosclerosis plaque size by ∼50%, with reduced inflammatory cell invasion and metalloproteinase expression. Integrin α5/2 T1D mice also had improved blood-flow recovery from hindlimb ischemia and improved biomechanical properties of the carotid artery. By contrast, the PDE4Dmut had no beneficial effects in T1D. FN signaling through integrin α5 is thus a major contributor to diabetic vascular disease but not through its interaction with PDE4D.

Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-β family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-β signaling., info:eu-repo/semantics/published

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The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA165 signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene. These differences are due to a significantly higher 6-O sulfation level in Sdc2 versus Sdc4 heparan sulfate (HS) chains, leading to an increase in VEGFA165 binding sites and formation of a ternary Sdc2-VEGFA165-VEGFR2 complex which enhances VEGFR2 activation. The increased Sdc2 HS chains 6-O sulfation is driven by a specific N-terminal domain sequence; the insertion of this sequence in Sdc4 N-terminal domain increases 6-O sulfation of its HS chains and promotes Sdc2-VEGFA165-VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities., Proteoglycans are glycosylated proteins that play a number of structural and signalling functions. Here, Corti, Wang et al. show that the N-terminal sequence of proteoglycan Syndecan-2 selectively increases 6-O sulfation of its heparan sulfate chains, and that this promotes formation of a ternary Sdc2/VEGFA/VEGFR2 complex leading to increased angiogenesis.

The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.

Largehead atractylodes rhizome, known as "the first essential medicine for invigorating qi and strengthening spleen" , is one of the most commonly used Chinese materia medica. According to the different clinical treatment requirements, largehead atractylodes rhizome can be processed into a variety types of products, such as raw, fried with earth, stir-frying with bran, and deep-fried largehead atractylodes rhizome. The processing quality is of great significance to ensure the efficacy, drug safety and improve the preparation process. Through the detailed research on the processing methods of largehead atractylodes rhizome in ancient books, modern documents and norms, this study clarifies the history and evolution of the processing technology of largehead atractylodes rhizome in ancient and modern times, and summarizes the internal laws and external factors of the processing technology changes by combining the processing technology differences, materials addition and theoretical analysis of pharmacodynamics. It not only saves the tedious and repeated steps, but also improves and optimizes the efficacy and quality of the preparation, and gets standardization and unification in the follow-up practice, which provides a reference for the research and development of the processing technology of largehead atractylodes rhizome and other Chinese materia medica.白术被古人誉为"补气健脾第一要药"，是中医临床常用的大宗药材之一。根据临床治疗要求的不同可有生用白术、土炒白术、麸炒白术、焦白术等多种炮制品。炮制质量对保障药效、用药安全及提高制剂工艺等具有十分重要的意义。通过对历代古籍、近现代文献和规范中白术炮制方法的详尽考证，厘清白术历代炮制沿革的脉络，并结合炮制工艺差异、辅料添加及药效理论分析等，总结得出炮制工艺变革的内在规律和外在因素，即省却了繁琐和重复的步骤又同时提高和优化了炮制方剂的疗效和质量，并在后续的实践中得到规范与统一，为白术乃至其他中药材炮制工艺研究与发展提供参考。.

Lei's medicine is the main school of traditional Chinese medicine in Quzhou, Zhejiang Province. It originated from Xin'an medical school. It has been passed on for more than 200 years, but it is still lack of in-depth study. From the perspective of regional medicine, combined with the regional characteristics of Quzhou, absorbing the research results of local social history and environmental history, starting with the historical materials such as Lei's medical works, local chronicles literature and so on, the school characteristics are summarized as: the formation of "treatment in accordance with three types of disease causes" , the academic inheritance of "inheriting the past and integrating the present" , the inheritance mode of "multiple integration" , the cultural connotation of "combining medicine with Confucianism" , and the school characteristics of "integration and innovation" . The purpose of this paper is to provide reference for the research of academic schools and the inheritance of traditional Chinese medicine.浙江衢州雷氏医学是当地主要的中医流派，发端于新安医派，迄今已传承200余年，但目前尚缺乏深入研究。引入地域医学视角，结合衢州地域特点，吸收当地社会史、环境史的研究成果，从雷氏医学著作、方志文献等史料入手，将其流派特点总结为：流派形成"三因制宜"、学术继承"承古融今"、传承方式"多元一体"、文化内涵"医儒相济"、流派特色"交融创新"。旨在为当今中医学术流派研究和中医传承工作提供借鉴。.

Coronary microvascular disease (MVD) remains a major clinical problem due to limited mechanistic understanding and a challenging diagnosis. In the present study we evaluated the utility of targeted imaging of active factor XIII (FXIII) for detection of coronary MVD associated with thrombus. We hypothesized that a high specificity and sensitivity FXIII targeted radiolabeled probe can serve as a biomarker for cross-linked thrombi in the microvasculature, and thus an indicator for underlying coronary MVD. To evaluate this approach, a coronary MVD model was established for local induction of singlet oxygen and reactive oxygen species (ROS) via a photochemical reaction (PCR). Methods: PCR was used to induce endothelial injury and microthrombi via focal over-production of ROS only in the coronary microvasculature. Oxidative stress was initially evaluated in primary coronary endothelial cells to optimize parameters of PCR, which were then translated to in vivo experiments. To develop the coronary MVD model, 64 mice were assigned to one of four groups after thoracotomy: 1) sham control; 2) rose bengal; 3) green light; or 4) their combination. Following interventions, the mice underwent transmission electron microscopy, fluorescent myocardial perfusion, coronary angiography, and immunohistochemical staining. Echocardiography (n = 12) and gene expression (n = 10) studies were also performed after MVD induction to monitor serial changes in cardiac function and explore possible mechanisms. To diagnose early onset MVD, FXIII radioactivity was assessed in 104 mice using ex vivo gamma well counting (GWC) and in 14 mice using in vivo serial single photon emission computed tomography / computed tomography (SPECT/CT) imaging of a FXIII targeted technetium-labeled probe (99mTc-NC100668). Results: In vitro experiments demonstrated that photosensitizer concentration and light illumination time were critical parameters for PCR. In vivo experiments demonstrated manifestations of clinical MVD, including endothelial damage, a “no flow zone,” arteriole rarefaction with patent epicardial coronary arteries, infiltration of inflammatory cells in the PCR-treated region, and preserved cardiac function. Gene expression also demonstrated a pro-thrombotic and impaired fibrinolytic status. In the early stages of MVD, enhanced FXIII activity was confirmed within the MVD region using GWC and in vivo SPECT/CT imaging. Conclusion: Our results demonstrate that molecular imaging of FXIII activity may allow for early detection of coronary MVD associated with thrombus, in a novel pre-clinical model.

Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis., VEGFR2 is a central regulator of angiogenesis. Here Zhou et al. report that SUMOylation of VEGFR2 regulates its subcellular localisation and activity, and that endothelial-specific knockout of the SUMO endopeptidase SENP1 protects against VEGFR2-mediated pathological angiogenesis.

In this study, a centroid-based type-2 fuzzy-probabilistic programming (CT2FP) approach is developed for supporting conjunctive use of surface water and groundwater under multiple uncertainties. CT2FP can not only tackle uncertainties expressed as type-2 fuzzy sets (in both objective function and constraints) but also address complexity with characteristic of randomness and two-layer fuzziness (i.e., type-2 fuzzy random variables). Solution method based on α -plane theory, enhanced Karnik–Mendel algorithm (EKM) and interactive algorithm are proposed to transform type-2 fuzzy-probabilistic constraints into their deterministic equivalents. A case study in Zhangweinan River Basin (China) is used to demonstrate the applicability of the proposed approach. Scenarios associated with different constraint-violation risk levels are examined to generate applicable cropping patterns and water-allocation schemes. The amount of groundwater used for irrigation can be determined (i.e., more than [462.84, 495.78] × 10 6 m 3 in dry season and no more than [470.83, 537.19] × 10 6 m 3 in wet season, respectively) to address the conflict between food security and ecological protection. The relationship among crop area, water allocation, and economic benefit can be reflected to enhance the agricultural sustainable development for the study basin.

An integrated simulation-optimization (ISO) approach is developed for assessing climate change impacts on water resources. In the ISO, uncertainties presented as both interval numbers and probability distributions can be reflected. Moreover, ISO permits in-depth analyses of various policy scenarios that are associated with different levels of economic consequences when the promised water-allocation targets are violated. A snowmelt-precipitation-driven watershed (Kaidu watershed) in northwest China is selected as the study case for demonstrating the applicability of the proposed method. Results of meteorological projections disclose that the incremental trend of temperature (e.g., minimum and maximum values) and precipitation exist. Results also reveal that (i) the system uncertainties would significantly affect water resources allocation pattern (including target and shortage); (ii) water shortage would be enhanced from 2016 to 2070; and (iii) the more the inflow amount decreases, the higher estimated water shortage rates are. The ISO method is useful for evaluating climate change impacts within a watershed system with complicated uncertainties and helping identify appropriate water resources management strategies hedging against drought.

Background The utilization of intrathecal opioids is an efficacious component of post-cesarean section pain management. Given that growing evidence indicates that calcitonin gene-related peptide (CGRP) plays a key role in the development of peripheral sensitization and is associated with enhanced pain, we hypothesized that CGRP 4218T/C polymorphism is associated with the variability in fentanyl consumption for post-cesarean analgesia. Methods We recruited 548 patients who presented for elective cesarean delivery, and used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze CGRP 4218T/C polymorphism. We examined the association of CGRP 4218T/C polymorphism and post-operative fentanyl consumption for analgesia as well as adverse reactions to fentanyl in those patients who received cesarean section surgeries. Results We found that the CGRP 4218T/C polymorphism has a significant effect on pain perception, analgesic requirement, and nausea and vomiting for the first 24 h after cesarean delivery in patients who received PCEA fentanyl. Individuals with the C/C genotype had more pain, required more PCEA fentanyl, and experienced a lower incidence of nausea and vomiting. Conclusion These results indicated that patients with C/C genotype may have reduced sensitivity to fentanyl analgesia and/or increased pain perception, and were more willing to use PCEA fentanyl to manage their pain.

Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.

In this study, an integrated simulation-based allocation modeling system (ISAMS) is developed for identifying water resources management strategies in response to climate change. The ISAMS incorporates global climate models (GCMs), a semi-distributed land use-based runoff process (SLURP) model, and a multistage interval-stochastic programming (MISP) approach within a general framework. The ISAMS can not only handle uncertainties expressed as probability distributions and interval values but also reveal climate change impacts on water resources allocation under different projections of GCMs. The ISAMS is then applied to the Kaidu-kongque watershed with cold arid characteristics in the Tarim River Basin (the largest inland watershed basin in China) for demonstrating its efficiency. Results reveal that different climate change models corresponding to various projections (e.g., precipitation and temperature) would lead to changed water resources allocation patterns. Variations in water availability and demand due to uncertainties could result in different water allocation targets and shortages. A variety of decision alternatives about water allocations adaptive to climate change are generated under combinations of different global climate models and ecological water release plans. These findings indicate that understanding the uncertainties in water resources system, building adaptive methods for generating sustainable water allocation patterns, and taking actions for mitigating water shortage problems are key adaptation strategies responding to climate change.

In this study, a Monte Carlo simulation based dual-interval stochastic programming (MC-DSP) method is developed for assessment of uncertainty effects on crop planning and irrigation water supply associated with multiple uncertainties expressed as dual intervals and probability distributions. MC-DSP can permit in-depth analyses of various policies that are associated with different levels of economic consequences (due to uncertain water inflow) when the pre-regulated irrigation targets are violated. The developed method is applied to crop planning and water allocation for the Zhangweinan River Basin in China. Solutions of crop planning and irrigation-water allocation under different probability distributions and plausibility degrees are generated. Results reveal that surface water availabilities associated with different probability distributions can lead to changed system benefits and irrigation shortages. Moreover, water is insufficient to satisfy the requirement for wheat due to its high requirement for irrigation, which may lead to the risk of food supply. Each subarea of farmland would suffer water deficit under all scenarios (particularly for subareas of Daming county and Neihuang county) when inflow level range from very-low to high. The conflicts between economic development and agricultural sustainability would be a challenged issue that would enforce the local authority to adjust the current food security policy.

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