Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure

CD8+ T Cells Mediate the Athero-Protective Effect of Immunization with an ApoB-100 Peptide

Immunization of hypercholesterolemic mice with selected apoB-100 peptide antigens reduces atherosclerosis but the precise immune mediators of athero-protection remain unclear. In this study we show that immunization of apoE (-/-) mice with p210, a 20 amino acid apoB-100 related peptide, reduced aortic atherosclerosis compared with PBS or adjuvant/carrier controls. Immunization with p210 activated CD8+ T cells, reduced dendritic cells (DC) at the site of immunization and within the plaque with an associated reduction in plaque macrophage immunoreactivity. Adoptive transfer of CD8+ T cells from p210 immunized mice recapitulated the athero-protective effect of p210 immunization in naïve, non-immunized mice. CD8+ T cells from p210 immunized mice developed a preferentially higher cytolytic response against p210-loaded dendritic cells in vitro. Although p210 immunization profoundly modulated DCs and cellular immune responses, it did not alter the efficacy of subsequent T cell dependent or independent immune response to other irrelevant antigens. Our data define, for the first time, a role for CD8+ T cells in mediating the athero-protective effects of apoB-100 related peptide immunization in apoE (-/-) mice

Comparing Signal Setting Design Methods through emissions and fuel consumption performance indicators

In order to address the Signal Setting Design at urban level two main approaches may be pursued: the coordination and the synchronisation approaches depending on the steps considered for the optimisation of decision variables (two steps vs. one step). Furthermore, in terms of objective functions mono-criterion or multi-criteria may be adopted. In this paper the coordination approach is implemented considering the multi-criteria optimisation at single junctions and mono-criterion optimisation at network level whereas the synchronisation is implemented considering the mono-criterion optimisation. The main purpose of the paper is the evaluation of the performances of two strategies not only considering indicators such as the total delay, the queue length etc. but also considering other indicators such as the emissions and the fuel consumption. The methodological framework is composed by three stages: (i) the decision variables (green timings and offsets) computation through optimisation methods; (ii) the implementation of optimal signal settings in a microscopic traffic flow simulator (“Simulation of Urban MObility”-SUMO); (iii) the estimation of emissions and fuel consumption indicators

An Improved ångström-type model for estimating solar radiation over the tibetan plateau

© 2017 by the authors. For estimating the annual mean of daily solar irradiation in plateau mountainous regions, observed data from 15 radiation stations were used to validate different empirical estimation methods over the Tibetan Plateau. Calibration indicates that sunshine-based site-dependent models perform better than temperature-based ones. Then, the highly rated sunshine-based Ångström model and temperature-based Bristow model were selected for regional application. The geographical models perform much better than the average models, but still not ideally. To achieve better performance, the Ångström-type model was improved using altitude and water vapor pressure as the leading factors. The improved model can accurately predict the coefficients at all the stations, and performs the best among all models with an average Nash-Sutcliffe Efficiency value of 0.856. Spatial distribution of the annual mean of daily solar irradiation was then estimated with the improved model. It is indicated that there is an increasing trend of radiation from east to west, with a great center of the annual mean of daily solar irradiation on southwest Tibetan Plateau ranging from 20 to 24 MJm2. The improved model should be further validated against observations before its applications in other plateau mountainous regions

Computational Validation of Injection Molding Tooling by Additive Layer Manufacture to Produce EPDM Exterior Automotive Seals

During the design and development of ethylene propylene diene monomer (EPDM) exterior automotive seals, prototype components can only manufactured through production tooling platforms by either injection molding or extrusion. Consequently, tooling is expensive and has long lead times. This paper investigates whether additive layer manufacture is a viable method for producing tooling used in injection molding of exterior automotive seals in EPDM. Specifically, a novel rapid tooling is a method that combines additive layer manufacture (ALM) with epoxy reinforcement. Computational validation is performed whereby the mechanical properties of the tool are evaluated. The research has concluded that the novel tooling configuration would be suitable for prototyping purposes which would drastically reduce both costly and environmentally detrimental pre-manufacturing processes. This work has laid the foundations to implement rapid tooling technology to the injection molding of prototype EPDM parts

Transcriptional Changes in Schistosoma mansoni during Early Schistosomula Development and in the Presence of Erythrocytes

Schistosome blood flukes cause more mortality and morbidity than any other human worm infection, but current control methods primarily rely on a single drug. There is a desperate need for new approaches to control this parasite, including vaccines. People become infected when the free-swimming larva, the cercaria, enters through the skin and becomes the schistosomulum. Schistosomula are susceptible to immune responses during their first few days in the host before they become adult parasites. We characterised the genes that these newly transformed parasites switch on when they enter the host to identify molecules that are critical for survival in the human host. Some of these highly up-regulated genes can be targeted for future development of new vaccines and drugs

Apoptosis Governs the Elimination of Schistosoma japonicum from the Non-Permissive Host Microtus fortis

The reed vole, Microtus fortis, is the only known mammalian host in which schistosomes of Schistosoma japonicum are unable to mature and cause significant pathogenesis. However, little is known about how Schistosoma japonicum maturation (and, therefore, the development of schistosomiasis) is prevented in M. fortis. In the present study, the ultrastructure of 10 days post infection schistosomula from BALB/c mice and M. fortis were first compared using scanning electron microscopy and transmission electron microscopy. Electron microscopic investigations showed growth retardation and ultrastructural differences in the tegument and sub-tegumental tissues as well as in the parenchymal cells of schistosomula from M. fortis compared with those in BALB/c mice. Then, microarray analysis revealed significant differential expression between the schistosomula from the two rodents, with 3,293 down-regulated (by ≥2-fold) and 71 up-regulated (≥2 fold) genes in schistosomula from the former. The up-regulated genes included a proliferation-related gene encoding granulin (Grn) and tropomyosin. Genes that were down-regulated in schistosomula from M. fortis included apoptosis-inhibited genes encoding a baculoviral IAP repeat-containing protein (SjIAP) and cytokine-induced apoptosis inhibitor (SjCIAP), genes encoding molecules involved in insulin metabolism, long-chain fatty acid metabolism, signal transduction, the transforming growth factor (TGF) pathway, the Wnt pathway and in development. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and PI/Annexin V-FITC assays, caspase 3/7 activity analysis, and flow cytometry revealed that the percentages of early apoptotic and late apoptotic and/or necrotic cells, as well as the level of caspase activity, in schistosomula from M. fortis were all significantly higher than in those from BALB/c mice

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe