To the Heart of IFs Function: Do they Aggregate on Purpose?

Background: One of the molecular hallmarks in the development of heart failure (HF) is loss of ultrastructure within the cardiac myocyte. In addition, HF is increasingly recognized as a proteinopathy characterized by the accumulation of misfolded proteins similar to Alzheimer and Parkinson disease. However, despite its increasing prevalence and poor prognosis, the advances in the pharmacological treatment of HF have been limited, highlighting an urgent need for the discovery of new therapeutic targets. We reported a consistent accumulation of mono-phosporylated desmin in experimental and clinical models of HF. We also demonstrated how mono-phosphorylated desmin is more prone to cleavage and aggregation in isolated cardiac myocytes. Therefore, if on the one hand desmin cleavage could easily explain the loss of a cardiac myocyte\u2019s ultrastructure, its high abundance and propensity to aggregate make it an ideal candidate as the seed generating pre-amyloid-oligomers (PAOs) and amyloid fibrils in the heart. Methods: Using a combination of novel and established protein biochemistry techniques, we aimed at demonstrating desmin\u2019s identity as the seed starting the nucleation process which leads to the formation of cardiac PAOs and amyloid fibrils. Results: Desmin displayed common features shared by other established PAOs and fibrils (e.g. tinctorial properties) in experimental and clinical models of HF. Conclusions: The inherent propensity of intermediate filaments to aggregate, combined with the use of cardiac tissue as a model for repeated mechanical stretch, suggest that intermediate filaments aggregation could be used as a way to dissipate/scavange mechanical as well as chemical stress. We will therefore use the highly organized structure of cardiac myocytes to infer IFs function in mammalian cells

Azacitidine and Lenalidomide Combination Therapy in Myelodysplastic Syndromes: Topography and Translational Relevance of Nuclear Phospholipase C β - dependent Signalling

Nuclear inositide signalling pathways, and particularly those regulated by PI-PLCβ1, are associated with cell proliferation and differentiation. Myelodysplastic syndromes (MDS) are a heterogeneous spectrum of chronic myeloid hemopathies with associated symptomatic cytopenias and substantial potential for evolution to acute myeloid leukemia (AML). MDS patients are currently treated with two main approaches, epigenetic (Azacitidine) and immunomodulatory (Lenalidomide: above all in cell clones bearing a deletion of the long arm of the chromosome 5 [del(5q)]). As Azacitidine and Lenalidomide alone can show adverse effects or patients can be refractory, an experimental current approach is the combination of the two drugs. Clinically, this combination therapy is promising, while its molecular effect has to be clarified. Stemming from these data, in this study the effect of an Azacitidine-Lenalidomide combination therapy was studied, in both MDS patients and hematopoietic cell lines. The specific aims of this study were to evaluate the effect of Azacitidine and Lenalidomide MDS therapy on: cell cycle regulation, hematopoietic differentiation, gene mutation and miR expression. Lenalidomide alone, via PI-PLCβ1/PKC pathway, was able to induce a selective G0/G1 arrest of the cell cycle in del(5q) cells, slowing down their rate proliferation and favouring erythropoiesis activation. In addition, although the mutation profile at baseline was not entirely capable of predicting the clinical effect of Azacitidine and Lenalidomide therapy, the presence of specific point mutations affecting three inositide genes (PI3KCD, AKT3, PLCG2) was correlated to and anticipated a negative clinical outcome. Moreover, the differential miR expression was detectable even from the 4th cycle of therapy in responder patients, as compared to non-responders. In MDS, this is the first evidence that the molecular mutation profiling of inositide genes or a specific mini-cluster of differentially expressed miRs, targeting inositide signaling molecules, can be associated with the clinical response, thus possibly predicting the effect of the therapy

Between quantity and quality: competing views on the role of Big Data for causal inference

When does more data help and when does it not in the sciences? In the past decade, this question has become central because of the phenomenon of Big Data. While these discussions started as a result of somewhat naive ideas that have been closely analyzed and mostly rejected in the philosophy of data, the question about the epistemic difference that more or less data make still matters, especially in light of the impressive performance of data science tools, which seem to improve their performance the more data are trained on. In several areas of the sciences, having more data is connected to methodological and epistemic benefits and something that research should strive towards. More data is often equated to better science: this elicits crucial questions about the epistemic value of the quantity of data. In this chapter, we discuss this problem in light of current discussions in the life and health sciences and the philosophy of data

CSR and Sustainability Report for Nonprofit Organizations. An Italian Best Practice

The purpose of this paper is to analyze the sustainability report for the communication of Corporate Social Responsibility (CSR) in a nonprofit organization. To this aim, an Italian case study is analyzed: the Fondazione Renato Piatti Onlus, a nonprofit organization of Social Utility. In the first part, we analyze the CSR for nonprofit organizations and the sustainability report (also called 'social balance'). In the second part, we present evidence from the case study. The research is exploratory in nature when considering the connection of corporate social responsibility efforts to the nonprofit sector, a qualitative methodology was chosen over quantitative methods. Specifically, the case study was used to show what strategy a nonprofit organization can develop. Nowadays CSR strategies received a growing attention from both businesses and nonprofit organizations but also from the EU which forced large public-interest entities to present a social balance. For nonprofit organizations, applying social responsibility is not a voluntary issue. Nonprofit organizations have an ethical obligation to their stakeholder and to the public to conduct their activities with accountability and transparency. Scholars have increasingly been studying the impact of corporate social responsibility as a business strategy in for-profit companies. However, there is still lack of researches on how nonprofit organizations implement CSR into the strategy. As a consequence of the above remarks, a large part of nonprofit organizations fails to correctly implement a successful long term CSR strategy. The Fondazione Renato Piatti Onlus belongs to that group that has been able to incorporate social responsibility within the organization, then expanding its content into a social report drawn up in accordance with the guidelines of the Italian Agency for the Third Sector

CSR and Sustainability Report for Nonprofit Organizations. An Italian Best Practice

The purpose of this paper is to analyze the sustainability report for the communication of Corporate Social Responsibility (CSR) in a nonprofit organization. To this aim, an Italian case study is analyzed: the Fondazione Renato Piatti Onlus, a nonprofit organization of Social Utility. In the first part, we analyze the CSR for nonprofit organizations and the sustainability report (also called ‘social balance’). In the second part, we present evidence from the case study. The research is exploratory in nature when considering the connection of corporate social responsibility efforts to the nonprofit sector, a qualitative methodology was chosen over quantitative methods. Specifically, the case study was used to show what strategy a nonprofit organization can develop. Nowadays CSR strategies received a growing attention from both businesses and nonprofit organizations but also from the EU which forced large public-interest entities to present a social balance. For nonprofit organizations, applying social responsibility is not a voluntary issue. Nonprofit organizations have an ethical obligation to their stakeholder and to the public to conduct their activities with accountability and transparency. Scholars have increasingly been studying the impact of corporate social responsibility as a business strategy in for-profit companies. However, there is still lack of researches on how nonprofit organizations implement CSR into the strategy. As a consequence of the above remarks, a large part of nonprofit organizations fails to correctly implement a successful long term CSR strategy. The Fondazione Renato Piatti Onlus belongs to that group that has been able to incorporate social responsibility within the organization, then expanding its content into a social report drawn up in accordance with the guidelines of the Italian Agency for the Third Sector

CSR and Sustainability Report for Nonprofit Organizations. An Italian Best Practice

The purpose of this paper is to analyze the sustainability report for the communication of Corporate Social Responsibility (CSR) in a nonprofit organization. To this aim, an Italian case study is analyzed: the Fondazione Renato Piatti Onlus, a nonprofit organization of Social Utility. In the first part, we analyze the CSR for nonprofit organizations and the sustainability report (also called ‘social balance’). In the second part, we present evidence from the case study. The research is exploratory in nature when considering the connection of corporate social responsibility efforts to the nonprofit sector, a qualitative methodology was chosen over quantitative methods. Specifically, the case study was used to show what strategy a nonprofit organization can develop. Nowadays CSR strategies received a growing attention from both businesses and nonprofit organizations but also from the EU which forced large public-interest entities to present a social balance. For nonprofit organizations, applying social responsibility is not a voluntary issue. Nonprofit organizations have an ethical obligation to their stakeholder and to the public to conduct their activities with accountability and transparency. Scholars have increasingly been studying the impact of corporate social responsibility as a business strategy in for-profit companies. However, there is still lack of researches on how nonprofit organizations implement CSR into the strategy. As a consequence of the above remarks, a large part of nonprofit organizations fails to correctly implement a successful long term CSR strategy. The Fondazione Renato Piatti Onlus belongs to that group that has been able to incorporate social responsibility within the organization, then expanding its content into a social report drawn up in accordance with the guidelines of the Italian Agency for the Third Sector

Content consumption cartography of the Paris urban region using cellular probe data

A present issue in the evolution of mobile cellular networks is determining whether, how and where to deploy adaptive content and cloud distribution solutions at base station and back-hauling network level. In order to answer these questions, in this paper we document the content consumption in Orange cellular network for Paris metropolitan area. From spatial and application-level extensive analysis of real data, we numerically and statistically quantify the geographical distribution of content consumption with per-service classifications. We provide experimental statistical distributions usable for further research in the area

The wide and growing range of lamin B‑related diseases: from laminopathies to cancer

B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scafold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifcations to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stifness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fuctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent fndings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer

Osteopathic Manipulative Treatment in a Paediatric Patient with Oesophageal Atresia and Tracheo-Oesophageal Fistula

This study is aimed to evaluate the effectiveness of osteopathic manipulative treatment (OMT) in dysphagia symptoms and aspiration risk. This is a clinical case report on a 40-day-old infant with a diagnosis of oesophageal atresia and tracheo-oesophageal fistula. The patient received one OMT every 15 days for 7 times. The clinical outcome was the clinical changes in dysphagia symptoms assessed by the Paediatric Eating Assessment Tool-10 (PEDI-EAT-10). At the first osteopathic evaluation (T0), the total score of the PEDI-EAT-10 was 7, at the fourth osteopathic evaluation (T1), the total score was 3, and at the seventh osteopathic evaluation (T2), the total score was 1. OMT was effective and safe in reducing dysphagia symptoms and aspiration risk