Identification and characterization of prokineticin receptor 2 splicing variant and its modulation in an animal model of alzheimer's disease

Prokineticin 2 is a peptide that is widely distributed in the nervous system and influences a variety of brain functions, such as pain, food intake and circadian rhythms. We previously demonstrated that, in the animal model of Alzheimer’s disease, induced by the intracerebroventricular administration of Aβ1-42, there is a modulation of the prokineticin system in rat hippocampus. Prokineticin 2 is a able to mediate its signaling through two different G-protein coupled receptors, designated PKR1 and PKR2, belonging to the neuropeptide Y receptor class. These two receptors have different tissue distributions: PKR1 is expressed in diverse peripheral organs with relatively high levels in the small intestines and lung, whereas PKR2 is predominantly expressed in the central nervous system. The PKRs activate multiple intracellular signal-transduction pathways: they are Gαq-coupled receptors and promoting intracellular calcium mobilization but they also couple to Gαi (especially PKR2) and Gαs proteins. In rat hippocampus we identified a mRNA encoding for a PKR2 splice variant, that lacking the second exon, gives rise to a four-transmembrane protein denominated TM 4-7. Expression of this splicing variant in yeast, allowed us to demonstrate that TM 4-7 dimerizes with PKR2 long form and that this heterodimer binds to G protein subtypes with different specificity respect to PKR2 wild-type. Moreover we evidenced that, following Aβ1-42 intracerebroventricular injection in rat, the PKR2 hippocampal levels slightly increased respect to control animals whereas there was a strong up-regulation of the PKR2 splicing variant, TM 4-7. We showed that the increased levels of TM 4-7 determined a modulation of PKR2 signal transduction hindering STAT3 activation

Immunogenicity and tolerability of an MF59-adjuvanted, egg-derived, A/H1N1 pandemic influenza vaccine in children 6-35 months of age

Background: Vaccines against pandemic A/H1N1 influenza should provide protective immunity in children, because they are at greater risk of disease than adults. This study was conducted to identify the optimal dose of an MF59 (R)-adjuvanted, egg-derived, A/H1N1 influenza vaccine for young children. Methods: Children 6-11 months (N = 144) and 12-35 months (N = 186) of age received vaccine formulations containing either 3.75 mu g antigen with half the standard dose of MF59 or 7.5 mu g antigen with a standard dose of MF59, or a nonadjuvanted formulation containing 15 mu g antigen (children 12-35 months only). Participants were given 2 primary vaccine doses 3 weeks apart, followed by 1 booster dose of MF59-adjuvanted seasonal influenza vaccine 1 year later. Immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. Results: All vaccine formulations were highly immunogenic and met all 3 European licensure criteria after 2 doses. MF59-adjuvanted vaccines met all licensure criteria after 1 dose in both age cohorts, while nonadjuvanted vaccine did not meet all criteria after 1 dose in children 12-35 months. A single booster dose was highly immunogenic, and stable antibody persistence was observed in response to all vaccines. All vaccines were well tolerated. Conclusions: In this study, a single dose of 3.75 mu g antigen with half the standard dose of MF59 was shown to be optimal, providing adequate levels of immediate and long-term antibodies in pediatric subjects 6-35 months of age. These data demonstrated that MF59 adjuvant allowed for reduced antigen content and promoted significant long-term antibody persistence in children, with a satisfactory safety profile

Some aspects of Relativistic Astrometry from within the Solar System

In this article we outline the structure of a general relativistic astrometric model which has been developed to deduce the position and proper motion of stars from 1-microarcsecond optical observations made by an astrometric satellite orbiting around the Sun. The basic assumption of our model is that the Solar System is the only source of gravity, hence we show how we modeled the satellite observations in a many-body perturbative approach limiting ourselves to the order of accuracy of $(v/c)^2$. The microarcsecond observing scenario outlined is that for the GAIA astrometric mission.Comment: 11 pages, 2 figures, accepted by Cel. Me

Neurotrophic Features of Human Adipose Tissue-Derived Stromal Cells: In Vitro and In Vivo Studies

Due to its abundance, easy retrieval, and plasticity characteristics, adipose-tissue-derived stromal cells (ATSCs) present unquestionable advantages over other adult-tissue-derived stem cells. Based on the in silico analysis of our previous data reporting the ATSC-specific expression profiles, the present study attempted to clarify and validate at the functional level the expression of the neurospecific genes expressed by ATSC both in vitro and in vivo. This allowed evidencing that ATSCs express neuro-specific trophins, metabolic genes, and neuroprotective molecules. They were in fact able to induce neurite outgrowth in vitro, along with tissue-specific commitment along the neural lineage and the expression of the TRKA neurotrophin receptor in vivo. Our observation adds useful information to recent evidence proposing these cells as a suitable tool for cell-based applications in neuroregenerative medicine

Editorial: Crosstalk between the Osteogenic and Neurogenic Stem Cell Niches: How Far are They from Each Other?

Despite the intense research on adult neural stem cell biology suggested possible translational outcomes in regenerative medicine for neurodegenerative diseases, neuroregeneration is unlikely to occur in adult brain, due to intrinsic features that characterize the neural stem cell niche. Mesenchymal stem cells (MSCs), osteogenic stem cells residing in the bone marrow stroma (also named bone marrow stromal cells), have been long considered highly plastic multipotent precursors, able to commit toward diversified lineages, including non-mesodermal ones. Their in vitro plasticity and ease of processing prompted their wide, sometimes untimely, exploitation in diversified regenerative medicine applications (Park et al., 2012; Bianco et al., 2013). They have been tested also for their putative, yet widely debated, neuroregenerative potential. This controversial issue stimulated this Research Topic, which aims to delve into relevant scientific milestones addressing the differences, possible interconnections, and overlaps between the osteogenic and the neurogenic niches' biology. The debated neuronal transdifferentiation potential of MSCs recently led to their inappropriate exploitation for the treatment of neurodegenerative disorders. The regulatory and ethical issues regarding this topic have been discussed in the Opinion paper by Solarino et al., delving into a recent Italian case of medical malpractice, which triggered significant international dispute (Abbott, 2013; Blasimme and Rial-Sebbag, 2013). Indeed, a better clarification of the specific features displayed by the osteogenic and the neurogenic stem cell niches is needed, as discussed by Lattanzi et al. This mini-review provides a pairwise comparison of the two niches within their in vivo environments, highlighting functionally relevant similarities and differences that should be considered to achieve a more rational clinical translation. The contribution by Salgado et al. provides an exhaustive description of osteogenic and neural stem cells' features, focusing on their possible interaction within the brain environment. In particular, the MSCs' secretome is known to exert autocrine and paracrine effects that may be relevant for potential therapeutic exploitations, also in the central nervous system (Ribeiro et al., 2011; Drago et al., 2013; Kim et al., 2013; Sart et al., 2014; Wright et al., 2014). The role of neural crest stem cells (NCSCs) in regulating the bone marrow niche is provided in the review by Coste et al. NCSCs are capable of epithelial-to-mesenchymal transition, and ultimately give rise to both neural precursors and nestin-positive MSCs, actively involved in the homeostatic regulation of the hematopoietic stem cell niche (Achilleos and Trainor, 2012; Mayor and Theveneau, 2013). A significant overlap between the two niches relies on the molecular (Wnt, NOTCH, FGF, TGF-BMP, SHH signaling pathways) and secretome (BDNF, NGF, VEGF, PDGF) profiles, along with the intimate relationship with vessels, being a common structural feature observed in adult stem cell niches. Diverse phylogenetically old signaling pathways, including nucleotides and neuropeptides, are shared between the osteogenic and the neurogenic niches, exerting trophic, and immunomodulatory functions. Cavaliere et al. exhaustively discussed the often opposing roles played by purinergic ligands. These establish a common paracrine pathway that modulates MSCs' and NSCs' activity, in both physiological and pathological conditions. They appear to be involved in the crosstalk between the two niches, by modulating the immune response, which triggers stem cell recruitment after stressful insults (Cavaliere et al.). Among neuropeptides, the direct effects of neuropeptide Y (NPY), mediator for signaling in both neurogenic and osteogenic niches, has been reviewed by Geloso et al., with special attention to its effects on neurogenic niche. Data indicating a direct pro-neurogenic effect of NPY on NSCs, as well as the concomitant modulatory action on astrocytes, microglia, and endothelium activities within the niche have been discussed. Interestingly, a possible crosstalk between released nucleotides and NPY related pathways emerges (Jia and Hegg, 2012), suggesting that they could also represent a point of intersection between shared ancient molecular pathways. Neurotransmitters released by the sympathetic nervous system, interestingly including NPY, as recently reviewed by Park et al. (2015), are known to be also involved in the regulation of hematopoietic stem cell (HSC) functions, mainly acting on endothelial cells and nestin-positive MSCs, which retain HSCs. In this regard, the relevance of catecholaminergic modulation of hematopoiesis has been extensively reviewed by Cosentino and coworkers (Cosentino et al.), highlighting their established role in the complex network of neural and neuroendocrine agents that regulate stem cell biology (Cosentino et al.). Within the wide range of external stimuli acting on the epigenetic control of adult tissue stem cell niches, the effects of extremely-low frequency electromagnetic field (ELFEF) stimulation is emerging as a tool to modulate neurogenic and osteogenic processes, as discussed by Leone et al. They highlighted the possible shared pathways induced by ELFEFS on both niches, including Wnt/beta-catenin signaling and the activation of p300 or other histone acetyltransferases by Runx2 (Leone et al.). The interdependence of brain and skull during development seems to rely also on the role of interposed meninges (Richtsmeier and Flaherty, 2013). Within this intriguing topic, Bifari et al. provided findings showing the distribution of neural precursor markers in rat meninges during development up to adulthood, related to the newly identified niche function of meninges (Decimo et al., 2011). Finally, an interesting evolutionary perspective on the relation between osteogenesis and neurogenesis is provided in the opinion paper by Boeckx and Benítez-Burraco, who approached this topic from a different “biolinguistic” standpoint. The Authors postulated that critical genes active in the osteogenic niche (including homeogenes, e.g. DLXs, morphogens, e.g. BMPs, and the master regulatory RUNX2 gene), hence giving rise to skull globularity in anatomically modern humans, also have important consequences in brain development and plasticity, ultimately leading to our distinctive mode of cognition (Boeckx and Benítez-Burraco). Taken together, the papers included in this research topic seem to suggest an emerging cross-domain scenario in which significant molecular signaling and biological features are shared between osteogenic and neurogenic stem cells niches. The two niches appear to be interconnected in evolution, during development, and further beyond. Nonetheless, relevant differences in the relative stem cell niche dynamics should not be neglected, in order to appropriately design potential cross-lineage tissue regenerative strategies

Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms

Effects of antihypertensive treatment on endothelial function in postmenopausal hypertensive women. A significant role for aldosterone inhibition

Introduction: Endothelial dysfunction is a well-demonstrated independent predictor of cardiovascular events in hypertensive postmenopausal women. Accordingly, it is plausible that improving endothelial function could represent an adjunctive target for antihypertensive treatment. The aim of our study was to evaluate the effect of pharmacologic treatment on endothelial function in the specific population of hypertensive postmenopausal women.Methods: A total of 320 consecutive hypertensive postmenopausal women underwent a high-resolution ultrasound study of the brachial artery at baseline and after six months, while 'optimal' control of blood pressure (maintenance of blood pressure values below 140/90 mmHg at all follow-up visits) was achieved using antihypertensive therapy. Endothelial function was measured as flow-mediated dilation, using ultrasound method.Results: After six months of treatment, flow-mediated dilatation (FMD) had significantly improved in the majority of patients (n = 257 [80.3% of the entire population]; FMD = 8.1 ± 1.0% at baseline vs. 10.6 ± 1.5% after follow-up; p < 0.001), but it had not changed or worsened in others (n = 63 [19.7%]; FMD = 8.2 ± 1.2% at baseline vs. 7.6 ± 1.0% after six months; p = ns). Improvement of endothelial function, at multivariate analysis, resulted independently associated with the use of aldosterone inhibitors (odds ratio = 2.15; 95% confidence interval: 1.55-2.75; p = 0.001).Conclusions: This study demonstrates that a significant improvement in endothelial function may be obtained after six months of an optimal antihypertensive therapy. Among all hypertensive postmenopausal women that achieved an optimal control of blood pressure during follow-up, the use of drugs that inhibit aldosterone receptors was associated with an improvement of endothelial function, beyond the 'optimal' blood pressure control. © SAGE Publications 2011

Emerging perspectives on laminopathies

Giovanna Lattanzi,1,2 Sara Benedetti,3 Maria Rosaria D'Apice,4 Lorenzo Maggi,5 Nicola Carboni,6 Emanuela Scarano,7 Luisa Politano8 1National Research Council of Italy, Institute for Molecular Genetics (CNR-IGM), Unit of Bologna, 2Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, 3Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, 4Fondazione Policlinico Tor Vergata, Rome, 5Neuromuscular Diseases and Neuroimmunology Unit, IRCCS Neurological Institute C Besta, Milan, 6Division of Neurology, Hospital San Francesco, Nuoro, 7Pediatric Endocrinology and Rare Diseases Unit, Department of Pediatrics, S Orsola-Malpighi University Hospital, University of Bologna, Bologna, 8Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy Abstract: Laminopathies are a group of inherited disorders caused by mutations in the lamin A/C gene, and can affect diverse organs or tissues, or can be systemic, causing premature aging. In the present review, we report on the composition and structure of the nuclear lamina and the role of lamins in nuclear mechanics and their involvement in human diseases, and provide some examples of laminopathies and current therapeutic approaches. Keywords: lamin A/C, emerin, laminopathies, Emery–Dreifuss muscular dystrophy, Hutchinson–Gilford progeri