The emerging role of epigenetics in therapeutic targeting of cardiomyopathies

Cardiomyopathies (CMPs) are a heterogeneous group of myocardial diseases accountable for the majority of cases of heart failure (HF) and/or sudden cardiac death (SCD) worldwide. With the recent advances in genomics, the original classification of CMPs on the basis of morphological and functional criteria (dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic ventricular cardiomyopathy (AVC)) was further refined into genetic (inherited or familial) and acquired (non-inherited or secondary) forms. Despite substantial progress in the identification of novel CMP-associated genetic variations, as well as improved clinical recognition diagnoses, the functional consequences of these mutations and the exact details of the signaling pathways leading to hypertrophy, dilation, and/or contractile impairment remain elusive. To date, global research has mainly focused on the genetic factors underlying CMP pathogenesis. However, growing evidence shows that alterations in molecular mediators associated with the diagnosis of CMPs are not always correlated with genetic mutations, suggesting that additional mechanisms, such as epigenetics, may play a role in the onset or progression of CMPs. This review summarizes published findings of inherited CMPs with a specific focus on the potential role of epigenetic mechanisms in regulating these cardiac disorders

Revisiting Sovereign Bankruptcy

Sovereign debt crises occur regularly and often violently. Yet there is no legally and politically recognized procedure for restructuring the debt of bankrupt sovereigns. Procedures of this type have been periodically debated, but so far been rejected, for two main reasons. First, countries have been reluctant to give up power to supranational rules or institutions, and creditors and debtors have felt that there were sufficient instruments for addressing debt crises at hoc. Second, fears that making debt easier to restructure would raise the costs and reduce the amounts of sovereign borrowing in many countries. This was perceived to be against the interests of both the providers of both creditors and major borrowers. This report argues that both the nature and our understanding of sovereign debt problems have changed, over the course of the last decade, in a direction that creates a much stronger case for an orderly sovereign bankruptcy regime today than ten years ago. Pre-crisis policy mistakes are now recognized to be a much more severe problem for borrowing countries than the costs or limited availability of private financing. Recent court rulings – particularly a recent U.S. ruling that gives holdout creditors that decline a restructuring offer the right to interfere with payments to the creditors that accept such an offer. This will complicate efforts to resolve future debt crises on an ad hoc basis. Finally, sovereign debt crises are no longer just a problem in emerging markets, but a core concern in advanced countries as well – particularly in the Euro area. If the Euro is to survive, this will require both better ways to resolve debt crises and stronger, market-based incentives that prevent debt problems from occurring in the first place. To address these problems, policy proposals are presented at two levels: for the Euro area, and globally. A Euro area sovereign debt restructuring regime could be developed by amending the Treaty establishing the European Stability Mechanism (ESM). This would both restrict the scope for lending to highly indebted countries without also restructuring their debts, and protect Euro area members receiving ESM financial assistance from legal action by holdout creditors. At the global level, a number of proposals are discussed, ranging from a coordinated introduction of aggregate collective action clauses that would allow a supermajority of bondholders across all bonds to amend bond payment terms to an amendment of the IMF articles that would limit the legal remedies of holdouts when a debt restructuring proposal has been accepted both by a majority of creditors and endorsed by the IMF

Industrial risk in the Lombardy Region (Italy): what people perceive and what are the gaps to improve the risk communication and the participatory processes

Risk communication is of vital importance in today\u2019s society, as audiences become ever more questioning about the causes and effects of risk. However, the communication of risk is a complex activity involving many different types of communicators and destinataries, from scientists, to the media, to government agencies, industry and consumer groups, each of which having its own agendas to fulfil. Such variation across the communication of the same risk can lead to confusion, misunderstandings, misreporting in the media and subsequent conflicts. The goal of risk communication is to produce an informed public. The personal nature of risk issues and the uncertainty associated with estimating risk can provoke considerable anxiety for the public and make adopted risk management strategies less acceptable. Lombardy is one of the most densely populated and industrialized regions in Europe and nearly 280 Seveso sites interest it. The Seveso Directive requires specific measures on risk communication to the population. Nevertheless, the Lombardy Region Authorities consider that the implementation of such provisions is too weak. Therefore an exploratory research has been concluded, in order to estimate the gaps in risk communication and to improve the participation of the population in the emergency preparedness activities. The paper reports the main results of the research and illustrates the potential strategies to improve the risk communication and the population participation and preparedness (\uc9upolis Lombardia 2011)

On generation of jets for vector bundles

Sin resume

Efficiency of microsatellite markers in assisted selection for resistance to soybean cyst nematode (race 3).

Four microsatellite sequences were tested in soybean DNA from cultivars and segregating genotypes. Three of them were close to the resistance locus rhg 1 on molecular linkage group G (Satt 309, Sat_168, Sat_163) and one was close to Rhg4 locus on group A2 (Sat_162). Progenies previously classified as cyst nematode (SNC) resistant and others with unknown reaction were tested, using the resistant cultivars Liderança, and Renascença and the susceptibles 'Cristalina' and 'OCEPAR-4' as control. The best primer for resistance to SCN was Sat_162. Twenty segregant progenies tested with Sat_162 presented a 150 bp band for homozygous resistant genotypes and 200 bp for susceptible ones, and both for the heterozigous genotypes. Previous studies have shown that this microsatellite marker is efficient to select genotypes carrying Peking-derivative resistance. 'Peking' takes part in the in the genealogy of all segregant progenies evaluated in this study. Thus, the obtained results showed that Sat_162 distinguished resistant and susceptible soybean genotypes to SCN, race 3

Formamide as the main building block in the origin of nucleic acids

The simplest molecules grouping the four most common elements of the universe H,C,O and N (with the exception of the biologically inert He) are isocyanate HNCO and formamide H2NCOH. Reasons for the availability of formamide on prebiotic Earth are presented. We review evidence showing that formamide in the presence of largely available catalysts and by moderate heating yields the complete set of nucleic bases necessary for the formation of nucleic acids. Formamide also favours the formation of acyclonucleosides and the phosphorylation and trans-phosphorylation of nucleosides, thus providing a plausible chemical frame for the passage from a simple one-carbon compound to nucleic polymers. Physico-chemical conditions exist in which formamide favours the stability of the phosphoester bonds in nucleic polymers relative to that of the same bonds in monomers. Starting from a formamide-laden environment subject only to the laws of chemistry, a hypothesis is outlined sketching the passage towards an aqueous world in which Darwinian rules apply

The New Paradigms in Clinical Research: From Early Access Programs to the Novel Therapeutic Approaches for Unmet Medical Needs.

Despite several innovative medicines gaining worldwide approval in recent years, there are still therapeutic areas for which unsatisfied therapeutic needs persist. For example, high unmet clinical need was observed in patients diagnosed with type 2 diabetes mellitus and hemophilia, as well as in specific age groups, such as the pediatric population. Given the urgent need to improve the therapy of clinical conditions for which unmet clinical need is established, clinical testing, and approval of new medicines are increasingly being carried out through accelerated authorization procedures. Starting from 1992, the Food and Drug Administration and the European Medicines Agency have supported the so-called Early Access Programs (EAPs). Such procedures, which can be based on incomplete clinical data, allow an accelerated marketing authorization for innovative medicines. The growth in pharmaceutical research has also resulted in the development of novel therapeutic approaches, such as biotech drugs and advanced therapy medicinal products, including new monoclonal antibodies for the treatment of asthma, antisense oligonucleotides for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy, and new anticancer drugs that act on genetic biomarkers rather than any specific type of cancer. Even though EAPs and novel therapeutic approaches have brought huge benefits for public health, their implementation is limited by several challenges, including the high risk of safety-related label changes for medicines authorized through the accelerated procedure, the high costs, and the reimbursement and access concerns. In this context, regulatory agencies should provide the best conditions for the implementation of the described new tools