Recognition mechanism of p63 by the E3 ligase Itch Novel strategy in the study and inhibition of this interaction.

The HECT-containing E3 ubiquitin ligase Itch mediates the degradation of several proteins, including p63 and p73, involved in cell specification and fate. Itch contains four WW domains, which are essential for recognition on the target substrate, which contains a short proline-rich sequence. Several signaling complexes containing these domains have been associated with human diseases such as muscular dystrophy, Alzheimer’s or Huntington’s diseases. To gain further insight into the structural determinants of the Itch-WW2 domain, we investigated its interaction with p63. We assigned, by 3D heteronuclear NMR experiments, the backbone and side chains of the uniformly 13C-15N-labeled Itch-WW2. In vitro interaction of Itch-WW2 domain with p63 was studied using its interactive p63 peptide, pep63. Pep63 is an 18-mer peptide corresponding to the region from 534–551 residue of p63, encompassing the PP xY motif that interacts with the Itch-WW domains, and we identified the residues involved in this molecular recognition. Moreover, here, a strategy of stabilization of the conformation of the PP xY peptide has been adopted, increasing the WW-ligand binding. We demonstrated that cyclization of pep63 leads to an increase of both the biological stability of the peptide and of the WW-ligand complex. Stable metal-binding complexes of the pep63 have been also obtained, and localized oxidative damage on Itch-WW2 domain has been induced, demonstrating the possibility of use of metal-pep63 complexes as models for the design of metal drugs to inhibit the Itch-WW-p63 recognition in vivo. Thus, our data suggest a novel strategy to study and inhibit the recognition mechanism of Itch E3-ligase

Can COVID-19 pandemic boost the epidemic of neurodegenerative diseases?

The pandemic of Coronavirus Disease 2019 (COVID-19) presents the world with the medical challenge associated with multifactorial nature of this pathology. Indeed COVID-19 affects several organs and systems and presents diversified clinical picture. COVID-19 affects the brain in many ways including direct infection of neural cells with SARS-CoV-2, severe systemic inflammation which floods the brain with pro-inflammatory agents thus damaging nervous cells, global brain ischaemia linked to a respiratory failure, thromboembolic strokes related to increased intravascular clotting and severe psychological stress. Often the COVID-19 is manifested by neurological and neuropsychiatric symptoms that include dizziness, disturbed sleep, cognitive deficits, delirium, hallucinations and depression. All these indicate the damage to the nervous tissue which may substantially increase the incidence of neurodegenerative diseases and promote dementia

Cell Death and Disease: a new journal for a central area of pathophysiology

If pathophysiology were a fan propeller, cell death would constitute the pivot. Indeed, most diseases are connected to deregulated cell death in some way. Excessive, unwarranted cell death accounts for pathological cell loss, be it slowly degenerative as in Alzheimer's disease or dramatically acute as in stroke and myocardial infarction. Infectious pathogens manipulate cell death pathways to induce or inhibit the death of host cells at will and to subvert the immune recognition of ‘dangerous’ cell death. Finally, cancer is inexorably linked to a partial suppression of cell death programs in tumor cells, although therapy aims to (re)activate such lethal programs. Cell Death and Disease, a new open-access, online journal aims to provide center stage to fundamental, disease-oriented and translational research in cell death. [Opening paragraph

Cell death in disease: from 2010 onwards

The strong interest in cell death, and the shift in emphasis from basic mechanisms to translational aspects fostered the launch last year of the new sister journal of Cell Death and Differentiation, named Cell Death and Disease, to reflect its stronger focus towards clinical applications. Here, we review that first year of activity, which reflects an enthusiastic response by the scientific community. On the basis of this, we now launch two novel initiatives, the start of a new section dedicated to cancer metabolism and the opening of a new editorial office in Shanghai

Association of cytogenetic abnormalities in a neuroblastoma and fragile sites expression.

A 15 month old boy with a stage IV right suprarenal gland neuroblastoma showed a number of raised biochemical parameters, whilst catecholamines and skeletal survey were normal. Treatment with peptichemio failed to give a clinical response. Histological evidence of neuroblastoma infiltration in the bone marrow aspirate was absent. Immunofluorescence on sedimented cells was negative using antibody UJ223.8, PI153/3 and H11; only UJ308 and to a lesser extent UJ13A gave positive results. After 21 days, however, the same cells in culture showed highly differentiated dendritic processes. Thirty-seven percent metaphases from bone marrow aspirate showed the following karyotype 45XY, del (1) (p32), and two markers. Mar1 = der (2) t (2; 2) (2qter----2q14::2p24----2qter). Mar2 = der (15) t (15; 2) (15qter----15p11::2p11----2pter). Treatment with methotrexate reduced the aberrant mitoses rate to 2%. N-myc in situ hybridisation showed significant signal on both markers confirming the cytogenetic interpretation. Peripheral blood lymphocytes at 72 h showed a higher level of breaks per cell than control. After treatment with aphidicolin (APC) or methotrexate (MTX) for the last 24 h, to induce fragile sites, the incidence of breaks per cells was increased. Moreover 11.4% of APC-induced breaks were in 1p31-32 (mean of normal controls = 2.3%). The mother presented an increased sensitivity to the inducibility of fragile sites, while the father's lymphocytes showed values within the control range. The genetic changes produced by the abnormalities on chromosomes 1 and 2 might be related to tumour progression. Furthermore this is the first description of correlation between a high frequency of fragile site 1p31-32 induced by APC in the patient's lymphocytes and deletion of 1p32 in tumour cells. The interpretation of these findings and of other similar correlations needs further study

Utilities Substations in Smart District Heating Networks

Abstract In the last decades the concept of distributed generation – i.e. the installation of (electrical and/or thermal) energy production systems at the final users – was born and found gradually increasing diffusion. For what concerns the electrical production, the distributed generation systems are directly connected to the National Electricity Transmission Grid, allowing a bidirectional energy flux at the utilities and giving rise to the so-called smart grid. In this scenario and considering that, even thanks to the direction taken by European regulations, in the European territory there is already a large number of thermal power generation's distributed systems (e.g. solar thermal panels), in the near future the concept of smart grid could be extended to the heat sector, especially in relation to District Heating Networks (DHNs). As a consequence, with the aim of analyzing the penetration of this type of networks, several possible layouts for the exchange utilities' substation have been developed and will be presented in this study. Such layouts allow to optimize thermal exchange, as a function of network design temperatures (for both the supply and the return), of utilities' thermal power requirement and depending on the characteristics of the production system

A Revealed Preference Analysis of Asset Pricing Under Recursive Utility

This paper considers a representative agent model of asset prices based on a recursive utility specification. A constant elasticity of intertemporal substitution is assumed but the risk-preference component of utility is restricted only by qualitative, nonparametric regularity conditions. The principal contribution is to determine the exhaustive implications of this semiparametric recursive utility model for the one-step ahead joint probability distribution for consumption growth and asset returns.

Integration of μ-SOFC Generator and ZEBRA Batteries for Domestic Application and Comparison with other μ-CHP Technologies

Abstract This study investigates the possibility to integrate a Solide Oxide Fuel Cell (SOFC) prime mover and ZEBRA batteries, with the aim to fulfill a domestic user energy demand and to reduce the primary energy consumption, thereby, to enhance the total efficiency in a μ-CHP (Combined Heat and Power) application on a yearly basis. A realistic operational sequence of the SOFC-ZEBRA integration has been calculated using simple logic conditions. Both electric and thermal integration have been considered, in order to exploit the SOFC residual heat for the battery stand-by feeding. The key advantage of this system architecture is that the SOFC is operated without major load variations close to constant load, resulting in longer lifetime and thus reducing total costs of operation. Eventually, a comparison with alternative μ-CHP technologies has been carried out, highlighting the SOFC-ZEBRA potential

Correction to: HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Specificity of ε and non-ε isoforms of Arabidopsis 14-3-3 proteins towards the H+-ATPase and other targets

14-3-3 proteins are a family of ubiquitous dimeric proteins that modulate many cellular functions in all eukaryotes by interacting with target proteins. 14-3-3s exist as a number of isoforms that in Arabidopsis identifies two major groups named ε and non-ε. Although isoform specificity has been demonstrated in many systems, the molecular basis for the selection of specific sequence contexts has not been fully clarified. In this study we have investigated isoform specificity by measuring the ability of different Arabidopsis 14-3-3 isoforms to activate the H+-ATPase. We observed that GF14 isoforms of the non-εgroup were more effective than ε group isoforms in the interaction with the H+-ATPase and in the stimulation of its activity. Kinetic and thermodynamic parameters of the binding of GF14ε and GF14ω isoforms, representative of ε and non-ε groups respectively, with the H+-ATPase, have been determined by Surface Plasmon Resonance analysis demonstrating that the higher affinity of GF14ω is mainly due to slower dissociation. The role of the C-terminal region and of a Gly residue located in the loop 8 and conserved in all non-ε isoforms has also been studied by deletion and site-specific mutagenesis. The C-erminal domains, despite their high divergence, play an auto-inhibitory role in both isoforms and they, in addition to a specific residue located in the loop 8, contribute to isoform specificity. To investigate the generality of these findings, we have used the SPOT-synthesis technology to array a number of phosphopeptides matching known or predicted 14-3-3 binding sites present in a number of clients. The results of this approach confirmed isoform specificity in the recognition of several target peptides, suggesting that the isoform specificity may have an impact on the modulation of a variety of additional protein activities, as suggested by probing of a phosphopeptide array with members of the two 14-3-3 groups. © 2014 Pallucca et al