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Emerging process-based urban management creates an urgent necessity to track the evolution of urban climate and assess the efficacy of existing plans and practices in building climate resilient cities. However, the complex interactions between urban surface and the upper atmosphere bring about non-linear, non-stationary, and multi-scale urban climate variations, making it challenging to isolate urban effects from other nature-induced variations. This study introduces two types of data-driven techniques, time series clustering and digital signal decomposition, to tackle the above challenge. Particularly, time series clustering is able to zone any study area into multiple geographical clusters according to the heterogeneity among temporal evolution trajectories of a given urban climate parameter, accounting for its non-linear and non-stationary variations. The clusters present diverse patterns of ascending, descending, or other complex temporal variations that can be used to identify both successes and failures of existing plans in combating adverse urban climate change. Digital signal decomposition can decompose the non-linear and non-stationary time series into multiple components with different time-scales, thereby offering the possibility to identify the part of long-term variation induced by the concerned urban effects. It can be used alone to identify the urban-induced climate change in a specific city, or in combination with time series clustering to recognize the similarities and disparities of urban-induced long-term trends across multiple clusters within a city. This study provides scientific basis and technical support for more robust and precise assessment of urban-induced local climate change, thereby empowers policymakers to develop targeted strategies to enhance climate-resilience.

A novel self-organizing neural fuzzy network is proposed for nonlinear soft-sensing modeling of a chemical process. It is a feedforward multiplayer network and learns in two main phases. The proposed [...]

In order to construct quasi-continuously networked reinforcement in titanium (Ti) matrix composites, in this study, Ti-6Al-4V spherical powders were uniformly coated with a graphene nanosheet (GNS) layer by high energy ball milling and then consolidated by spark plasma sintering. Results showed that the GNS layer on the powder surface inhibited continuous metallurgy bonding between powders during sintering, which led to the formation of quasi-networked hybrid reinforcement structure consisting of in-situ TiC and remained GNSs. The networked GNSs/Ti64 composite possessed noticeably higher tensile strength but similar ductility to the Ti64 alloy, leading to both better tensile strength and ductility than the GNSs/Ti composite with randomly dispersed GNSs and TiC. The formation mechanism and the fracture mechanism of the networked hybrid reinforcement were discussed. The results provided a method to fabricate Ti matrix composites with high strength and good ductility. • Networked GNSs/Ti composite was fabricated by combination of two-step mixing and SPS. • Increment defects of GNSs would cause GNSs chemically reacting and forming TiC wall. • GNSs or TiC inhibited the powder metallurgy bond and kept a powder size of networks. • Different phase interfaces of networked GNSs/Ti64 were observed by HRTEM and STEM. • Formation mechanisms and strengthening effects of networked structure were discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS.Significance StatementAngiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.

ABSTRACTThis paper reports an experiment that aims at providing new evidence to reinforce contradictory conclusions, as available in engineering design literature, on the effect of analogical distance on ideation performance of designers. The experiment involved 84 graduate students in Mechanical Engineering, with typical competencies on engineering design, but without any specific skill on analogy-based idea generation. The subjects were exposed to three different treatments (near-, medium-, far-field analogies) whose design performance has been compared to a control group. The observation confirms that designers not specifically trained in designing-by-analogy get benefit from sources of inspiration that share the same (sub-)functions and context of the target system, as their idea generation process lead to ideas having higher novelty and quality compared to the outcomes of subjects exposed to more distant analogies. The observed results also show that the exploration of the design space gets positively affected.

Reactive oxygen species (ROS) are essential for cellular signaling and physiological function. An imbalance between ROS production and antioxidant protection results in a state of oxidative stress (OS), which is associated with perturbations in reduction/oxidation (redox) regulation, cellular dysfunction, organ failure, and disease. The pathophysiology of OS is closely interlinked with inflammation, mitochondrial dysfunction, and, in the case of surgery, ischemia/reperfusion injury (IRI). Perioperative OS is a complex response that involves patient, surgical, and anesthetic factors. The magnitude of tissue injury inflicted by the surgery affects the degree of OS, and both duration and nature of the anesthetic procedure applied can modify this. Moreover, the interindividual susceptibility to the impact of OS is likely to be highly variable and potentially linked to underlying comorbidities. The pathological link between OS and postoperative complications remains unclear, in part due to the complexities of measuring ROS- and OS-mediated damage. Exogenous antioxidant use and exercise have been shown to modulate OS and may have potential as countermeasures to improve postoperative recovery. A better understanding of the underlying mechanisms of OS, redox signaling, and regulation can provide an opportunity for patient-specific phenotyping and development of targeted interventions to reduce the disruption that surgery can cause to our physiology. Anesthesiologists are in a unique position to deliver countermeasures to OS and improve physiological resilience. To shy away from a process so fundamental to the welfare of these patients would be foolhardy and negligent, thus calling for an improved understanding of this complex facet of human biology.

Human immunodeficiency virus (HIV) is membrane-enveloped, and an initial infection step is joining/fusion of viral and cell membranes. This step is catalyzed by gp41, which is a single-pass integral viral membrane protein. The protein contains an ∼170-residue ectodomain located outside the virus that is important for fusion and includes the fusion peptide (FP), N-helix, loop, C-helix, and viral membrane-proximal external region (MPER). The virion initially has noncovalent complexes between three gp41 ectodomains and three gp120 proteins. A gp120 contains ∼500 residues and functions to identify target T-cells and macrophages via binding to specific protein receptors of the target cell membrane. gp120 moves away from the gp41 ectodomain, and the ectodomain is thought to bind to the target cell membrane and mediate membrane fusion. The secondary and tertiary structures of the ectodomain are different in the initial complex with gp120 and the final state without gp120. There is not yet imaging of gp41 during fusion, so the temporal relationship between the gp41 and membrane structures is not known. This study describes biophysical and functional characterization of large gp41 constructs that include the ectodomain and transmembrane domain (TM). Significant fusion is observed of both neutral and anionic vesicles at neutral pH, which reflects the expected conditions of HIV/cell fusion. Fusion is enhanced by the FP, which in HIV/cell fusion likely contacts the host membrane, and the MPER and TM, which respectively interfacially contact and traverse the HIV membrane. Initial contact with vesicles is made by protein trimers that are in a native oligomeric state that reflects the initial complex with gp120 and also is commonly observed for the ectodomain without gp120. Circular dichroism data support helical structure for the N-helix, C-helix, and MPER and nonhelical structure for the FP and loop. Distributions of monomer, trimer, and hexamer states are observed by size-exclusion chromatography (SEC), with dependences on solubilizing detergent and construct. These SEC and other data are integrated into a refined working model of HIV/cell fusion that includes dissociation of the ectodomain into gp41 monomers followed by folding into hairpins that appose the two membranes, and subsequent fusion catalysis by trimers and hexamers of hairpins. The monomer and oligomer gp41 states may therefore satisfy dual requirements for HIV entry of membrane apposition and fusion.

Submarine pipelines can be divided into three types based on their laying status: pipelines laid flat on the seabed, pipelines without buried, and pipelines buried in shallow trenches. In addition, there is also a suspended span state caused by waves and currents erosion. The four laying states of submarine pipelines indicate that the seabed, as the foundation supporting the pipeline, must provide sufficient support to ensure the stability of the pipeline. This article studies the erosion span data of existing pipelines, evaluates and predicts the pipeline span state through theoretical calculation and analysis, and then uses numerical simulation calculation methods to predict the pipeline span depth, and compares and verifies it with measured data.

Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke.

The velocity‐current relation of positive leader discharges is of great importance in the research of lightning physics. However, the measured data in a wide range of current up to several hundred amperes are not available so far. To fill the gap, experiments on positive leader discharges in long air gaps under lightning impulses were carried out on the test site at an altitude of 2.1 km. The velocity and current of positive leaders were measured with the synchronized discharge current and high‐speed video frames. An empirical formula for the velocity‐current relation of positive leaders is given with the leader current up to 500 A. The measurements are also compared with the numerical simulations, and it is suggested that the initial tip radius of a propagating leader grows as the leader current increases. Lightning propagates in air in the form of electrical discharges we named as “leaders.” The leader advances itself by ionizing and heating the air in front of it. It is found that the leader velocity is almost only dependent on the electric current flowing through it. A lot of experiments have been done to obtain the leader velocity‐current relation. However, it is doubtful if the extrapolation of the curve is valid since there is a big difference between the current amplitude of laboratory leaders (a few amperes) and that of lightning leaders (up to a few hundreds of amperes). One way to achieve large leader current in the laboratory is to do the experiments under low air pressure. This idea motivated us to perform a series of experiments at an altitude of 2.1 km. The maximum leader current we could generate and measure is up to 500 A. Based on the data, we propose an empirical formula of the velocity‐current relation that can be used to predict the lightning velocity through numerical simulations. The comparison with the published measurements shows that our formula could provide quite accurate estimations, while the previous extrapolation approach fails. The first measurement on the velocity‐current relation for positive leader discharges with the leader current up to 500 A is reportedThe charge per unit length required for positive leader propagation is obtained as a function of leader currentThe experimental measurements are compared with simulation results obtained from the state‐of‐the‐art numerical model

Nutrient Expert is a new nutrient management approach and is confirmed for use in north‐central China.The continual feasibility of Nutrient Expert was evaluated through multiple‐point field experiments.This is the first report of Nutrient Expert on improving environmental benefits of winter wheat. Over application of N and P and poor nutrient management have become a common practice on the North China Plain, and lead to low nutrient use efficiency (NUE) and serious environmental problems. Thus, nutrient management for crops must be improved. In this study, 315 field experiments were conducted from 2011 to 2014 in major winter wheat domains in north‐central China to validate the continual feasibility of the Nutrient Expert (NE) system for improving NUE and reducing greenhouse gas (GHG) emission. The NE system significantly increased grain yield, profitability, and NUE, and decreased GHG emission. Compared with farmers’ practice (FP), the NE treatment reduced N and P inputs by 41.4 and 30.1% (115 kg N ha−1and 36 kg P2O5ha−1), respectively, and increased K input by 51.5% (25 kg K2O ha−1). Compared with the FP and soil testing (ST) treatments, the NE treatment increased agronomic efficiency of nitrogen (AEN) by 70.0 and 13.3%, recovery efficiency of nitrogen (REN) by 73.8 and 13.3%, and partial factor productivity of nitrogen (PFPN) by 58.5 and 22.2%, respectively. Compared with the FP and ST treatments, the NE treatment reduced total N2O emissions by 54.8 and 26.3%, total GHG emissions by 44.8 and 22.9%, and GHG emission intensity by 45.8 and 22.0%, respectively. These results confirmed that NE is an effective method to make fertilizer recommendations for wheat in north‐central China and has the potential to improve yield, NUE, and profitability, with low environmental pollution.

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

Metal oxides have long been used as charge transport layers in thin film solar cells due to their suitable energy band levels, high charge carrier mobilities, and excellent long-term stability. One example is non-stoichiometric nickel oxide (NiOx), a hole transport material which can be deposited in a conformal, scalable, and solvent-free manner via sputtering. However, sputtered NiOxhas only ever been combined with spin-coated perovskite films in perovskite solar cells (PSCs). Here we report the fabrication of the first co-evaporated PSCs with sputtered NiOxas the hole transport layer. We reveal how the amount of argon gas used during sputtering affects important physical properties such as hole conductivity, visible light transmittance, and suitability of the NiOxsurface for perovskite nucleation and growth. Optimized sputtering conditions led to CH3NH3PbI3(MAPbI3) PSCs with an 18.6% power conversion efficiency (PCE), which was further increased to 19.5% by adding a spiro-TTB interlayer between NiOxand MAPbI3. We also show that removing the NiOxannealing step only reduced the device PCE by 1%, paving the way toward low-temperature deposition of metal oxide transport layers. This work exhibits the versatility of NiOxsputtering and perovskite evaporation as a powerful combination for solvent-free and low-temperature fabrication of highly efficient PSCs.

Although the electrochemical water splitting is considered as one of the ideal hydrogen production methods, the high costs and low reserves of precious metals-based electrocatalysts severely hamper its large scale commercial application, which motivates the exploration and usage of high-efficiency non-precious metal electrocatalysts. Herein, we report a robust and controllable bottom-up strategy to fabricate a delicate two-dimensional porous nanoarchitecture constructed from iron-based metal-organic frameworks (MIL-100) and Ti3C2TxMXene nanosheets (MIL/Ti3C2Tx) via an in situsolvothermal assembly process. The intercalated MIL-100 nanocrystals not only inhibit the interlayer restacking and agglomeration of Ti3C2Txnanoflakes but also create a large number of interconnected pore channels for the adequate exposure of catalytic active sites, thus affording remarkable synergistic coupling effects. By the structural virtues of two-dimensional thin-sheet configuration, large specific surface area, high porosity, uniform MIL-100 dispersion, and exceptional electrical conductivity, the as-produced MIL/Ti3C2Txnanoarchitecture exhibits enhanced electrocatalytic hydrogen evolution properties in terms of a low onset potential of 29 mV, an operating overpotential of 107 mV at 10 mA/cm2, a small Tafel slope of 61 mV/dec, and a long working life, all of which are significantly superior to those of bare MIL-100 and Ti3C2Txelectrocatalysts.

Sodium–glucose co-transporter-2 inhibitors are increasingly prescribed for patients with type 2 diabetes. Their use has been associated with life-threatening diabetic ketoacidosis. The risk is increased during times of fasting and intercurrent medical illness, which are common in the perioperative period. Diagnosis can be difficult, so perioperative clinicians must be familiar with preventing and recognising such complications.

Background Gastrointestinal bleeding (GIB) is a complication reported in patients post left ventricular assist device (LVAD) implantation that is associated with high mortality rates. Thalidomide is an anti-angiogenic compound that may offer a potential option for management of refractory LVAD-related GIB.Methods A single-center, retrospective review was conducted from January 2009 to October 2016 at a tertiary cardiology center. It included LVAD patients initiated on thalidomide for refractory GIB.Results All patients (n = 11) were started on thalidomide 50 mg nocte and there was resolution of GIB in all patients except one (90.9%) during initial thalidomide treatment. The median duration of thalidomide therapy was 98 days (interquartile range: 34–215). The dose of thalidomide was reduced for 2 patients due to adverse effects. Thalidomide therapy was discontinued in 6 patients due to cessation of GIB (n = 4) and adverse effects (n = 2). Reported adverse effects included LVAD thrombosis (n = 2), somnolence (n = 1), neuropathy (n = 1), constipation (n = 1), and transaminitis (n = 1). Recurrent GIB occurred in 4 patients (45.4%) post-discontinuation of thalidomide therapy, which led to the re-initiation of therapy.Conclusions Thalidomide appears to be a safe and effective option for management of refractory LVAD-related GIB. Monitoring for recurrent GIB should be performed closely following cessation of thalidomide therapy.

ANG II has many biological effects in renal physiology, particularly in Ca2+handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT1and AT2receptors (AT1R and AT2R) to stimulate sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT1R/AT2R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK1cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT1R/AT2R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine—but not Pitstop2—blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT1R, AT2R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT1/AT2complex to target ER, where it might trigger intracellular Ca2+responses.

Nutrient expert is a nutrient decision support tool and this study confirmed that it could be used in north‐central China.The continual performance of nutrient expert was evaluated through multiple‐point field experiments.This is the first report of nutrient expert on improving environmental benefits of summer maize. Modern agriculture needs environmentally friendly approaches to increase production, improve nitrogen use efficiency (NUE), and promote ecologically sustainable agriculture. This study was conducted from 2010 to 2014 in 389 farmers’ fields across major summer maize growing regions in north‐central China to evaluate the continual performance of the nutrient expert (NE) system for improving NUE and environmental benefits. Results indicated that NE significantly increased grain yield and profitability by reducing N fertilizer rate by 35.1% (84.6 kg N ha−1), increasing the K rate by 68.1% (25.8 kg K2O ha−1), and keeping the P rate the same as the farmers’ practice (FP). On average, NUE achieved in the NE treatment was significantly higher than for FP and fertilizer recommendation based on soil testing (OPTS). The NE increased agronomic efficiency of nitrogen (AEN) by 50.8 and 17.3%, recovery efficiency of nitrogen (REN) by 67.7 and 15.9%, and partial factor productivity of nitrogen (PFPN) by 43.8 and 21.2% compared with FP and OPTS, respectively. Furthermore, the calculated total N2O emission, total greenhouse gas (GHG) emission, and GHG emission intensity were 35.1 and 17.5%, 35.2 and 18.4%, and 37.3 and 17.4% lower in the NE treatment when compared with FP and OPTS, respectively. The differences in yield, economic benefits, NUE, and GHG emission among NE, FP, and OPTS treatments confirmed that NE is a promising nutrient decision support tool and has the potential to improve NUE and environmental benefits for summer maize (Zea maysL.) in north‐central China.

The small GTPase Arf6 is a conserved protein that is expressed in all metazoans. Arf6 remodels cytoskeletal actin and mediates membrane protein trafficking between the plasma membrane in its active form and endosomal compartments in its inactive form. While a rich knowledge exists for the cellular functions of Arf6, relatively little is known about its physiological role in development. This study examines the function of Arf6 in mediating cellular morphogenesis in early development. We dissect the function of Arf6 with a loss-of-function morpholino and constitutively active Arf6-Q67Lconstruct. We focus on the two cell types that undergo active directed migration: the primary mesenchyme cells (PMCs) that give rise to the sea urchin skeleton and endodermal cells that form the gut. Our results indicate that Arf6 plays an important role in skeleton formation and PMC migration, in part due to its ability to remodel actin. We also found that embryos injected with Arf6 morpholino have gastrulation defects and embryos injected with constitutively active Arf6have endodermal cells detached from the gut epithelium with decreased junctional cadherin staining, indicating that Arf6 may mediate the recycling of cadherin. Thus, Arf6 impacts cells that undergo coordinated movement to form embryonic structures in the developing embryo.

Little is known about the effect of tillage erosion on the distribution of CaCO3, phosphorus and changes in the ratio of CaCO3/available phosphorus (AP) in the hillslope landscape. The aims of the present study were to elucidate the mechanisms underlying changes in CaCO3 and AP concentrations induced by tillage erosion along slope transects and to reconstruct the historical changes in CaCO3 in soil layers at different landscape positions. Two adjacent slopes were selected from the Sichuan Basin, China, one with downslope tillage (Slope 1) and the other with upslope tillage (Slope 2) for 29 years. Then, consecutive downslope tillage by hoeing was applied five and 20 times on Slope 1. Under normal tillage (both downslope and upslope) conditions, CaCO3 concentrations increased exponentially with soil depth. However, the mixing effect of consecutive tillage (five and 20 tills) changed the vertical CaCO3 distribution patterns. For downslope tillage, the topsoil layer CaCO3 concentration was significantly lower at the toeslope than at other slope positions, but there were no significant differences between toeslope and other slope positions for upslope tillage. Consecutive tillage with five and 20 tills increased CaCO3 concentrations in the topsoil layer by 27.7% and 30.8% respectively compared with downslope tillage, but AP concentrations decreased by 26.1% and 29.0% respectively. Under normal tillage, AP concentrations decreased with increasing CaCO3 concentrations due to the adsorption and precipitation of AP by CaCO3, but this relationship disappeared after consecutive tillage. After consecutive tillage with five and 20 tills, the mean CaCO3/AP ratios of the topsoil layer were 93.5% and 88.4% greater than those for downslope tillage respectively, whereas there were no significant differences between downslope and upslope tillage. In conclusion, tillage is a process of CaCO3 replenishment and AP dilution in the surface layer of soil derived from carbonate-rich bedrocks.

The renin-angiotensin system (RAS) is an essential hormonal system involved in water and sodium reabsorption, renal blood flow regulation, and arterial constriction. Systemic stimulation of the RAS with infusion of the main peptide angiotensin II (Ang II) in animals as well as pathological elevation of renin (i.e renovascular hypertension) to increase circulatory Ang II in humans ultimately lead to hypertension and end-organ damage. In addition to hypertension, accumulating evidence support that the Ang II type 1 receptor exerts a critical role in cardiovascular and kidney diseases independent of blood pressure elevation. In the last two decades, the identification of an increased number of peptides and receptors has facilitated the concept that the RAS has both detrimental and beneficial effects on the cardiovascular system depending on which RAS components are activated. For example, angiotensin 1-7 and Ang II type 2 receptors act as a counter-regulatory system against the classical RAS by mediating vasodilation. While the RAS as an endocrine system for regulation of blood pressure is well established, there remain many unanswered questions and controversial findings regarding blood pressure regulation and pathophysiological regulation of cardiovascular diseases at the tissue level. This review article will include the latest knowledge gleaned from cell type-selective gene deleted mice regarding cell type-specific roles of AngII receptors and discuss their significance in health and diseases. In particular, we focus on the roles of these receptors expressed in vascular, cardiac, and kidney epithelial cells.

This paper first proposed to modify the GeSe monolayer by doping Co and Cr atoms and investigated the potential application in the monitoring SF6insulation equipment. The adsorption mechanism of these three gases on Co/Cr-Gese monolayers is systematically studied based on density functional theory. The adsorption mechanism of three gas molecules on the new sensors (Co-GeSe and Cr-GeSe) was evaluated from the aspects of adsorption energy, charge transfer amount, energy band structure, molecular frontier orbital, and recovery time. The results show that Co and Cr modification can significantly improve surface activity of the intrinsic GeSe monolayer, which can make the intrinsic GeSe monolayer possess better absorption and sensing performance. Especially, the Cr-GeSe monolayer gets more sensitive to the target gas, indicating this monolayer has the prospect of becoming the adsorption material of the target gas (SO2, SOF2, and SO2F2). The reasonable adsorption energy and large change of bandgap indicate that Co-GeSe monolayer can be a potential candidate for SO2and SOF2sensors. In addition, this work provides theoretical guidance for the further study of transition metal-doped GeSe monolayer for detecting the decomposition products of SF6in the field of electrical engineering.

New regulations implemented by the Canadian federal government to limit greenhouse gas (GHG) emissions from coal burning power plants had sparked intense activity in the utility industry to find ways to reduce emissions. Several studies have indicated that carbon capture and storage (CCS) is not going to be economically available in the short term. Co-firing biomass appears to be an option for many of the coal-fired power plants, as Canada has a significant amount of biomass resources. Although biomass combustion can reduce greenhouse gas emissions, it can also generate other air pollutants. To determine emission factors for co-firing biomass and coal, pilot-scale tests were performed. These tests were conducted in CanmetENERGY’s 0.5 MWthpilot-scale pulverized fuel research furnace, which was configured with a dual-burner system, electrostatic precipitator, and baghouse. Gaseous emissions were recorded with two monitoring systems, and traditional methods for batch sampling of halogens, mercury, and particulate matter were implemented. Emission factors were developed for a 100% coal baseline, for two co-firing ratios of 20% and 55% biomass by heating value and biomass-only firing.

Androgen receptor (AR)-mediated gene expression continues to have a critical role in promoting castration-resistant prostate cancer (CRPC) survival and growth even after androgen deprivation therapy. AR cistrome analyses in CRPC cells have identified a large number of AR target genes involved in proliferative and cell cycle-related functions, and hold promise for development of novel therapeutic approaches for CRPC. However, there is little understanding of how these genes function in vivoand what the clinical implications are. We previously reported that secretory leukocyte peptidase inhibitor (SLPI) is regulated by the AR in a ligand-independent manner in CRPC cells and required for CRPC cell proliferation under androgen-deprived conditions. SLPI is a secreted serine protease inhibitor, which is overexpressed in a number of cancers, including lung, breast and ovarian cancer, and involved in tumor progression. However, the oncogenic potential of SLPI in prostate cancer remains unknown. Here we provide the first evidence that SLPI is upregulated in a subset of CRPC cell lines and CRPC patient tumors. In addition, serum SLPI levels are significantly elevated in metastatic CRPC patients compared with hormone naive patients, raising the possibility that this could serve as a biomarker. We demonstrated that SLPI expression has functional significance, as it promotes CRPC cell survival and growth after androgen withdrawal in vivoand in vitro. Last, we demonstrated that the oncogenic effect of SLPI may be due to protection of growth factor progranulin from enzymatic cleavage or suppression of CRPC cell apoptosis independent of anti-protease activity of SLPI. These findings implicate SLPI as a potential biomarker of resistance to AR inhibition and therapeutic target for CRPC treatment.

Long-term angiotensin II (ANG II) infusion significantly increases ANG II levels in the kidney through two major mechanisms: AT1receptor-mediated augmentation of angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubules. However, it is not known whether intracellular ANG II stimulates AGT expression in the proximal tubule. In the present study, we overexpressed an intracellular cyan fluorescent ANG II fusion protein (Ad-sglt2-ECFP/ANG II) selectively in the proximal tubule of rats and mice using the sodium and glucose cotransporter 2 (sglt2) promoter. AGT mRNA and protein expression in the renal cortex and 24-h urinary AGT excretion were determined 4 wk following overexpression of ECFP/ANG II in the proximal tubule. Systolic blood pressure was significantly increased with a small antinatriuretic effect in rats and mice with proximal tubule-selective expression of ECFP/ANG II (P< 0.01). AGT mRNA and protein expression in the cortex were increased by >1.5-fold and 61 ± 16% (P< 0.05), whereas urinary AGT excretion was increased from 48.7 ± 5.7 (n= 13) to 102 ± 13.5 (n= 13) ng/24 h (P< 0.05). However, plasma AGT, renin activity, and ANG II levels remained unaltered by ECFP/ANG II. The increased AGT mRNA and protein expressions in the cortex by ECFP/ANG II were blocked in AT1a-knockout (KO) mice. Studies in cultured mouse proximal tubule cells demonstrated involvement of AT1areceptor/MAP kinases/NF-кB signaling pathways. These results indicate that intracellular ANG II stimulates AGT expression in the proximal tubules, leading to increased AGT formation and secretion into the tubular fluid, which contributes to ANG II-dependent hypertension.

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an important tumour-suppressor gene, is mutated, downregulated or dysfunctional in many tumours. The phosphatase activity of PTEN depends on membrane translocation (activation). As promising anti-cancer agents, histone deacetylase (HDAC) inhibitors, particularly trichostatin A (TSA), can promote PTEN membrane translocation, but the underlying mechanism remains unknown. In this study, we revealed that non-selective HDAC inhibitors, namely, TSA or suberoylanilide hydroxamic acid (SAHA), induced PTEN membrane translocation through PTEN acetylation at K163 by inhibiting HDAC6. K163 acetylation inhibited the interaction of the PTEN C-tail with the remaining part of PTEN, resulting in PTEN membrane translocation. Overexpression of wild-type PTEN, but not K163-mutated PTEN, facilitated the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth, induced by SAHA or tubastatin A, an HDAC6-specific inhibitor. These results indicated that PTEN activation by inhibiting HDAC6 significantly contributed to tumour inhibition. Therefore, non-selective HDAC or HDAC6-specific inhibitors may be more clinically suitable to treat tumours without PTEN mutations or deletions.

The Kruppel-like factor 5 (KLF5) transcription factor is highly expressed in high-grade and basal-like breast cancers. However, the mechanism by which KLF5 promotes cell migration and invasion is still not completely understood. In this study, we demonstrate that TNFAIP2, a tumor necrosis factor-a (TNFa)-induced gene, is a direct KLF5 target gene. The expression of TNFAIP2 is highly correlated with the expression of KLF5 in breast cancers. The manipulation of KLF5 expression positively alters TNFAIP2 expression levels. KLF5 directly binds to the TNFAIP2gene promoter and activates its transcription. Functionally, KLF5 promotes cancer cell proliferation, migration and invasion in part through TNFAIP2. TNFAIP2 interacts with the two small GTPases Rac1 and Cdc42, thereby increasing their activities to change actin cytoskeleton and cell morphology. These findings collectively suggest that TNFAIP2is a direct KLF5 target gene, and both KLF5 and TNFAIP2 promote breast cancer cell proliferation, migration and invasion through Rac1 and Cdc42.

Additive manufacturing (AM) has enabled the emergence of intricate lattice materials with controlled structural or functional properties unfeasible for conventional materials. A striking feature of these novel materials is the substantial number of constituent strut elements contained in them, e.g., more than 5 × 105struts (diameter: 0.5 mm; length: 5.0 mm) in a common tetrahedron lattice with dimensions of 200 × 200 × 200 mm3. A prerequisite for realizing the full design potential of these structures is to ensure the robust additive continuity of each constituent strut, which refers to geometric continuity between two successive layers of a strut, in order to achieve high lattice structural integrity. This critical issue has, however, remained unanswered. Herein we formulate a design-and-manufacture interlocked strut additive continuity model for powder bed fusion (PBF) and apply it to the entire design gamut of Ti-6Al-4 V struts. On this basis, a strut additive continuity threshold value (φ = 0.9) is proposed and validated with 23,100 inclined struts in Ti-6Al-4 V lattices manufactured by electron beam PBF (EB-PBF). Design maps are then constructed for EB-PBF of lattice materials. Furthermore, a minimum powder-bed density (0.6ρTD) for powder selection and a powder-specific initial layer thickness (0.6Dv(90)) are recommended. This work establishes a necessary basis for the design and manufacture of robust lattice materials by EB-PBF including graded lattices.

The effect of heat treatment on the mechanical strength of a three-phase NbSS/Nb5Si3/Cr2Nb alloy with composition Nb–22Ti–12Si–14Cr–2Al–2Hf was investigated. This included the evaluation of microstructure, room temperature mechanical strength and the fracture behaviours. The microstructures of heat treated samples were composed of NbSS, Nb5Si3and Cr2Nb, and the phase size changed under different heat treatment schemes. The results showed that the microstructure composed of large NbSSand fine Nb5Si3exhibited best mechanical strength due to the deformation of NbSSin these samples. Moreover, fractographic analysis indicated that the Nb5Si3and Cr2Nb fractured in cleavage manner in all heat treated samples.

Caveolin 1 (CAV-1) functions not only as a constitutive scaffolding protein of caveolae but also as a vesicular transporter and signaling regulator. In the present study, we tested the hypothesis that CAV-1 knockout (CAV-1 KO) inhibits ANG II type 1 [AT1(AT1a)] receptor-mediated uptake of ANG II in the proximal tubule and attenuates blood pressure responses in ANG II-induced hypertension. To determine the role of CAV-1 in mediating the uptake of FITC-labeled ANG II, wild-type (WT) mouse proximal convoluted tubule cells were transfected with CAV-1 small interfering (si)RNA for 48 h before AT1receptor-mediated uptake of FITC-labeled ANG II was studied. CAV-1 siRNA knocked down CAV-1 expression by >90% (P< 0.01) and inhibited FITC-labeled ANG II uptake by >50% (P< 0.01). Moreover, CAV-1 siRNA attenuated ANG II-induced activation of MAPK ERK1/2 and Na+/H+exchanger 3 expression, respectively (P< 0.01). To determine whether CAV-1 regulates ANG II uptake in the proximal tubule, Alexa 488-labeled ANG II was infused into anesthetized WT and CAV-1 KO mice for 60 min (20 ng/min iv). Imaging analysis revealed that Alexa 488-labeled ANG II uptake was decreased by >50% in CAV-1 KO mice (P< 0.01). Furthermore, Val5-ANG II was infused into WT and CAV-1 KO mice for 2 wk (1.5 mg·kg−1·day−1ip). Basal systolic pressure was higher, whereas blood pressure and renal excretory and signaling responses to ANG II were attenuated, in CAV-1 KO mice (P< 0.01). We concluded that CAV-1 plays an important role in AT1receptor-mediated uptake of ANG II in the proximal tubule and modulates blood pressure and renal responses to ANG II.

The synergy of Cr concentration and withdraw rate on the microstructure of directionally solidified and heat treated Nb–14Si–24Ti–xCr (x?=?0, 2, 8, 10, 14 at-) alloys was investigated. The phases present in the directionally solidified alloys were sensitive to Cr concentration and withdraw rate. The addition of Cr changed the solidification path of ternary alloys. High Cr concentration stabilised the Nb5Si3and facilitated the formation of Cr2Nb during the directional solidification process. However, the effect of Cr was suppressed by the increase in withdraw rate. The competition between the effect of Cr addition and withdraw rate determined the microstructure of alloys and resulted in a four-phase microstructure. During heat treatment, the Nb3Si phases in Nb–14Si–24Ti–0Cr alloys were stable, while in the Cr contained alloys, the Nb3Si decomposed into NbSS/Nb5Si3eutectoid through the eutectoid reaction (Nb3Si?NbSS+Nb5Si3).

The present study tested the hypothesis that the multiligand endocytic receptor megalin is partially involved in the uptake of ANG II and downstream signaling responses in mouse proximal tubule cells (mPCT) by interacting with AT1areceptors. mPCT cells of wild-type (WT) and AT1areceptor-deficient (AT1a-KO) mice were treated with vehicle, the AT1receptor blocker losartan (10 μM), or a selective megalin small interfering (si) RNA for 48 h. The uptake of fluorescein (FITC)-labeled ANG II (10 nM, 37°C) and downstream signaling responses were analyzed by fluorescence imaging and Western blotting. AT1areceptors and megalin were abundantly expressed in mPCT cells, whereas AT1areceptors were absent in AT1a-KO mPCT cells (P< 0.01). In WT mPCT cells, FITC-ANG II uptake was visualized at 30 min in the cytoplasm and in the nuclei 1 h after exposure. Losartan alone completely blocked the uptake of FITC-ANG II, whereas megalin siRNA inhibited only 30% of the response (P< 0.01). The remaining FITC-ANG II uptake in the presence of megalin siRNA was completely abolished by losartan. ANG II induced threefold increases in phosphorylated MAP kinases ERK1/2 and a onefold increase in phosphorylated sodium and hydrogen exchanger 3 (NHE3) proteins, which were also blocked by losartan and megalin-siRNA. By contrast, losartan and megalin siRNA had no effects on these signaling proteins in AT1a-KO mPCT cells. We conclude that the uptake of ANG II and downstream MAP kinases ERK1/2 and NHE3 signaling responses in mPCT cells are mediated primarily by AT1areceptors. However, megalin may also play a partial role in these responses to ANG II.

By taking the method of liquid–metal cooled directional solidification, alloys with a nominal composition of Nb–14Si–24Ti–10Cr–2Al–2Hf (at-) were prepared under different conditions. Alloys were initially directional solidified with different withdrawal rates (R?=?1·2, 6, 18 mm min-1) at 1750°C and subsequently heat treated at 1450°C for 10 h. These processes aimed to investigate the microstructure of directionally solidified (DS) and heat treated (HT) alloys by XRD, SEM, and EDS. The microstructure of DS alloy was composed of (Nb,Ti)SS, (Nb,Ti)5Si3, and Laves phase Cr2Nb, and the former two components formed (Nb,Ti)SS+(Nb,Ti)5Si3eutectics. In addition, (Nb,Ti)5Si3laths only presented in DS1·2 alloy. With the increasing withdrawal rates, the microstructure of alloy altered from hypereutectic into pseudo-eutectic, accompanied with the eutectic morphology transformation from petaloid into coupled. Also, the dimension of constituent phases reduced. However, after heat treatment, the constituent phases did not change. The petaloid morphology of eutectics in DS specimens disappeared and coupled eutectic transferred into network. The block or needle-like Cr2Nb gathered along the boundary between (Nb,Ti)5Si3and (Nb,Ti)SS, and the overall alloy composition became homogenisation.

Tubular structures have been widely applied in offshore structures and civil buildings in past decades. Some research has been carried out on rigidity of unstiffened circular hollow section (CHS) joints with various types, e.g. T-, Y-, K- and X-joints by former researchers. However, limited investigations on the in-plane flexural rigidity of multiplanar CHS X-joints which are commonly used in single-layered latticed structures are found in available literatures. In this paper, first a finite element model was calibrated through comparison with test results, and then a numerical parametric study on elastic axial rigidity of multiplanar unstiffened CHS X-joints was carried out using the calibrated models with package ABAQUS. Based on the parametric results, an in-plane flexural rigidity formula for the joints was fitted. Finally, a comparison among the different formulae in predicting joint rigidity of unstiffened CHS X-joints was carried out, which indicated a good reliability of the proposed formula.

ABSTRACTThe Lie symmetry and Hojman conserved quantity of Lagrange equations for a weakly nonholonomic system and its first-degree approximate holonomic system are studied. The differential equations of motion for the system are established. Under the special infinitesimal transformations of group in which the time is invariable, the definition of the Lie symmetry for the weakly nonholonomic system and its first-degree approximate holonomic system are given, and the exact and approximate Hojman conserved quantities deduced directly from the Lie symmetry are obtained. Finally, an example is given to study the exact and approximate Hojman conserved quantity for the system.

In this investigation, Nb–16Si–24Ti–4Cr–2Al–2Hf alloy was directionally solidified and then heat treated, and the microstructure, fracture toughness KQand tensile strength sbof the alloy were studied. The directionally solidified microstructure consisted of primary Nb5Si3blocks and NbSS+Nb5Si3eutectic cells. The cross section of eutectic cells changed from the square morphology to the nearly round morphology with the increasing withdrawal rate. During heat treatment, the boundaries of the round eutectic cells were eliminated as the NbSSconnected to be a net-like structure. The values of KQand sbincreased with the increase of withdrawal rate. The toughening from the crack deflection of continuous Nbssnetwork was significant and refinement of the microstructure improved the tensile strength in heat treated samples.

Rapid water quenching experiments were first carried out according to differential scanning calorimetry results, and then the microstructure and phase composition of such water quenching Cu–8·33Ni–1·67Si (wt-) samples were investigated. Subsequently, calculation on the competition nucleation of the primary phase was also carried out. Based on the experimental and calculational results, the phase transformation behaviour of Cu–8·33Ni–1·67Si melts during the cooling process was discussed, and the results can be summarised as follows. First, the a-Cu phase formed as a primary phase due to the shorter incubation time and higher time dependent nucleation rate. Subsequently, a eutectic reaction occurred in the interdendritic residual liquid phase of the primary a-Cu grains, and its product was a-Cu+Ni3Si. The third and fourth phase transformation could be described to the precipitation of the d-Ni2Si phase in the region close to the grain boundary phase and the internal of the primary a-Cu grains respectively.

Dysregulation of the Axl receptor tyrosine kinase (RTK) has been implicated in the development and progression of a variety of malignancies. Axl is known to activate strong anti-apoptotic signaling pathways that promote oncogenesis. However, the role of Axl plays in osteosarcoma (OS) remains elusive. The present study aimed to investigate the clinical significance and function of Axl in human OS. Forty cases of OS and corresponding adjacent non-cancerous tissues (ANCT) were collected. The expression of Axl was assessed using immunohistochemical assay through tissue microarray procedure. A loss-of-function experiment was performed to investigate the effects of small hairpin RNA (shRNA)-mediated knockdown of Axl on the expression of p-AKT, poly ADP-ribose polymerase (PARP) and Ki-67, the proliferative activities, indicated by MTT assay, and the apoptotic index in OS MG-63 cells. As a result, the expression of Axl was found in OS tissues with higher strong reactivity rate, compared with the ANCT (75.0% vs 20.0%, P=0.000), but it did not associate with the age, gender, tumor size, TNM staging and distant metastases (each P>0.05). Furthermore, knockdown of Axl inhibited the proliferative activities and induced apoptosis in MG-63 cells with decreased expression of p-AKT, and Ki-67 and increased expression of PARP. In conclusion, our findings suggest that Axl is highly expressed in most of the OS tissues compared with the ANCT, and knockdown of Axl inhibits proliferation and induces apoptosis of OS cells possibly through downregulation of the AKT pathway, suggesting that our findings may provide new insights into the potential therapeutic target for cancer.

It is well recognized that ANG II interacts with arginine vasopressin (AVP) to regulate water reabsorption and urine concentration in the kidney. The present study used ANG II type 1a (AT1a) receptor-deficient (Agtr1a−/−) mice to test the hypothesis that AT1areceptor signaling is required for basal and water deprivation-induced urine concentration in the renal medulla. Eight groups of wild-type (WT) and Agtr1a−/−mice were treated with or without 24-h water deprivation and 1-desamino-8-d-AVP (DDAVP; 100 ng/h ip) for 2 wk or with losartan (10 mg/kg ip) during water deprivation. Under basal conditions, Agtr1a−/−mice had lower systolic blood pressure (P< 0.01), greater than threefold higher 24-h urine excretion (WT mice: 1.3 ± 0.1 ml vs. Agtr1a−/−mice: 5.9 ± 0.7 ml, P< 0.01), and markedly decreased urine osmolality (WT mice: 1,834 ± 86 mosM/kg vs. Agtr1a−/−mice: 843 ± 170 mosM/kg, P< 0.01), without significant changes in 24-h urinary Na+excretion. These responses in Agtr1a−/−mice were associated with lower basal plasma AVP (WT mice: 105 ± 8 pg/ml vs. Agtr1a−/−mice: 67 ± 6 pg/ml, P< 0.01) and decreases in total lysate and membrane aquaporin-2 (AQP2; 48.6 ± 7% of WT mice, P< 0.001) and adenylyl cyclase isoform III (55.6 ± 8% of WT mice, P< 0.01) proteins. Although 24-h water deprivation increased plasma AVP to the same levels in both strains, 24-h urine excretion was still higher, whereas urine osmolality remained lower, in Agtr1a−/−mice (P< 0.01). Water deprivation increased total lysate AQP2 proteins in the inner medulla but had no effect on adenylyl cyclase III, phosphorylated MAPK ERK1/2, and membrane AQP2 proteins in Agtr1a−/−mice. Furthermore, infusion of DDAVP for 2 wk was unable to correct the urine-concentrating defects in Agtr1a−/−mice. These results demonstrate that AT1areceptor-mediated ANG II signaling is required to maintain tonic AVP release and regulate V2receptor-mediated responses to water deprivation in the inner medulla.

OBJECTIVE: Overexpression of the clusterin (CLU) gene occurs in breast cancer and is associated with lymph node metastasis. The present study explored the effect of CLUsilencing on invasion and metastasis, and the relationship between CLUexpression and the extracellular signal-regulated kinase (ERK) / matrix metalloproteinase-9 (MMP) signalling pathway in human breast cancer cells. METHODS: A pcDNA3.1-based RNA interference approach was used to knockdown the CLUgene in MDA-231 cells (MDA-231-CLUi); control MDA-231 cells were transfected with an empty vector (MDA-231-Vec). Reverse transcription-polymerase chain reaction was used to assess CLU and MMP-9 mRNA levels, and Western blotting was used to analyse CLU, MMP-9 and ERK protein levels. Metastatic potential was evaluated using in vitroand in vivomodels of invasion and metastasis. RESULTS: Compared with MDA-231-Vec cells, the MDA-231-CLUi cells demonstrated reduced migration and invasion in vitroand decreased metastatic potential in vivo. Reintroduction and reexpression of the CLUgene into the MDA-231-CLUi cells restored the invasive phenotype. MMP-9 mRNA and protein levels were reduced in MDA-231-CLUi cells, and there was a correlation between activated ERK and CLU and MMP-9 protein levels. CONCLUSION: CLUmay regulate the aggressive behaviour of human breast cancer cells through modulation of ERK signalling and MMP9expression.

Cu–Ni–Si alloys with four different Cu contents were fabricated by means of smelting. Subsequently, isothermal aging and hot rolling followed by aging treatment were carried out. The microstructure and phase composition were characterised by optical microscope, transmission electron microscope and X-ray diffractometer. Electrical conductivity was measured by using an eddy current based technique. The results show that the electrical conductivities of as cast Cu–Ni–Si alloys decrease obviously with a decline in Cu content. Isothermal aging is favourable to enhance the electrical conductivities of Cu–Ni–Si alloys with higher than 90Cu content rather than that with <90Cu content containing an integrated netted structure of grain boundary phases. The electrical conductivities of as rolled Cu–Ni–Si alloys can obviously be increased by subsequent aging treatment. The above results suggest that the disintegration of the integrated netted structure at the grain boundary is a promise to achieve high electrical conductivity for Cu–Ni–Si alloys.

There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid ß immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models.

For anthracites and petroleum cokes, the typical combustion temperature in a circulating fluidized bed (CFB) is > 900 °C. At CO2concentrations of 80–85 % (typical of oxy‐fuel CFBC conditions), limestone still calcines. When the ash which includes unreacted CaO cools to the calcination temperature, carbonation of fly ash deposited on cool surfaces may occur. At the same time, indirect and direct sulfation of limestone also will occur, possibly leading to more deposition. In this study, CaO was carbonated and sulfated simultaneously in a thermogravimetric analyzer (TGA) under conditions expected in an oxy‐fuel CFBC. It was found that temperature, and concentrations of CO2, SO2, and especially H2O are important factors in determining the carbonation/sulfation reactions of CaO.

The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT1(AT1a) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P< 0.01) and more than threefold in proximal tubules (P< 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 ± 6 mmHg (P< 0.01), whereas fractional sodium excretion was decreased by 20% (P< 0.01) and fractional lithium excretion was reduced by 24% (P< 0.01). These effects were blocked by losartan and prevented in AT1aknockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT1areceptors and increasing sodium reabsorption in proximal tubules.

The SCF (Skp1, Cullins, F-box proteins) multisubunit E3 ubiquitin ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is the largest E3 ubiquitin ligase family that promotes the ubiquitination of various regulatory proteins for targeted degradation, thus regulating many biological processes, including cell cycle progression, signal transduction, and DNA replication. The efforts to discover small molecule inhibitors of a SCF-type ligase or its components were expedited by the FDA approval of Bortezomib (also known as Velcade or PS-341), the first (and only) class of general proteasome inhibitor, for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma. Although Bortezomib has demonstrated a certain degree of cancer cell selectivity with measurable therapeutic index, the drug is, in general, cytotoxic due to its inhibition of overall protein degradation. An alternative and ideal approach is to target a specific E3 ligase, known to be activated in human cancer, for a high level of specificity and selectivity with less associated toxicity, since such inhibitors would selectively stabilize a specific set of cellular proteins regulated by this E3. Here, we review recent advances in validation of SCF E3 ubiquitin ligase as an attractive anti-cancer target and discuss how MLN4924, a small molecule inhibitor of NEDD8-activating enzyme, can be developed as a novel class of anticancer agents by inhibiting SCF E3 ligase via removal of cullin neddylation. Finally, we discuss under future perspective how basic research on SCF biology will direct the drug discovery efforts surrounding this target.