Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

Long-term retinal PEDF overexpression prevents neovascularization in a murine adult model of retinopathy

Neovascularization associated with diabetic retinopathy (DR) and other ocular disorders is a leading cause of visual impairment and adult-onset blindness. Currently available treatments are merely palliative and offer temporary solutions. Here, we tested the efficacy of antiangiogenic gene transfer in an animal model that mimics the chronic progression of human DR. Adeno-associated viral (AAV) vectors of serotype 2 coding for antiangiogenic Pigment Epithelium Derived Factor (PEDF) were injected in the vitreous of a 1.5 month-old transgenic model of retinopathy that develops progressive neovascularization. A single intravitreal injection led to long-term production of PEDF and to a striking inhibition of intravitreal neovascularization, normalization of retinal capillary density, and prevention of retinal detachment. This was parallel to a reduction in the intraocular levels of Vascular Endothelial Growth Factor (VEGF). Normalization of VEGF was consistent with a downregulation of downstream effectors of angiogenesis, such as the activity of Matrix Metalloproteinases (MMP) 2 and 9 and the content of Connective Tissue Growth Factor (CTGF). These results demonstrate long-term efficacy of AAV-mediated PEDF overexpression in counteracting retinal neovascularization in a relevant animal model, and provides evidence towards the use of this strategy to treat angiogenesis in DR and other chronic proliferative retinal disorders

Microspatial variability in community structure and photophysiology of calcified macroalgal microbiomes revealed by coupling of hyperspectral and high-resolution fluorescence imaging

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Chemical warfare between leafcutter ant symbionts and a co-evolved pathogen

Acromyrmex leafcutter ants form a mutually beneficial symbiosis with the fungus Leucoagaricus gongylophorus and with Pseudonocardia bacteria. Both are vertically transmitted and actively maintained by the ants. The fungus garden is manured with freshly cut leaves and provides the sole food for the ant larvae, while Pseudonocardia cultures are reared on the ant-cuticle and make antifungal metabolites to help protect the cultivar against disease. If left unchecked, specialized parasitic Escovopsis fungi can overrun the fungus-garden and lead to colony collapse. We report that Escovopsis upregulates the production of two specialized metabolites when it infects the cultivar. These compounds inhibit Pseudonocardia and one, shearinine D, also reduces worker behavioral defences and is ultimately lethal when it accumulates in ant tissues. Our results are consistent with an active evolutionary arms race between Pseudonocardia and Escovopsis, which modifies both bacterial and behavioral defences such that colony collapse is unavoidable once Escovopsis infections escalate

Application of the modal superposition technique combined with analytical elastoplastic approaches to assess the fatigue crack initiation on structural components

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Local fatigue approaches, such as, the stress-life, strain-life or energetic approaches defines a framework to estimate the fatigue crack initiation from notches of structural details. Various engineering structures, such as, bridges, wind towers, among others, are subjected to cyclic dynamic loadings which may substantially reduce the strength of these structures. Nowadays, the structural systems tend to be more complex being necessary to find computationally efficient solutions to perform their fatigue analysis, accounting for dynamic actions corresponding to long complex loading events (e.g. diversity of trains crossing a bridge), mainly if local approaches are envisaged. Thus, this paper aims at presenting and validating a generalization of a methodology based on modal superposition technique, for fatigue damage parameters evaluation, which can be applied in fatigue analysis using local approaches. This technique was applied recently in the context of fatigue crack propagation based on fracture mechanics, although it can be extended to compute the history of local notch stresses and strains at notches. A very important conclusion is that the technique can be explored for the case of local confined plasticity at notches whenever the global elastic behaviour of the component prevails. Local submodelling can be explored with this technique to avoid the necessity of large computational models. Local models are only needed to be run under linear elastic conditions for the selected modal shapes of the structure, being the local time history of fatigue damage variable computed by modal superposition for each loading event. That time history may be further post-processed for elastoplastic conditions using Neuber or Glinka's analyses. Comparisons with direct integration elastoplastic dynamic analysis confirmed the feasibility of the proposed approach.Authors acknowledge the Portuguese Foundation for Science and Technology for the funding, particularly through the iRail doctoral program and the grants PD/BD/114101/2015 and SFRH/BPD/107825/2015. Authors gratefully acknowledge the funding of SciTech – Science and Technology for Competitive and Sustainable Industries (NORTE-01-0145-FEDER-000022), R&D project co-financed by Programa Operacional Regional do Norte

Study of hadronic event-shape variables in multijet final states in pp collisions at √s=7 TeV

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Constraints on parton distribution functions and extraction of the strong coupling constant from the inclusive jet cross section in pp collisions at √s=7 TeV

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Search for Dark Matter and Supersymmetry with a Compressed Mass Spectrum in the Vector Boson Fusion Topology in Proton-Proton Collisions at root s=8 TeV

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Study of double parton scattering using W+2-jet events in proton-proton collisions at √s=7 TeV

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Measurements of the tt¯ charge asymmetry using the dilepton decay channel in pp collisions at √s=7 TeV

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