A Population Where Men Live As Long As Women: Villagrande Strisaili, Sardinia

Usually women live longer than men and female centenarians largely outnumber male centenarians. The findings of previous studies identifying a population with a femininity ratio close to 1.0 among centenarians in the mountainous region of Sardinia was the starting point of an in-depth investigation in order to compare mortality trajectories between men and women in that population. The exceptional survival of men compared to women emerges from the comparison with similar Italian data. Age exaggeration for men has been strictly excluded as a result of the age validation procedure. The discussion suggests that besides biological/genetic factors, the behavioral factors including life style, demographic behavior, family support, and community characteristics may play an important role. No single explanation is likely to account for such an exceptional situation and a fully integrated multidisciplinary approach is urgently needed

Binding to DPF-motif by the POB1 EH domain is responsible for POB1-Eps15 interaction

<p>Abstract</p> <p>Background</p> <p>Eps15 homology (EH) domains are protein interaction modules binding to peptides containing Asn-Pro-Phe (NPF) motifs and mediating critical events during endocytosis and signal transduction. The EH domain of POB1 associates with Eps15, a protein characterized by a striking string of DPF triplets, 15 in human and 13 in mouse Eps15, at the C-terminus and lacking the typical EH-binding NPF motif.</p> <p>Results</p> <p>By screening a multivalent nonapeptide phage display library we have demonstrated that the EH domain of POB1 has a different recognition specificity since it binds to both NPF and DPF motifs. The region of mouse Eps15 responsible for the interaction with the EH domain of POB1 maps within a 18 amino acid peptide (residues 623–640) that includes three DPF repeats. Finally, mutational analysis in the EH domain of POB1, revealed that several solvent exposed residues, while distal to the binding pocket, mediate specific recognition of binding partners through both hydrophobic and electrostatic contacts.</p> <p>Conclusion</p> <p>In the present study we have analysed the binding specificity of the POB1 EH domain. We show that it differs from other EH domains since it interacts with both NPF- and DPF-containing sequences. These unusual binding properties could be attributed to a different conformation of the binding pocket that allows to accommodate negative charges; moreover, we identified a cluster of solvent exposed Lys residues, which are only found in the EH domain of POB1, and influence binding to both NPF and DPF motifs. The characterization of structures of the DPF ligands described in this study and the POB1 EH domain will clearly determine the involvement of the positive patch and the rationalization of our findings.</p

MINT: the Molecular INTeraction database

The Molecular INTeraction database (MINT, ) aims at storing, in a structured format, information about molecular interactions (MIs) by extracting experimental details from work published in peer-reviewed journals. At present the MINT team focuses the curation work on physical interactions between proteins. Genetic or computationally inferred interactions are not included in the database. Over the past four years MINT has undergone extensive revision. The new version of MINT is based on a completely remodeled database structure, which offers more efficient data exploration and analysis, and is characterized by entries with a richer annotation. Over the past few years the number of curated physical interactions has soared to over 95 000. The whole dataset can be freely accessed online in both interactive and batch modes through web-based interfaces and an FTP server. MINT now includes, as an integrated addition, HomoMINT, a database of interactions between human proteins inferred from experiments with ortholog proteins in model organisms ()

Acute anterior myocardial infarction: Streptokinase prevents ventricular thrombosis independently of its effect on infarct size

Left ventricular thrombosis (LVT) is a frequent complication after acute anterior myocardial infarction (AMI). The purpose of this study is to evaluate whether streptokinase (SK) therapy prevents LVT, and whether this effect is due to the preservation of left ventricular function or to the fibrinolytic action of the drug. Sixty-five patients who underwent a left ventricular angiography within 2 months after a first AMI were studied. Twenty-eight patients (SK group) received SK 1,500,000 U i.v. administered over 60 min within 6 h from the onset of symptoms. A lower incidence of LVT was found in the SK group (p = 0.0003). We divided patients into two classes according to the value of akinetic-dyskinetic area (AD): the first group with a lower value of AD, the second group with a higher value of AD. In both groups, a reduced incidence of LVT was associated with SK therapy (p = 0.014, p = 0.015, respectively). Early infusion of SK during AMI seems to prevent the development of LVT, with an effect partly independent from its action on infarct size for small to large myocardial infarction

CUBAN, a Case Study of Selective Binding:Structural Details of the Discrimination between Ubiquitin and NEDD8

The newly identified CUBAN (Cullin binding domain associating with NEDD8) domain recognizes both ubiquitin and the ubiquitin-like NEDD8. Despite the high similarity between the two molecules, CUBAN shows a clear preference for NEDD8, free and conjugated to cullins. We previously characterized the domain structure, both alone and in complex with NEDD8. The results here reported are addressed to investigate the determinants that drive the selective binding of CUBAN towards NEDD8 and ubiquitin. The 15N HSQC NMR perturbation pattern of the labeled CUBAN domain, when combined with either NEDD8 or ubiquitin, shows a clear involvement of hydrophobic residues that characterize the early stages of these interactions. After a slow conformational selection step, hydrophobic and then neutral and polar interactions take place, which drive the correct orientation of the CUBAN domain, leading to differences in the recognition scheme of NEDD8 and ubiquitin. As a result, a cascade of induced fit steps seems to determine the structural preference shown for NEDD8 and therefore the basis of the selectivity of the CUBAN domain. Finally, molecular dynamics analysis was performed to determine by fluctuations the internal flexibility of the CUBAN/NEDD8 complex. We consider that our results, based on a structural investigation mainly focused on the early stages of the recognition, provide a fruitful opportunity to report the different behavior of the same protein with two highly similar binding partners

A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism

Some inherited or somatically-acquired gene variants are observed significantly more frequently in the genome of cancer cells. Although many of these cannot be confidently classified as driver mutations, they may contribute to shaping a cell environment that favours cancer onset and development. Understanding how these gene variants causally affect cancer phenotypes may help developing strategies for reverting the disease phenotype. Here we focus on variants of genes whose products have the potential to modulate metabolism to support uncontrolled cell growth. Over recent months our team of expert curators has undertaken an effort to annotate in the database SIGNOR 1) metabolic pathways that are deregulated in cancer and 2) interactions connecting oncogenes and tumour suppressors to metabolic enzymes. In addition, we refined a recently developed graph analysis tool that permits users to infer causal paths leading from any human gene to modulation of metabolic pathways. The tool grounds on a human signed and directed network that connects similar to 8400 biological entities such as proteins and protein complexes via causal relationships. The network, which is based on more than 30,000 published causal links, can be downloaded from the SIGNOR website. In addition, as SIGNOR stores information on drugs or other chemicals targeting the activity of many of the genes in the network, the identification of likely functional paths offers a rational framework for exploring new therapeutic strategies that revert the disease phenotype

DOMINO: a database of domain–peptide interactions

Many protein interactions are mediated by small protein modules binding to short linear peptides. DOMINO () is an open-access database comprising more than 3900 annotated experiments describing interactions mediated by protein-interaction domains. DOMINO can be searched with a versatile search tool and the interaction networks can be visualized with a convenient graphic display applet that explicitly identifies the domains/sites involved in the interactions

SIGNOR 3.0, the SIGnaling network open resource 3.0: 2022 update

The SIGnaling Network Open Resource (SIGNOR 3.0, ) is a public repository that captures causal information and represents it according to an 'activity-flow' model. SIGNOR provides freely-accessible static maps of causal interactions that can be tailored, pruned and refined to build dynamic and predictive models. Each signaling relationship is annotated with an effect (up/down-regulation) and with the mechanism (e.g. binding, phosphorylation, transcriptional activation, etc.) causing the regulation of the target entity. Since its latest release, SIGNOR has undergone a significant upgrade including: (i) a new website that offers an improved user experience and novel advanced search and graph tools; (ii) a significant content growth adding up to a total of approx. 33,000 manually-annotated causal relationships between more than 8900 biological entities; (iii) an increase in the number of manually annotated pathways, currently including pathways deregulated by SARS-CoV-2 infection or involved in neurodevelopment synaptic transmission and metabolism, among others; (iv) additional features such as new model to represent metabolic reactions and a new confidence score assigned to each interaction

Enhanced selective sonosensitizing efficacy of ultrasound-based anticancer treatment by targeted gold nanoparticles

partially_open9noThis study investigates cancer targeted gold nanoparticles as ultrasound sensitizers for the treatment of cancer.his study investigates cancer targeted gold nanoparticles as ultrasound sensitizers for the treatment of cancer. Methods: The ultrasound sensitizer activity of folate-PEG decorated gold nanoparticles (FA-PEG-GNP) has been studied on human cancer cell lines that overexpress folate receptors (KB and HCT-116) and another that does not (MCF7), at two ultrasound energy densities (8 × 10-6 J cm-2 and 8 × 10-5 J cm-2, for 5 min at 1.866 MHz). Results: FA-PEG-GNP selectively targeted KB and HCT-116 cells and a remarkable reduction in cancer cell growth was observed upon ultrasound exposure, along with significant reactive oxygen species generation and increase in necrotic cells. Conclusion: The combined use of targeting capacity and the ultrasound sensitizing effect, make FA-PEG-GNP promising candidates for the site-specific cancer treatment. © 2016 Future Medicine Ltd.partially_openBrazzale, Chiara; Canaparo, Roberto; Racca, Luisa; Foglietta, Federica; Durando, Giovanni; Fantozzi, Roberto; Caliceti, Paolo; Salmaso, Stefano; Serpe, LoredanaBrazzale, Chiara; Canaparo, Roberto; Racca, Luisa; Foglietta, Federica; Durando, Giovanni; Fantozzi, Roberto; Caliceti, Paolo; Salmaso, Stefano; Serpe, Loredan

iSPOT: A Web Tool for the Analysis and Recognition of Protein Domain Specificity

Methods that aim at predicting interaction partners are very likely to play an important role in the interpretation of genomic information. iSPOT (iSpecificity Prediction Of Target) is a web tool (accessible at http://cbm.bio.uniroma2.it/iSPOT) developed for the prediction of protein-protein interaction mediated by families of peptide recognition modules. iSPOT accesses a database of position specific residue-residue interaction frequencies for members of the SH3 and PDZ protein domain families. The software utilises this database to provide a score for any potential domain peptide interaction