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Ras–ERK Signaling in Behavior: Old Questions and New Perspectives
Stefania Fasano,Riccardo Brambilla
Frontiers in Behavioral Neuroscience , 2011, DOI: 10.3389/fnbeh.2011.00079
Abstract: The role of Ras–ERK signaling in behavioral plasticity is well established. Inhibition studies using the blood–brain barrier permeable drug SL327 have conclusively demonstrated that this neuronal cell signaling cascade is a crucial component of the synaptic machinery implicated in the formation of various forms of long-term memory, from spatial learning to fear and operant conditioning. However, abnormal Ras–ERK signaling has also been linked to a number of neuropsychiatric conditions, including mental retardation syndromes (“RASopathies”), drug addiction, and L-DOPA induced dyskinesia (LID). The work recently done on these brain disorders has pointed to previously underappreciated roles of Ras–ERK in specific subsets of neurons, like GABAergic interneurons of the hippocampus or the cortex, as well as in the medium spiny neurons of the striatum. Here we will highlight the open questions related to Ras–ERK signaling in these behavioral manifestations and propose crucial experiments for the future.
"Sequencing-grade" screening for BRCA1 variants by oligo-arrays
Alessandro Monaco, Filippo Menolascina, Yingdong Zhao, Stefania Tommasi, Marianna Sabatino, Ross Fasano, Angelo Paradiso, Francesco M Marincola, Ena Wang
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-64
Abstract: High throughput $1,000 whole genome sequencing may be rapidly approaching[1,2], meanwhile, a clinical need exists for the screening of genes whose polymorphisms determine disease predisposition, natural history or therapeutic outcome. Screening of the BRCA1 (OMIM 113705) cancer predisposition genes is an example of such a situation and it was well exemplified by [3,4] by Gerhardus et al [5], who systematically reviewed 3816 publications to estimate the accuracy of diagnostic methods used for the detection of BRCA1 and BRCA2 mutations. They concluded that many of the alternative screening methods were as time- and cost-intensive as direct sequencing, but did not provide the same definitive information. In addition, many of these methods could not be recommended for routine screening because of low sensitivity. Denaturing high-performance liquid chromatography was shown to outperform other methods but still required to be complemented by sequencing. Significantly, none of the techniques evaluated in the study, including direct sequencing, could detect large rearrangements, such as whole exon germline deletions/insertions.Germline mutations in BRCA1 account for a small but significant proportion of breast cancers. Genetic testing has been routinely applied to women from high risk families since 1994 [6,7]. BRCA1 spans an approximately 81 Kb region encompassing 24 exons (22 coding), and so any screening method must confront the challenge of monitoring this large genomic region over which the relevant variants are scattered[8] (Figure 1). Sequencing using semi high-throughput Sanger sequencing technology remains the gold standard for evaluating the BRCA1 gene despite its relatively high cost and time commitment[5].We used a previously described flourimetric SNP detection strategy based on the proportional hybridization of test and reference material with an oligonucleotide array platform [9] to design a BRCA1-specific array covering the entire coding region. This array w
Mice Lacking Ras-GRF1 Show Contextual Fear Conditioning but not Spatial Memory Impairments: Convergent Evidence from Two Independently Generated Mouse Mutant Lines
Raffaele d’Isa,Steven J. Clapcote,Vootele Voikar,David P. Wolfer,Karl Peter Giese,Riccardo Brambilla,Stefania Fasano
Frontiers in Behavioral Neuroscience , 2011, DOI: 10.3389/fnbeh.2011.00078
Abstract: Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning Brambilla’s mice with a third mouse line (GENA53) in which a non-sense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdala functions but possibly to some distinct hippocampal connections specific to contextual learning.
Novel Therapeutic/Integrative Approaches for Celiac Disease and Dermatitis Herpetiformis
Alessio Fasano
Clinical and Developmental Immunology , 2012, DOI: 10.1155/2012/959061
Abstract: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet.
Novel Therapeutic/Integrative Approaches for Celiac Disease and Dermatitis Herpetiformis
Alessio Fasano
Journal of Immunology Research , 2012, DOI: 10.1155/2012/959061
Abstract: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet. 1. Introduction Celiac disease (CD) is an immune-mediated chronic enteropathy with a wide range of presenting manifestations of variable severity. It is triggered by the ingestion of gliadin fraction of wheat gluten and similar alcohol-soluble proteins (prolamins) of barley and rye in genetically susceptible subjects with subsequent immune reaction leading to small bowel inflammation and normalization of the villous architecture in response to a gluten-free diet (GFD). CD not only affects the gut, but it is a systemic disease that may cause injury to the skin (dermatitis herpetiformis, the topic of this special issue), liver, joints, brain, heart, and other organs. It is a complex genetic disorder, and human leukocyte antigen (HLA) status appears to be the strongest genetic determinant of risk for celiac autoimmunity. There is a propensity for individuals with CD to carry specific HLA class II alleles, which has been estimated to account for up to 40% of the genetic load [1]. In affected individuals, 95% have either DQ2 (HLA-DQA1*05-DQB1*02) or DQ8 (HLADQA1*03-DQB1*0302), in comparison with the general population in which 39.5% have either DQ2 or DQ8 [2]. It is the interplay between genes (both HLA and non-HLA associated) and environment (i.e., gluten) that leads to the intestinal damage typical of the disease [3]. Under physiological circumstances, this interplay is prevented by competent intercellular tight junctions (TJs), structures that limit the passage of macromolecules (including gluten) across the intestinal epithelial barrier. Recent evidence suggests that the gluten-induced upregulation of zonulin, a recently described intestinal peptide involved in TJ regulation, is responsible, at least in part, for the aberrant increase in gut permeability characteristic of the early phase of CD [4] and the subsequent abnormal passage of gluten into the lamina propria. Here, the protein is deamidated by tissue transglutaminase and is then recognized by HLA-DQ2/DQ8
A Framework of Conjugate Direction Methods for Symmetric Linear Systems in Optimization
Giovanni Fasano
Mathematics , 2014, DOI: 10.1007/s10957-014-0600-0
Abstract: In this paper we introduce a parameter dependent class of Krylov-based methods, namely CD, for the solution of symmetric linear systems. We give evidence that in our proposal we generate sequences of conjugate directions, extending some properties of the standard Conjugate Gradient (CG) method, in order to preserve the conjugacy. For specific values of the parameters in our framework we obtain schemes equivalent to both the CG and the scaled-CG. We also prove the finite convergence of the algorithms in CD, and we provide some error analysis. Finally, preconditioning is introduced for CD, and we show that standard error bounds for the preconditioned CG also hold for the preconditioned CD.
Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target
Stefania Crispi, Raffaele A. Calogero, Mario Santini, Pasquale Mellone, Bruno Vincenzi, Gennaro Citro, Giovanni Vicidomini, Silvia Fasano, Rosaria Meccariello, Gilda Cobellis, Simona Menegozzo, Riccardo Pierantoni, Francesco Facciolo, Alfonso Baldi, Massimo Menegozzo
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007016
Abstract: Background The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets. Methodology We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002). Conclusions Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma.
Inspiratory muscle training in difficult to wean patients: work it harder, make it better, do it faster, makes us stronger
Stefano Nava, Luca Fasano
Critical Care , 2011, DOI: 10.1186/cc10125
Abstract: Martin and colleagues [1] recently published in Critical Care an article entitled 'Inspiratory muscle strength training improves the outcome in failure to wean patients: a randomized trial'. Failure-to-wean patients comprise a subset of patients receiving mechanical ventilation who have weaning difficulties such that the duration of ventilation may be abnormally prolonged (>15 days). In the US, about 300,000 patients every year receive prolonged life support in the ICU, and this number is likely to double within a decade, with associated costs of more than US$ 50 billion [2]. Weaning from prolonged mechanical ventilation is a complex, time-consuming process that does not involve just selecting the best ventilation method for a particular patient.Due to the nature of critical illness and the modalities used to manage it, prolonged bed rest, with well-known adverse physiological effects, seems to be the rule in the ICU. Rehabilitation has the potential to restore lost function, but with few exceptions is traditionally not started until after ICU discharge since critically ill patients are often viewed as 'too sick' to tolerate a retraining program. Several reports have shown that the diaphragm and the other respiratory muscles are weak in these patients; this occurs for many reasons, including the effects of controlled mechanical ventilation (that is, disuse atrophy), electrolyte depletion, use of drugs affecting inotropic properties (that is, steroids and myorelaxants), and the presence of co-morbidities (for example, chronic obstructive pulmonary disease (COPD), congestive heart failure and sepsis) [3]. Despite the fact that respiratory muscle fatigue has not been demonstrated so far, even in patients sufficiently ill to require mechanical ventilation [4], the loss of force/generating capacity (that is, the reduction in maximal inspiratory pressure) seems to be a major determinant of weaning failure, although it is not a specific predictor of inability to sustain to
Otter (Lutra lutra) presence in Lattari mountains (Campania Region, Southern Italy)
Roberto Fasano,Guglielmo Maglio
Hystrix : the Italian Journal of Mammalogy , 1995, DOI: 10.4404/hystrix-7.1-2-4076
Abstract: A new area of presence of the otter (Lutra lutra) was found in Campania region (Southern Italy). It included the "Valle delle Ferriere" and "Vècite" canyons close to Amalfi town (Salerno province). A total of 24 sprainting sites was recorded. Riassunto Presenza della lontra (Lutra lutra) nei monti Lattari (Campania) - Si descrive un'area di presenza della lontra (Lutra lutra) in Campania mai segnalata prima, comprendente la "Valle delle Ferriere" attraversata dal torrente Ceraso e la valle denominata "Vècite" (Amalfi, Provincia di Salerno). In totale sono stati trovati 24 siti di marcamento.
Salvatore, Ricardo D.: Wandering Paysanos. State order and subaltern experience in Buenos Aires during the Rosas era, Durham y Londres, Duke University Press, 2003, 523 págs
Juan Pablo Fasano
Bolet?-n del Instituto de Historia Argentina y Americana Dr. Emilio Ravignani , 2005,
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