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Showing papers by "University of Milan published in 2010"


Journal ArticleDOI
TL;DR: A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention and provide a paradigm for macrophage plasticity and function.
Abstract: Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.

3,133 citations


Journal ArticleDOI
TL;DR: Genetic loci associated with body mass index map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor, which may provide new insights into human body weight regulation.
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

2,632 citations


Journal ArticleDOI
TL;DR: The POWHEG BOX is illustrated to provide an illustration of the needed theoretical ingredients, a view of how the code is organized and a description of what a user should provide in order to use it.
Abstract: In this work we illustrate the POWHEG BOX, a general computer code framework for implementing NLO calculations in shower Monte Carlo programs according to the POWHEG method. Aim of this work is to provide an illustration of the needed theoretical ingredients, a view of how the code is organized and a description of what a user should provide in order to use it.

2,560 citations


Journal ArticleDOI
Hana Lango Allen1, Karol Estrada2, Guillaume Lettre3, Sonja I. Berndt4  +341 moreInstitutions (90)
14 Oct 2010-Nature
TL;DR: It is shown that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, and indicates that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

1,768 citations


Journal ArticleDOI
Riccardo Velasco, Andrey Zharkikh1, Jason P. Affourtit2, Amit Dhingra3, Alessandro Cestaro, Ananth Kalyanaraman3, Paolo Fontana, Satish Bhatnagar1, Michela Troggio, Dmitry Pruss1, Silvio Salvi4, Massimo Pindo, Paolo Baldi, Sara Castelletti, Marina Cavaiuolo, G. Coppola, Fabrizio Costa, V. Cova, Antonio Dal Ri, Vadim V. Goremykin, M. Komjanc, Sara Longhi, P. Magnago, Giulia Malacarne, Mickael Malnoy, Diego Micheletti, Marco Moretto, Michele Perazzolli, Azeddine Si-Ammour, Silvia Vezzulli, E. Zini, Glenn Eldredge1, Lisa M. Fitzgerald1, N. Gutin1, Jerry S. Lanchbury1, Teresita Macalma1, J.T. Mitchell1, Julia Reid1, Bryan Wardell1, Chinnappa D. Kodira2, Zhoutao Chen2, Brian Desany2, Faheem Niazi2, Melinda Palmer2, Tyson Koepke3, Derick Jiwan3, Scott Schaeffer3, Vandhana Krishnan3, Changjun Wu3, Vu T. Chu5, Stephen T. King5, Jessica Vick5, Quanzhou Tao, Amy Mraz, Aimee Stormo, Keith E. Stormo, Robert Bogden, Davide Ederle6, Alessandra Stella6, Alberto Vecchietti6, Martin M. Kater7, Simona Masiero7, Pauline Lasserre, Yves Lespinasse, Andrew C. Allan8, Vincent G. M. Bus8, David Chagné8, Ross N. Crowhurst8, Andrew P. Gleave8, Enrico Lavezzo9, Jeffrey A. Fawcett10, Jeffrey A. Fawcett11, Sebastian Proost11, Sebastian Proost10, Pierre Rouzé10, Pierre Rouzé11, Lieven Sterck10, Lieven Sterck11, Stefano Toppo9, Barbara Lazzari6, Roger P. Hellens8, Charles-Eric Durel, Alexander Gutin1, Roger E. Bumgarner5, Susan E. Gardiner8, Mark H. Skolnick1, Michael Egholm2, Yves Van de Peer10, Yves Van de Peer11, Francesco Salamini6, Roberto Viola 
TL;DR: It is shown that a relatively recent (>50 million years ago) genome-wide duplication has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae, which partly support the monophyly of the ancestral paleohexaploidy of eudicots.
Abstract: We report a high-quality draft genome sequence of the domesticated apple (Malus × domestica). We show that a relatively recent (>50 million years ago) genome-wide duplication (GWD) has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae. Traces of older GWDs partly support the monophyly of the ancestral paleohexaploidy of eudicots. Phylogenetic reconstruction of Pyreae and the genus Malus, relative to major Rosaceae taxa, identified the progenitor of the cultivated apple as M. sieversii. Expansion of gene families reported to be involved in fruit development may explain formation of the pome, a Pyreae-specific false fruit that develops by proliferation of the basal part of the sepals, the receptacle. In apple, a subclade of MADS-box genes, normally involved in flower and fruit development, is expanded to include 15 members, as are other gene families involved in Rosaceae-specific metabolism, such as transport and assimilation of sorbitol.

1,718 citations


Journal ArticleDOI
TL;DR: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated LP(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD.
Abstract: AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.

1,446 citations


Journal ArticleDOI
TL;DR: It is concluded that, although there are several mechanisms through which one can understand the behaviour of other individuals, the parieto-frontal mechanism is the only one that allows an individual to understand the action of others 'from the inside' and gives the observer a first-person grasp of the motor goals and intentions of other Individuals.
Abstract: The parieto-frontal cortical circuit that is active during action observation is the circuit with mirror properties that has been most extensively studied. Yet, there remains controversy on its role in social cognition and its contribution to understanding the actions and intentions of other individuals. Recent studies in monkeys and humans have shed light on what the parieto-frontal cortical circuit encodes and its possible functional relevance for cognition. We conclude that, although there are several mechanisms through which one can understand the behaviour of other individuals, the parieto-frontal mechanism is the only one that allows an individual to understand the action of others 'from the inside' and gives the observer a first-person grasp of the motor goals and intentions of other individuals.

1,423 citations


Journal ArticleDOI
TL;DR: This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants.
Abstract: The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

1,267 citations


Journal ArticleDOI
TL;DR: This meta-analysis provides comprehensive evidence-based assessment of risk factors for falls in older people, confirming their multifactorial etiology and finding some nonspecific indicators of high baseline risk were also strong predictors of the risk of falling.
Abstract: Background:Falls are the main cause of accidental death in persons aged 65 years or older.Methods:Using MEDLINE and previous reviews, we searched for prospective studies investigating risk factors for falls among community-dwelling older people. For risk factors investigated by at least 5 studies in

1,192 citations



Journal ArticleDOI
Helena Furberg1, Yunjung Kim1, Jennifer Dackor1, Eric Boerwinkle2, Nora Franceschini1, Diego Ardissino, Luisa Bernardinelli3, Luisa Bernardinelli4, Pier Mannuccio Mannucci5, Francesco Mauri, Piera Angelica Merlini, Devin Absher, Themistocles L. Assimes6, Stephen P. Fortmann6, Carlos Iribarren7, Joshua W. Knowles6, Thomas Quertermous6, Luigi Ferrucci8, Toshiko Tanaka8, Joshua C. Bis9, Curt D. Furberg10, Talin Haritunians11, Barbara McKnight9, Bruce M. Psaty12, Bruce M. Psaty9, Kent D. Taylor11, Evan L. Thacker9, Peter Almgren13, Leif Groop13, Claes Ladenvall13, Michael Boehnke14, Anne U. Jackson14, Karen L. Mohlke1, Heather M. Stringham14, Jaakko Tuomilehto15, Jaakko Tuomilehto16, Emelia J. Benjamin17, Shih-Jen Hwang8, Daniel Levy17, Sarah R. Preis8, Ramachandran S. Vasan17, Jubao Duan18, Pablo V. Gejman18, Douglas F. Levinson6, Alan R. Sanders18, Jianxin Shi8, Esther H. Lips19, James McKay19, Antonio Agudo, Luigi Barzan, Vladimir Bencko20, Simone Benhamou21, Simone Benhamou22, Xavier Castellsagué, Cristina Canova23, David I. Conway24, Eleonora Fabianova, Lenka Foretova, Vladimir Janout25, Claire M. Healy26, Ivana Holcatova20, Kristina Kjærheim, Pagona Lagiou27, Jolanta Lissowska, Ray Lowry28, Tatiana V. Macfarlane29, Dana Mates, Lorenzo Richiardi30, Peter Rudnai, Neonilia Szeszenia-Dabrowska31, David Zaridze32, Ariana Znaor, Mark Lathrop, Paul Brennan19, Stefania Bandinelli, Timothy M. Frayling33, Jack M. Guralnik8, Yuri Milaneschi, John R. B. Perry33, David Altshuler34, David Altshuler35, Roberto Elosua, S. Kathiresan35, S. Kathiresan34, Gavin Lucas, Olle Melander13, Christopher J. O'Donnell8, Veikko Salomaa16, Stephen M. Schwartz9, Benjamin F. Voight36, Brenda W.J.H. Penninx37, Johannes H. Smit37, Nicole Vogelzangs37, Dorret I. Boomsma37, Eco J. C. de Geus37, Jacqueline M. Vink37, Gonneke Willemsen37, Stephen J. Chanock8, Fangyi Gu34, Susan E. Hankinson34, David J. Hunter34, Albert Hofman38, Henning Tiemeier38, André G. Uitterlinden38, Cornelia M. van Duijn38, Stefan Walter38, Daniel I. Chasman34, Brendan M. Everett34, Guillaume Paré34, Paul M. Ridker34, Ming D. Li39, Hermine H. Maes40, Janet Audrain-McGovern41, Danielle Posthuma37, Laura M. Thornton1, Caryn Lerman41, Jaakko Kaprio15, Jaakko Kaprio16, Jed E. Rose42, John P. A. Ioannidis43, John P. A. Ioannidis44, Peter Kraft34, Danyu Lin1, Patrick F. Sullivan1 
TL;DR: A meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium found the strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3, and three loci associated with number of cigarettes smoked per day were identified.
Abstract: Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

Journal ArticleDOI
TL;DR: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered.
Abstract: BACKGROUND: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System. OBJECTIVES: To revise these guidelines. METHODS: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. RECOMMENDATIONS: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).

Journal ArticleDOI
TL;DR: In cancer patients developing AC-CMP, LVEF recovery and cardiac event reduction may be achieved when cardiac dysfunction is detected early and a modern HF treatment is promptly initiated.

Journal ArticleDOI
TL;DR: This article performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects, and genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls.
Abstract: We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Journal ArticleDOI
08 Jan 2010-Cell
TL;DR: The isolation to near purity of human normal mammary SCs (hNMSCs) is reported on the basis of their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature, to support the notion that the heterogeneous phenotypical and molecular traits of human breast cancers are a function of their CSC content.

Journal ArticleDOI
A. A. Abdo1, A. A. Abdo2, Markus Ackermann3, Ivan Agudo4  +270 moreInstitutions (51)
Abstract: We have conducted a detailed investigation of the broadband spectral properties of the gamma-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated Fermi gamma-ray spectra with Swift, radio, infra-red, optical, and other hard X-ray/gamma-ray data, collected within 3 months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous spectral energy distributions (SED) for 48 LBAS blazars. The SED of these gamma-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual log nu-log nu F-nu representation, the typical broadband spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SED to characterize the peak intensity of both the low-and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broadband colors (i.e., the radio to optical, alpha(ro), and optical to X-ray, alpha(ox), spectral slopes) and from the gamma-ray spectral index. Our data show that the synchrotron peak frequency (nu(S)(peak)) is positioned between 10(12.5) and 10(14.5) Hz in broad-lined flat spectrum radio quasars (FSRQs) and between 10(13) and 10(17) Hz in featureless BL Lacertae objects. We find that the gamma-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron-inverse Compton scenarios. However, simple homogeneous, one-zone, synchrotron self-Compton (SSC) models cannot explain most of our SED, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. More complex models involving external Compton radiation or multiple SSC components are required to reproduce the overall SED and the observed spectral variability. While more than 50% of known radio bright high energy peaked (HBL) BL Lacs are detected in the LBAS sample, only less than 13% of known bright FSRQs and LBL BL Lacs are included. This suggests that the latter sources, as a class, may be much fainter gamma-ray emitters than LBAS blazars, and could in fact radiate close to the expectations of simple SSC models. We categorized all our sources according to a new physical classification scheme based on the generally accepted paradigm for Active Galactic Nuclei and on the results of this SED study. Since the LAT detector is more sensitive to flat spectrum gamma-ray sources, the correlation between nu(S)(peak) and gamma-ray spectral index strongly favors the detection of high energy peaked blazars, thus explaining the Fermi overabundance of this type of sources compared to radio and EGRET samples. This selection effect is similar to that experienced in the soft X-ray band where HBL BL Lacs are the dominant type of blazars.

01 Jan 2010
TL;DR: Variants from 13 new regions reached genome-wide significance and most contain genes with immune functions, with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection.
Abstract: We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.


Journal ArticleDOI
TL;DR: The data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution are reviewed and data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive are summarized.
Abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.


Journal ArticleDOI
TL;DR: These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions.
Abstract: Aberrant DNA replication is a major source of the mutations and chromosome rearrangements that are associated with pathological disorders. When replication is compromised, DNA becomes more prone to breakage. Secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymatic activities for their stabilization and subsequent advance. These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions. The mechanisms that operate in eukaryotic cells to promote replication fork integrity and coordinate replication with other aspects of chromosome maintenance are becoming clear.

Journal ArticleDOI
TL;DR: Among a range of other findings, EC effects were stronger for high than for low contingency awareness, for supraliminal than for subliminal US presentation, for postacquisition than for postextinction effects, and for self-report than for implicit measures.
Abstract: This article presents a meta-analysis of research on evaluative conditioning (EC), defined as a change in the liking of a stimulus (conditioned stimulus; CS) that results from pairing that stimulus with other positive or negative stimuli (unconditioned stimulus; US). Across a total of 214 studies included in the main sample, the mean EC effect was d = .52, with a 95% confidence interval of .466-.582. As estimated from a random-effects model, about 70% of the variance in effect sizes were attributable to true systematic variation rather than sampling error. Moderator analyses were conducted to partially explain this variation, both as a function of concrete aspects of the procedural implementation and as a function of the abstract aspects of the relation between CS and US. Among a range of other findings, EC effects were stronger for high than for low contingency awareness, for supraliminal than for subliminal US presentation, for postacquisition than for postextinction effects, and for self-report than for implicit measures. These findings are discussed with regard to the procedural boundary conditions of EC and theoretical accounts about the mental processes underlying EC.

Journal ArticleDOI
TL;DR: Acute MI up-regulated miR-1, - 133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR -122 and -375 were lower than control only in STEMI patients and in mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs.
Abstract: Aims Circulating microRNAs (miRNAs) may represent a novel class of biomarkers; therefore, we examined whether acute myocardial infarction (MI) modulates miRNAs plasma levels in humans and mice. Methods and results Healthy donors ( n = 17) and patients ( n = 33) with acute ST-segment elevation MI (STEMI) were evaluated. In one cohort ( n = 25), the first plasma sample was obtained 517 ± 309 min after the onset of MI symptoms and after coronary reperfusion with percutaneous coronary intervention (PCI); miR-1, -133a, -133b, and -499-5p were ∼15- to 140-fold control, whereas miR-122 and -375 were ∼87–90% lower than control; 5 days later, miR-1, -133a, -133b, -499-5p, and -375 were back to baseline, whereas miR-122 remained lower than control through Day 30. In additional patients ( n = 8; four treated with thrombolysis and four with PCI), miRNAs and troponin I (TnI) were quantified simultaneously starting 156 ± 72 min after the onset of symptoms and at different times thereafter. Peak miR-1, -133a, and -133b expression and TnI level occurred at a similar time, whereas miR-499-5p exhibited a slower time course. In mice, miRNAs plasma levels and TnI were measured 15 min after coronary ligation and at different times thereafter. The behaviour of miR-1, -133a, -133b, and -499-5p was similar to STEMI patients; further, reciprocal changes in the expression levels of these miRNAs were found in cardiac tissue 3–6 h after coronary ligation. In contrast, miR-122 and -375 exhibited minor changes and no significant modulation. In mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs. Conclusion Acute MI up-regulated miR-1, -133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR-122 and -375 were lower than control only in STEMI patients. These miRNAs represent novel biomarkers of cardiac damage.

Journal ArticleDOI
TL;DR: The pre-print version of the Published Article can be accessed from the link below - Copyright @ 2010 Springer Verlag as discussed by the authors, which can be viewed as a preprint of the published article.
Abstract: This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer Verlag

Journal ArticleDOI
TL;DR: Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing.
Abstract: Background Geographical differences in the incidence of amyotrophic lateral sclerosis (ALS) have been reported in the literature but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled analysis of European population based ALS registries. Methods All new incident ALS cases in subjects aged 18 years old and older were identified prospectively in six population based registries in three European countries (Ireland, UK and Italy) in the 2 year period 1998–1999, with a reference population of almost 24 million. Results Based on 1028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100 000 person years; 95% CI 2.0 to 2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100 000 person years; 95% CI 2.8 to 3.3) than among women (2.4 per 100 000 person years; 95% CI 2.2 to 2.6). Spinal onset ALS was more common among men compared with women, particularly in the 70–80 year age group. Disease occurrence decreased rapidly after 80 years of age. Conclusions ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing.

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TL;DR: The various kinds of symbols used to characterize the topology of vertices in 3-periodic nets, tiles and polyhedra, and symbols for tilings are reviewed, making a recommendation for uniform nomenclature where there is some confusion and misapplication of terminology.
Abstract: We review the various kinds of symbols used to characterize the topology of vertices in 3-periodic nets, tiles and polyhedra, and symbols for tilings, making a recommendation for uniform nomenclature where there is some confusion and misapplication of terminology.

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TL;DR: This review critically evaluate the results of the research on interpersonal touch that have emerged from disciplines, such as cognitive and social psychology, neuroscience, and cultural anthropology to develop a more complete understanding of interpersonal touch in the years to come.


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Georges Aad1, Brad Abbott2, Jalal Abdallah3, A. A. Abdelalim4  +3098 moreInstitutions (192)
TL;DR: In this article, the authors used the ATLAS detector to detect dijet asymmetry in the collisions of lead ions at the Large Hadron Collider and found that the transverse energies of dijets in opposite hemispheres become systematically more unbalanced with increasing event centrality, leading to a large number of events which contain highly asymmetric di jets.
Abstract: By using the ATLAS detector, observations have been made of a centrality-dependent dijet asymmetry in the collisions of lead ions at the Large Hadron Collider. In a sample of lead-lead events with a per-nucleon center of mass energy of 2.76 TeV, selected with a minimum bias trigger, jets are reconstructed in fine-grained, longitudinally segmented electromagnetic and hadronic calorimeters. The transverse energies of dijets in opposite hemispheres are observed to become systematically more unbalanced with increasing event centrality leading to a large number of events which contain highly asymmetric dijets. This is the first observation of an enhancement of events with such large dijet asymmetries, not observed in proton-proton collisions, which may point to an interpretation in terms of strong jet energy loss in a hot, dense medium.

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TL;DR: It is demonstrated that NOTCH pathway blockade depletes stem‐like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.
Abstract: Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by γ-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.