Showing papers by "Sapienza University of Rome published in 2011"
Edinburgh Royal Infirmary1, University of St. Gallen2, Charité3, Sahlgrenska University Hospital4, University of Texas MD Anderson Cancer Center5, University of Alberta6, Mayo Clinic7, McGill University8, University of Cagliari9, Cleveland Clinic10, Sapienza University of Rome11, Nottingham University Hospitals NHS Trust12
TL;DR: A framework exists on a framework for the definition and classification of cancer cachexia, a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.
Abstract: Summary To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] 2 ) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.
3,548 citations
TL;DR: It is shown that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice and this work suggests that deficits in microglian function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
Abstract: Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
3,011 citations
Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
2,511 citations
United States Department of Agriculture1, French Institute of Health and Medical Research2, Research Triangle Park3, Boston University4, Saint Louis University5, University of Pittsburgh6, University of Erlangen-Nuremberg7, Nestlé8, Uppsala University9, Merck & Co.10, Sapienza University of Rome11, National Institutes of Health12, Novartis13, University of Verona14
TL;DR: Sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health, and patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions.
2,378 citations
TL;DR: It is demonstrated that linc-MD1 exerts the same control over differentiation timing in human myoblasts, and that its levels are strongly reduced in Duchenne muscle cells, indicating that the ceRNA network plays an important role in muscle differentiation.
2,231 citations
TL;DR: A critical overview of the latest developments in the lithium ion batteries technology is reported in this paper, where the focus is on the electrode materials presently considered the most promising for enhancing the energy density of the batteries.
Abstract: A critical overview of the latest developments in the lithium ion batteries technology is reported. We first describe the evolution in the electrolyte area with particular attention to ionic liquids, discussing the expected application of these room temperature molten salts and listing the issues that still prevent their practical implementation. The attention is then focused on the electrode materials presently considered the most promising for enhancing the energy density of the batteries. At the anode side a discussion is provided on the status of development of high capacity tin and silicon lithium alloys. We show that the morphology that is the most likely to ensure commercial exploitation of these alloy electrodes is that involving carbon-based nanocomposites. We finally touch on super-high-capacity batteries, discussing the key cases of lithium-sulfur and lithium-air and attempting to forecast their chances to eventually reach the status of practically appealing energy storage systems. We conclude with a brief reflection on the amount of lithium reserves in view of its large use in the case of global conversion from gasoline-powered cars to hybrid and electric cars.
2,157 citations
TL;DR: Non-depressed people with insomnia have a twofold risk to develop depression, compared to people with no sleep difficulties, so early treatment programs for insomnia might reduce the risk for developing depression in the general population and be considered a helpful general preventive strategy in the area of mental health care.
1,829 citations
TL;DR: The T2K experiment observes indications of ν (μ) → ν(e) appearance in data accumulated with 1.43×10(20) protons on target, and under this hypothesis, the probability to observe six or more candidate events is 7×10(-3), equivalent to 2.5σ significance.
Abstract: The T2K experiment observes indications of nu(mu) -> nu(mu) e appearance in data accumulated with 1.43 x 10(20) protons on target. Six events pass all selection criteria at the far detector. In a three-flavor neutrino oscillation scenario with |Delta m(23)(2)| = 2.4 x 10(-3) eV(2), sin(2)2 theta(23) = 1 and sin(2)2 theta(13) = 0, the expected number of such events is 1.5 +/- 0.3(syst). Under this hypothesis, the probability to observe six or more candidate events is 7 x 10(-3), equivalent to 2.5 sigma significance. At 90% C.L., the data are consistent with 0.03(0.04) < sin(2)2 theta(13) < 0.28(0.34) for delta(CP) = 0 and a normal (inverted) hierarchy.
1,361 citations
Posted Content•
TL;DR: Euclid as mentioned in this paper is a space-based survey mission from the European Space Agency designed to understand the origin of the universe's accelerating expansion, using cosmological probes to investigate the nature of dark energy, dark matter and gravity by tracking their observational signatures.
Abstract: Euclid is a space-based survey mission from the European Space Agency designed to understand the origin of the Universe's accelerating expansion. It will use cosmological probes to investigate the nature of dark energy, dark matter and gravity by tracking their observational signatures on the geometry of the universe and on the cosmic history of structure formation. The mission is optimised for two independent primary cosmological probes: Weak gravitational Lensing (WL) and Baryonic Acoustic Oscillations (BAO). The Euclid payload consists of a 1.2 m Korsch telescope designed to provide a large field of view. It carries two instruments with a common field-of-view of ~0.54 deg2: the visual imager (VIS) and the near infrared instrument (NISP) which contains a slitless spectrometer and a three bands photometer. The Euclid wide survey will cover 15,000 deg2 of the extragalactic sky and is complemented by two 20 deg2 deep fields. For WL, Euclid measures the shapes of 30-40 resolved galaxies per arcmin2 in one broad visible R+I+Z band (550-920 nm). The photometric redshifts for these galaxies reach a precision of dz/(1+z) \lt 0.05. They are derived from three additional Euclid NIR bands (Y, J, H in the range 0.92-2.0 micron), complemented by ground based photometry in visible bands derived from public data or through engaged collaborations. The BAO are determined from a spectroscopic survey with a redshift accuracy dz/(1+z) =0.001. The slitless spectrometer, with spectral resolution ~250, predominantly detects Ha emission line galaxies. Euclid is a Medium Class mission of the ESA Cosmic Vision 2015-2025 programme, with a foreseen launch date in 2019. This report (also known as the Euclid Red Book) describes the outcome of the Phase A study.
1,213 citations
14 Oct 2011
TL;DR: Euclid as discussed by the authors is a space-based survey mission from the European Space Agency designed to understand the origin of the universe's accelerating expansion, using cosmological probes to investigate the nature of dark energy, dark matter and gravity by tracking their observational signatures.
Abstract: Euclid is a space-based survey mission from the European Space Agency designed to understand the origin of the Universe's accelerating expansion. It will use cosmological probes to investigate the nature of dark energy, dark matter and gravity by tracking their observational signatures on the geometry of the universe and on the cosmic history of structure formation. The mission is optimised for two independent primary cosmological probes: Weak gravitational Lensing (WL) and Baryonic Acoustic Oscillations (BAO). The Euclid payload consists of a 1.2 m Korsch telescope designed to provide a large field of view. It carries two instruments with a common field-of-view of ~0.54 deg2: the visual imager (VIS) and the near infrared instrument (NISP) which contains a slitless spectrometer and a three bands photometer. The Euclid wide survey will cover 15,000 deg2 of the extragalactic sky and is complemented by two 20 deg2 deep fields. For WL, Euclid measures the shapes of 30-40 resolved galaxies per arcmin2 in one broad visible R+I+Z band (550-920 nm). The photometric redshifts for these galaxies reach a precision of dz/(1+z) < 0.05. They are derived from three additional Euclid NIR bands (Y, J, H in the range 0.92-2.0 micron), complemented by ground based photometry in visible bands derived from public data or through engaged collaborations. The BAO are determined from a spectroscopic survey with a redshift accuracy dz/(1+z) =0.001. The slitless spectrometer, with spectral resolution ~250, predominantly detects Ha emission line galaxies. Euclid is a Medium Class mission of the ESA Cosmic Vision 2015-2025 programme, with a foreseen launch date in 2019. This report (also known as the Euclid Red Book) describes the outcome of the Phase A study.
1,189 citations
TL;DR: A variable number (range 20–90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin.
Abstract: Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.
Journal Article•
TL;DR: An important role is shown for neutrophils in lupus pathogenesis, whereby neutrophil activated by anti-self antibodies release NETs, which contain antimicrobial peptides complexed with self-DNA and can entrap bacteria, enabling them to be killed.
Abstract: Systemic lupus erythematosus (SLE) is a severe and incurable autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here, we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9). SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors; this was further stimulated by the antimicrobial autoantibodies, suggesting a mechanism for the chronic release of immunogenic complexes in SLE. Our data establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease.
University of Bologna1, University of Copenhagen2, Imperial College London3, University of Bergen4, University of Trieste5, Ludwig Maximilian University of Munich6, University of Paris7, University of Verona8, Sapienza University of Rome9, University of Regensburg10, Innsbruck Medical University11, Institut Gustave Roussy12, Hai phong University Of Medicine and Pharmacy13, University of Cambridge14, The Royal Marsden NHS Foundation Trust15, Katholieke Universiteit Leuven16
TL;DR: Authors F. Piscaglia, C. Nolsøe, M. M. Gilja, and H. P. Weskott review the manuscript and suggest ways in which the manuscript could have been improved.
Abstract: Authors F. Piscaglia1, C. Nolsøe2, C. F. Dietrich3, D. O. Cosgrove4, O. H. Gilja5, M. Bachmann Nielsen6, T. Albrecht7, L. Barozzi8, M. Bertolotto9, O. Catalano10, M. Claudon11, D. A. Clevert12, J. M. Correas13, M. D’Onofrio14, F. M. Drudi15, J. Eyding16, M. Giovannini17, M. Hocke18, A. Ignee19, E. M. Jung20, A. S. Klauser21, N. Lassau22, E. Leen23, G. Mathis24, A. Saftoiu25, G. Seidel26, P. S. Sidhu27, G. ter. Haar28, D. Timmerman29, H. P. Weskott30
TL;DR: In this article, two empirical correlations for predicting the effective thermal conductivity and dynamic viscosity of nanofluids, based on a high number of experimental data available in the literature, are proposed and discussed.
University of Helsinki1, French Institute of Health and Medical Research2, University of Wisconsin-Madison3, Lancaster University4, Sapienza University of Rome5, Karolinska University Hospital6, Johns Hopkins University7, University College London8, Aarhus University Hospital9, University of Liverpool10, Imperial College London11, University of California, San Francisco12, University of Würzburg13, University of Aberdeen14, Heidelberg University15
TL;DR: Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes and quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes.
Abstract: This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.
University of Southampton1, University of Paris2, Nestlé3, French Institute of Health and Medical Research4, The Coca-Cola Company5, University of Naples Federico II6, University of Düsseldorf7, Spanish National Research Council8, University of Crete9, Kraft Foods10, Sapienza University of Rome11, Maastricht University12, University of Helsinki13, University of Graz14
TL;DR: Potential mechanisms are described and research gaps, which limit the understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified.
Abstract: Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified.
TL;DR: The BRAF V600E mutation was present in all patients with HCL who were evaluated, and may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL.
Abstract: Background Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. Methods We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. Results Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with spl...
Saint Louis University1, University of Barcelona2, University of Alberta3, University of Erlangen-Nuremberg4, Boston University5, Uppsala University Hospital6, University of East Anglia7, University of California, San Francisco8, Duke University9, Western General Hospital10, National Institutes of Health11, Tufts University12, Kagoshima University13, University of California, Los Angeles14, SOCAR15, University of Cagliari16, Sapienza University of Rome17, Tufts Medical Center18, Tampa General Hospital19, University of Toulouse20, Charité21, Stony Brook University Hospital22
TL;DR: It is concluded that "Sarcopenia, ie, reduced muscle mass, with limited mobility" should be considered an important clinical entity and that most older persons should be screened for this condition.
Medical Research Council1, University of Oxford2, National Institute for Health Research3, Structural Genomics Consortium4, University of Bristol5, University of Bath6, University of Queensland7, National Institutes of Health8, Cedars-Sinai Medical Center9, University of Toronto10, University of Alberta11, Memorial University of Newfoundland12, University of Leeds13, Norfolk and Norwich University Hospital14, Repatriation General Hospital15, University of Porto16, Sapienza University of Rome17, QIMR Berghofer Medical Research Institute18, Second Military Medical University19, Telethon Institute for Child Health Research20, Wellcome Trust Sanger Institute21, University of London22, Trinity College, Dublin23, Cardiff University24, Wellcome Trust25, Wellcome Trust Centre for Human Genetics26, St George's, University of London27, King's College London28, Churchill Hospital29, University of Leicester30, University of Cambridge31, Moorfields Eye Hospital32, University College London33, University of Texas Health Science Center at Houston34, Princess Alexandra Hospital35
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
TL;DR: In this article, the transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transversal momentum resolution.
Abstract: Measurements of the jet energy calibration and transverse momentum resolution in CMS are presented, performed with a data sample collected in proton-proton collisions at a centre-of-mass energy of 7TeV, corresponding to an integrated luminosity of 36pb−1. The transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transverse momentum resolution. The results are presented for three different methods to reconstruct jets: a calorimeter-based approach, the ``Jet-Plus-Track'' approach, which improves the measurement of calorimeter jets by exploiting the associated tracks, and the ``Particle Flow'' approach, which attempts to reconstruct individually each particle in the event, prior to the jet clustering, based on information from all relevant subdetectors
University of Groningen1, Queen Mary University of London2, VU University Amsterdam3, University of Milan4, University of Pittsburgh5, Wellcome Trust Sanger Institute6, University of Naples Federico II7, Radboud University Nijmegen Medical Centre8, Sapienza University of Rome9, University of Maribor10, University of Cambridge11, University of Virginia12, University College London13, University of Delhi14, Hospital Clínico San Carlos15, University Medical Center Utrecht16, Leiden University17, University of Milano-Bicocca18
TL;DR: The complex genetic architecture of the risk regions of and refine the risk signals for celiac disease are defined, providing the next step toward uncovering the causal mechanisms of the disease.
Abstract: Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.
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11 Dec 2011-Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment
TL;DR: The T2K experiment as discussed by the authors is a long-baseline neutrino oscillation experiment whose main goal is to measure the last unknown lepton sector mixing angle by observing its appearance in a particle beam generated by the J-PARC accelerator.
Abstract: The T2K experiment is a long-baseline neutrino oscillation experiment Its main goal is to measure the last unknown lepton sector mixing angle {\theta}_{13} by observing {
u}_e appearance in a {
u}_{\mu} beam It also aims to make a precision measurement of the known oscillation parameters, {\Delta}m^{2}_{23} and sin^{2} 2{\theta}_{23}, via {
u}_{\mu} disappearance studies Other goals of the experiment include various neutrino cross section measurements and sterile neutrino searches The experiment uses an intense proton beam generated by the J-PARC accelerator in Tokai, Japan, and is composed of a neutrino beamline, a near detector complex (ND280), and a far detector (Super-Kamiokande) located 295 km away from J-PARC This paper provides a comprehensive review of the instrumentation aspect of the T2K experiment and a summary of the vital information for each subsystem
TL;DR: A new BLAST search tool, complementary to retrieval by keyword and UniProt accession number, allows users to submit a protein query to search against the curated data set of phosphorylated peptides.
Abstract: The Phospho.ELM resource (http://phospho.elm.eu.org) is a relational database designed to store in vivo and in vitro phosphorylation data extracted from the scientific literature and phosphoproteomic analyses. The resource has been actively developed for more than 7 years and currently comprises 42,574 serine, threonine and tyrosine non-redundant phosphorylation sites. Several new features have been implemented, such as structural disorder/order and accessibility information and a conservation score. Additionally, the conservation of the phosphosites can now be visualized directly on the multiple sequence alignment used for the score calculation. Finally, special emphasis has been put on linking to external resources such as interaction networks and other databases.
University of Glasgow1, University of Salerno2, Max Planck Society3, University of Southampton4, University of Paris-Sud5, University of Nice Sophia Antipolis6, Washington State University7, Istituto Nazionale di Fisica Nucleare8, University of Warsaw9, University of Naples Federico II10, University of Birmingham11, Cardiff University12, University of Rome Tor Vergata13, Moscow State University14, California Institute of Technology15, VU University Amsterdam16, fondazione bruno kessler17, Leibniz University of Hanover18, University of Cambridge19, University of Tübingen20, University of Urbino21, University of Jena22, University of the Balearic Islands23, Northwestern University24, University of Minnesota25, University of Savoy26, Pennsylvania State University27, University of Pisa28, Roma Tre University29, Sapienza University of Rome30, University of Mississippi31
TL;DR: In this article, a special focus is set on evaluating the frequency band below 10 Hz where a complex mixture of seismic, gravity gradient, suspension thermal and radiation pressure noise dominates, including the most relevant fundamental noise contributions.
Abstract: Advanced gravitational wave detectors, currently under construction, are expected to directly observe gravitational wave signals of astrophysical origin. The Einstein Telescope (ET), a third-generation gravitational wave detector, has been proposed in order to fully open up the emerging field of gravitational wave astronomy. In this paper we describe sensitivity models for ET and investigate potential limits imposed by fundamental noise sources. A special focus is set on evaluating the frequency band below 10 Hz where a complex mixture of seismic, gravity gradient, suspension thermal and radiation pressure noise dominates. We develop the most accurate sensitivity model, referred to as ET-D, for a third-generation detector so far, including the most relevant fundamental noise contributions.
TL;DR: This work shows that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation in the α1-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α1
Abstract: Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.
TL;DR: In this article, the authors studied the effect of collision centrality on the transverse momentum of PbPb collisions at the LHC with a data sample of 6.7 inverse microbarns.
Abstract: Jet production in PbPb collisions at a nucleon-nucleon center-of-mass energy of 2.76 TeV was studied with the CMS detector at the LHC, using a data sample corresponding to an integrated luminosity of 6.7 inverse microbarns. Jets are reconstructed using the energy deposited in the CMS calorimeters and studied as a function of collision centrality. With increasing collision centrality, a striking imbalance in dijet transverse momentum is observed, consistent with jet quenching. The observed effect extends from the lower cut-off used in this study (jet transverse momentum = 120 GeV/c) up to the statistical limit of the available data sample (jet transverse momentum approximately 210 GeV/c). Correlations of charged particle tracks with jets indicate that the momentum imbalance is accompanied by a softening of the fragmentation pattern of the second most energetic, away-side jet. The dijet momentum balance is recovered when integrating low transverse momentum particles distributed over a wide angular range relative to the direction of the away-side jet.
TL;DR: Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis.
Abstract: The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.
TL;DR: Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated, and more research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in Patients with A IIRD.
Abstract: Objectives To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune infl ammatory rheumatic diseases (AIIRD). Methods A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/ rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defi ned in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I–IV, the strength of recommendations was graded in categories A–D and Delphi voting was applied to determine the level of agreement between the experts of the task force. Results Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. Conclusion Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.
TL;DR: SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications, and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.
Abstract: to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis. Two hundred six consecutive patients with 310 cerebral metastases less than 3.5 cm were treated with SRS as primary treatment and followed prospectively at University of Rome La Sapienza Sant'Andrea Hospital. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. Univariate and multivariate analysis using a Cox proportional hazards regression model were performed to determine the predictive value of prognostic factors for treatment outcome and SRS-related complications. Median overall survival and brain control were 14.1 months and 10 months, respectively. The 1-year and 2-year survival rates were 58% and 24%, and respective brain control were 43% and 22%. Sixteen patients recurred locally after SRS, with 1-year and 2-year local control rates of 92% and 84%, respectively. On multivariate analysis, stable extracranial disease and KPS >70 were associated with the most significant survival benefit. Neurological complications were recorded in 27 (13%) patients. Severe neurological complications (RTOG Grade 3 and 4) occurred in 5.8% of patients. Brain radionecrosis occurred in 24% of treated lesions, being symptomatic in 10% and asymptomatic in 14%. On multivariate analysis, V10 through V16 Gy were independent risk factors for radionecrosis, with V10 Gy and V12 Gy being the most predictive (p = 0.0001). For V10 Gy >12.6 cm3 and V12 Gy >10.9 cm3 the risk of radionecrosis was 47%. SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications. Lesions with V12 Gy >8.5 cm3 carries a risk of radionecrosis >10% and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.