Pa28γ: New insights on an ancient proteasome activator

PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog

DNA Sequence Determinants Controlling Affinity, Stability and Shape of DNA Complexes Bound by the Nucleoid Protein Fis.

The abundant Fis nucleoid protein selectively binds poorly related DNA sequences with high affinities to regulate diverse DNA reactions. Fis binds DNA primarily through DNA backbone contacts and selects target sites by reading conformational properties of DNA sequences, most prominently intrinsic minor groove widths. High-affinity binding requires Fis-stabilized DNA conformational changes that vary depending on DNA sequence. In order to better understand the molecular basis for high affinity site recognition, we analyzed the effects of DNA sequence within and flanking the core Fis binding site on binding affinity and DNA structure. X-ray crystal structures of Fis-DNA complexes containing variable sequences in the noncontacted center of the binding site or variations within the major groove interfaces show that the DNA can adapt to the Fis dimer surface asymmetrically. We show that the presence and position of pyrimidine-purine base steps within the major groove interfaces affect both local DNA bending and minor groove compression to modulate affinities and lifetimes of Fis-DNA complexes. Sequences flanking the core binding site also modulate complex affinities, lifetimes, and the degree of local and global Fis-induced DNA bending. In particular, a G immediately upstream of the 15 bp core sequence inhibits binding and bending, and A-tracts within the flanking base pairs increase both complex lifetimes and global DNA curvatures. Taken together, our observations support a revised DNA motif specifying high-affinity Fis binding and highlight the range of conformations that Fis-bound DNA can adopt. The affinities and DNA conformations of individual Fis-DNA complexes are likely to be tailored to their context-specific biological functions

Marketing Innovation And Firm Performance Research Model, Research Hypotheses, And Managerial Implications

This research conceptualizes and develops a scale for the marketing innovation construct for the purpose of furthering research in marketing strategy. This marketing innovation construct and its associated strategic activities are clearly distinguished from product and process innovation, better enabling researchers and practitioners to identify new and updated paths from innovation to firm performance. Marketing innovation is defined as the degree of novelty in the implementation of three core business processes: (1) product development management, (2) supply chain management, and (3) customer relationship management, as identified in the Srivastava, Shervani & Fahey (1999) framework. Results from qualitative interviews indicate marketing innovation is developed and fostered by marketing insight and marketing imagination, and these relationships appear to be moderated by the market orientation of the firm. As conceptualized, marketing innovation is suggested to enhance firm performance via (1) the marketing-product space, (2) the marketing-process space, and (3) the marketing-relationship space. This enhancement process, however, is conjectured to be moderated by the degree of radical product innovation the firm is currently undergoing as well as the degree of process innovation the firm practices. A complete discussion of marketing innovation‘s antecedents, manifestations, and consequences is presented. A comprehensive research model, method, and results from an empirical study of qualified business executives, testing key relationships in the marketing innovation framework, are discussed. Empirical study results confirm marketing innovation‘s powerful ability to predict firm performance, even in the presence of a multiple of control variables. Further, these quantitative findings lend statistically and practically significant support for (1) the antecedent roles of marketing insight and marketing imagination, (2) the negative (as predicted) moderating role of product innovation radicalness, and (3) several iv specific inter-workings among the marketing-innovation spaces that that offer substantial research contributions to the marketing strategy literature for researchers and managers

A previously unreported numph cocoon of Alphasida puncticollis on the islet of Lampione (Sicilian Channel) (Coleoptera Tenebrionidae).

In this paper we present an unusual case of cocoons produced by larvae of Tenebrionid Alphasida (Glabrasida) puncticollis (Solier, 1836), which has been observed on the islet of Lampione (Sicilian Channel). Pupal cocoons have never been recorded for species belonging to this genus, and their occurrence results rarely documented within the family Tenebrionidae. Some ecological implications are discussed

Control of DNA minor groove width and Fis protein binding by the purine 2-amino group.

The width of the DNA minor groove varies with sequence and can be a major determinant of DNA shape recognition by proteins. For example, the minor groove within the center of the Fis-DNA complex narrows to about half the mean minor groove width of canonical B-form DNA to fit onto the protein surface. G/C base pairs within this segment, which is not contacted by the Fis protein, reduce binding affinities up to 2000-fold over A/T-rich sequences. We show here through multiple X-ray structures and binding properties of Fis-DNA complexes containing base analogs that the 2-amino group on guanine is the primary molecular determinant controlling minor groove widths. Molecular dynamics simulations of free-DNA targets with canonical and modified bases further demonstrate that sequence-dependent narrowing of minor groove widths is modulated almost entirely by the presence of purine 2-amino groups. We also provide evidence that protein-mediated phosphate neutralization facilitates minor groove compression and is particularly important for binding to non-optimally shaped DNA duplexes

Uno studio inedito di Enrico Pirajno di Mandralisca sull’entomofauna delle isole Eolie.

Tra i manoscritti inediti di Enrico Pirajno, conservati presso l’Archivio Storico della FondazioneMandralisca, esiste un elenco dei “Coleotteri delle isole Eolie”, che rappresenta il primo tentativo pionieristico di un catalogo dell’entomofauna dell’arcipelago. Nel presente contributo ne viene illustrato il contenuto e brevemente discussi gli aspetti relativi al suo valore storico, documentale e scientifico

Direct-acting antivirals and visceral leishmaniasis: A case report

Background: Visceral leishmaniasis is a vector-borne parasitic disease caused by protozoa belonging to the genus Leishmania. The clinical presentation of visceral leishmaniasis strictly depends on the host immunocompetency, whereas depressive conditions of the immune system impair the capability to resolve the infection and allow reactivation from sites of latency of the parasite. Case presentation: We describe a case of visceral leishmaniasis (VL) that occurred in a patient with chronic hepatitis C treated with direct-acting antiviral drugs (DAA). The hypothesized mechanism is the alteration of protective inflammation mechanisms secondary to DAA therapy. Downregulation of type II and III IFNs, their receptors, which accompany HCV clearance achieved during treatment with sofosbuvir and ribavirin might have a negative impact on a risk for reactivation of a previous Leishmania infection. We know indeed that IFN-\u3b3 is important to enhance killing mechanisms in macrophages, which are the primary target cells of Leishmania. Conclusion: Since VL is endemic in Sicily as well as in other countries of the Mediterranean basin, physicians should be aware of the possible unmasking of cryptic Leishmania infection by DAAs

The Role of Emotional Intelligence in Health Care Professionals Burnout

The purpose of this study is to explore the relationship between Emotional Intelligence (EI) and burnout in health care professionals. More specifically, this survey has the purpose of demonstrating the role of EI as a protective factor against the risk of burnout. Health professionals (doctors, nurses, and other caregivers) composed the sample. Data, collected during professional training, provided 148 employees. Major results of this survey underline the relationship between EI and burnout. As we expected, there is a negative and significant correlation between burnout and Emotional Intelligence. Moreover, burnout varies depending on length of service: burnout increases between 5 and 10 years of experience and decreases over 10 years. Indeed, burnout is differently expressed amongst healthcare professionals: more specifically, Psycho-physical exhaustion, Detriment of the relationships and Burnout (total score) has an impact on physician (doctors) more than other investigated health professionals. These findings seem to suggest the opportunity to improve Emotional Intelligence abilities through specific training programs, useful to promote the ability to cope with stress and to enrich the relationships in the workplace

Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subsets were assessed by flow cytometry while NETosis and phagocytosis were evaluated by confocal microscopy. Expression analysis was performed by using the semi-quantitative RT-PCR array technology. Elevated numbers of total neutrophils and a high neutrophil/lymphocyte ratio distinguished patients with active TB from all the other groups. PBMCs of patients with active TB disease contained elevated percentages of LDNs compared with those of H.D., with an increased expression of CD66b, CD33, CD15, and CD16 compared to NDNs. Transcriptomic analysis of LDNs and NDNs purified from the peripheral blood of TB patients identified 12 genes differentially expressed: CCL5, CCR5, CD4, IL10, LYZ, and STAT4 were upregulated, while CXCL8, IFNAR1, NFKB1A, STAT1, TICAM1, and TNF were downregulated in LDNs, as compared to NDNs. Differently than NDNs, LDNs failed to phagocyte live Mycobacterium tuberculosis (M. tuberculosis) bacilli, to make oxidative burst and NETosis, but caused significant suppression of antigen-specific and polyclonal T cell proliferation which was partially mediated by IL-10. These insights add a little dowel of knowledge in understanding the pathogenesis of human TB