Avoiding a Brexit will be crucial for the success of Europe’s Capital Markets Union

An EU Capital Markets Union has been proposed with the aim of providing a boost to Europe’s economy by creating funding channels between providers of loanable funds and the firms best placed to use them. Umberto Marengo writes on the potential benefits from the system and some of the key issues that could undermine its implementation. He argues that Britain’s secession from the EU would have negative consequences for capital flows, and would not only spell the end for the Capital Markets Union, but could also close the door to British financial industry in Europe at a time when its services would be much needed

Inhibition of the de-myelinating properties of Aicardi-Goutières syndrome lymphocytes by cathepsin D silencing.

Molecular mechanisms relating interferon-alpha (IFN-alpha) to brain damage have recently been identified in a microarray analysis of cerebrospinal fluid lymphocytes from patients with Aicardi-Goutières Syndrome (AGS). These findings demonstrate that the inhibition of angiogenesis and the activation of neurotoxic lymphocytes are the major pathogenic mechanisms involved in the brain damage consequent to elevated interferon-alpha levels. Our previous study demonstrated that cathepsin D, a lysosomal aspartyl endopeptidase, is the primary mediator of the neurotoxicity exerted by AGS lymphocytes. Cathepsin D is a potent pro-apoptotic, neurotoxic, and demyelinating protease if it is not properly inhibited by the activities of leukocystatins. In central nervous system white matter, demyelination results from cathepsin over-expression when not balanced by the expression of its inhibitors. In the present study, we used RNA interference to inhibit cathepsin D expression in AGS lymphocytes with the aim of decreasing the neurotoxicity of these cells. Peripheral blood lymphocytes collected from an AGS patient were immortalized and co-cultured with astrocytes in the presence of interferon alpha with or without cathepsin D RNA interference probes. Cathepsin D expression was measured by qPCR, and neurotoxicity was evaluated by microscopy. RNA interference inhibited cathepsin D over-production by 2.6-fold (P<0.01) in AGS lymphocytes cultured in the presence of interferon alpha. AGS lymphocytes treated using RNA interference exhibited a decreased ability to induce neurotoxicity in astrocytes. Such neurotoxicity results in the inhibition of astrocyte growth and the inhibition of the ability of astrocytes to construct web-like aggregates. These results suggest a new strategy for repairing AGS lymphocytes in vitro by inhibiting their ability to induce astrocyte damage and leukodystroph

PKCδ Sensitizes Neuroblastoma Cells to L-Buthionine-Sulfoximine and Etoposide Inducing Reactive Oxygen Species Overproduction and DNA Damage

Neuroblastoma is a type of pediatric cancer. The sensitivity of neuroblastoma (NB) cancer cells to chemotherapy and radiation is inhibited by the presence of antioxidants, such as glutathione (GSH), which is crucial in counteracting the endogenous production of reactive oxygen species (ROS). We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and Protein kinase C (PKC) δ activation. In the present study, we transfected PKCδ in NB cells resistant to oxidative death induced by L-buthionine-S,R-sulfoximine (BSO), a GSH-depleting agent. Cell responses, in terms of ROS production, apoptosis and DNA damage were evaluated. Moreover, PKCδ activation was monitored by analyzing the phosphorylation status of threonine 505 residue, carrying out PKC activity assay and investigating the subcellular localization of the kinase. The cell responses obtained in BSO-resistant cells were also compared with those obtained in BSO-sensitive cells subjected to the same experimental protocol. Our results demonstrate, for the first time, that PKCδ induces DNA oxidation and ROS overproduction leading to apoptosis of BSO-resistant NB cells and potentiates the cytotoxic effects induced by BSO in sensitive cells. Moreover, PKCδ overexpression enhances the sensitivity of NB cells to etoposide, a well-characterised drug, commonly used in neuroblastoma therapy. Altogether our data provide evidence of a pro-oxidant role of PKCδ that might be exploited to design new therapeutic strategies aimed at selective killing of cancer cells and overcoming drug resistance. However, it becomes evident that a more detailed understanding of ROS-mediated signaling in cancer cells is necessary for the development of redox-modulated therapeutic approaches

Incidence of adverse events at 3 months versus at 12 months after dual antiplatelet therapy cessation in patients treated with thin stents with unprotected left main or coronary bifurcations

Incidence and predictors of adverse events after dual antiplatelet therapy (DAPT) cessation in patients treated with thin stents (<100 microns) in unprotected left main (ULM) or coronary bifurcation remain undefined. All consecutive patients presenting with a critical lesion of an ULM or involving a main coronary bifurcation who were treated with very thin strut stents were included. MACE (a composite end point of cardiovascular death, myocardial infarction [MI], target lesion revascularization [TLR], and stent thrombosis [ST]) was the primary endpoint, whereas target vessel revascularization (TVR) was the secondary endpoint, with particular attention to type and occurrence of ST and occurrence of ST, CV death, and MI during DAPT or after DAPT discontinuation. All analyses were performed according to length of DAPT dividing the patients in 3 groups: Short DAPT (3-months), intermediate DAPT (3 to 12 months), and long DAPT (12-months). A total of 117 patients were discharged with an indication for DAPT ≤3 months (median 1: 1 to 2.5), 200 for DAPT between 3 and 12 months (median 8: 7 to 10), and 1,958 with 12 months DAPT. After 12.8 months (8 to 20), MACE was significantly higher in the 3-month group compared with 3 to 12 and 12-month groups (9.4% vs 4.0% vs 7.2%, p ≤0.001), mainly driven by MI (4.4% vs 1.5% vs 3%, p ≤0.001) and overall ST (4.3% vs 1.5% vs 1.8%, p ≤0.001). Independent predictors of MACE were low GFR and a 2 stent strategy. Independent predictors of ST were DAPT duration <3 months and the use of a 2-stent strategy. In conclusion, even stents with very thin strut when implanted in real-life ULM or coronary bifurcation patients discharged with short DAPT have a relevant risk of ST, which remains high although not significant after DAPT cessation

A concise review of small-strain phase-field modeling of ductile fracture

The computational modeling of ductile fracture is a complex problem due to the simultaneous presence of various competing dissipation mechanisms at the microscale resulting in evolving displacement discontinuities at the macroscale. Phase-field modeling of brittle fracture has emerged as one of the more computationally efficient smeared approaches for simulating crack propagation in solids. In recent years, there has been significant attention towards extending this approach to ductile fracture. The first papers on this topic were published approximately a decade ago, and since then, there has been a growing number of new contributions proposing different approaches and applications. The purpose of this work is to offer an extensive bibliography on phase-field modeling of ductile fracture, together with a concise presentation of some of the most widely used formulations, specifically limited to small-strain plasticity under monotonic loading. Few aspects of particular interest are also discussed in detail

Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies. Thus, a dietary antioxidant supplementation has been proposed in order to prevent aging, cardiovascular and degenerative diseases as well as carcinogenesis. However, this approach has failed to demonstrate efficacy, often leading to harmful side effects, in particular in patients affected by cancer. In this latter case, an approach based on endogenous antioxidant depletion, leading to ROS overproduction, has shown an interesting potential for enhancing susceptibility of patients to anticancer therapies. Therefore, a deep investigation of molecular pathways involved in redox balance is crucial in order to identify new molecular targets useful for the development of more effective therapeutic approaches. The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application

A rigorous and efficient explicit algorithm for irreversibility enforcement in phase-field finite element and isogeometric modeling of brittle crack propagation

In the present work, a computationally efficient and explicit algorithm for the rigorous enforcement of the irreversibility constraint in the phase-field modeling of brittle fracture is presented. The proposed approach is staggered and relies on the alternate minimization of the total energy functional. The phase-field evolution turns out to be governed by a complementarity boundary-value problem, where the complementarity stems from the irreversibility, while the boundary-value problem is originated by the presence of the gradient term in the phase-field functional. Several different techniques have been proposed in the literature to account for damage irreversibility in a computationally effective way. Following a similar approach proposed in the past for a gradient-plasticity problem, a particularly simple and effective solution strategy based on the Projected Successive Over-Relaxation (PSOR) method for constrained optimization, where an iterative explicit scheme is used for the solution of symmetric linear complementarity problems, is presented. Even though the proposed method is restricted to linear complementarity problems, it can be applied to the numerical simulation of a wide range of problems discussed in the literature. The performance of the suggested solution algorithm on a number of test cases is compared with that of a recently proposed penalty approach for the approximated enforcement of irreversibility

Cholesterol and Alzheimer’s disease: a still poorly understood correlation

none7noneRoberta Ricciarelli; Elisa Canepa; Barbara Marengo; Umberto M. Marinari; Giuseppe Poli; Maria A. Pronzato; Cinzia DomenicottiRicciarelli, Roberta; Canepa, Elisa; Marengo, Barbara; Marinari, Umberto; Poli, Giuseppe; Pronzato, MARIA ADELAIDE; Domenicotti, CINZIA MARI