Showing papers by "Autonomous University of Barcelona published in 2010"
Broad Institute1, Harvard University2, Novartis3, Brigham and Women's Hospital4, Jikei University School of Medicine5, Boston Children's Hospital6, University of North Carolina at Chapel Hill7, University of Texas Southwestern Medical Center8, Nagoya City University9, Autonomous University of Barcelona10, University Health Network11, Cornell University12, Beth Israel Deaconess Medical Center13, Memorial Sloan Kettering Cancer Center14, University of Pennsylvania15, University of Michigan16, University of Washington Medical Center17, Howard Hughes Medical Institute18, Massachusetts Institute of Technology19
TL;DR: It is demonstrated that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival, and a large majority of SCNAs identified in individual cancer types are present in several cancer types.
Abstract: A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.
3,375 citations
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TL;DR: It is proved that the envelope of the hesitant fuzzy sets is an intuitionistic fuzzy set, and it is proved also that the operations proposed are consistent with the ones of intuitionist fuzzy sets when applied to the envelope.
Abstract: Several extensions and generalizations of fuzzy sets have been introduced in the literature, for example, Atanassov's intuitionistic fuzzy sets, type 2 fuzzy sets, and fuzzy multisets. In this paper, we propose hesitant fuzzy sets. Although from a formal point of view, they can be seen as fuzzy multisets, we will show that their interpretation differs from the two existing approaches for fuzzy multisets. Because of this, together with their definition, we also introduce some basic operations. In addition, we also study their relationship with intuitionistic fuzzy sets. We prove that the envelope of the hesitant fuzzy sets is an intuitionistic fuzzy set. We prove also that the operations we propose are consistent with the ones of intuitionistic fuzzy sets when applied to the envelope of the hesitant fuzzy sets. © 2010 Wiley Periodicals, Inc.
2,232 citations
TL;DR: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.
Abstract: BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)
2,040 citations
TL;DR: This work aims to review different strategies of surface modification and functionalization of inorganic colloidal nanoparticles with a special focus on the material systems gold and semiconductor nanoparticles, such as CdSe/ZnS.
Abstract: Inorganic colloidal nanoparticles are very small, nanoscale objects with inorganic cores that are dispersed in a solvent. Depending on the material they consist of, nanoparticles can possess a number of different properties such as high electron density and strong optical absorption (e.g. metal particles, in particular Au), photoluminescence in the form of fluorescence (semiconductor quantum dots, e.g. CdSe or CdTe) or phosphorescence (doped oxide materials, e.g. Y(2)O(3)), or magnetic moment (e.g. iron oxide or cobalt nanoparticles). Prerequisite for every possible application is the proper surface functionalization of such nanoparticles, which determines their interaction with the environment. These interactions ultimately affect the colloidal stability of the particles, and may yield to a controlled assembly or to the delivery of nanoparticles to a target, e.g. by appropriate functional molecules on the particle surface. This work aims to review different strategies of surface modification and functionalization of inorganic colloidal nanoparticles with a special focus on the material systems gold and semiconductor nanoparticles, such as CdSe/ZnS. However, the discussed strategies are often of general nature and apply in the same way to nanoparticles of other materials.
1,477 citations
Rhode Island Hospital1, University of Medicine and Dentistry of New Jersey2, University of Massachusetts Medical School3, University of Toronto4, Queen Elizabeth Hospital Birmingham5, Autonomous University of Barcelona6, Guy's and St Thomas' NHS Foundation Trust7, Stony Brook University8, Harvard University9, University of Pittsburgh10
TL;DR: The Surviving Sepsis Campaign was associated with sustained, continuous quality improvement in sepsis care and a reduction in reported hospital mortality rates wasassociated with participation.
Abstract: Objective
The Surviving Sepsis Campaign (SSC or “the Campaign”) developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes.
1,323 citations
TL;DR: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy, but in the meantime, carotin artery stent should remain the treatment of choice for patients suitable for surgery.
1,115 citations
Spanish National Research Council1, Autonomous University of Barcelona2, Academy of Sciences of the Czech Republic3, Environmental Protection Agency4, University of Bern5, Klaipėda University6, Institut national de la recherche agronomique7, Natural Environment Research Council8, Canterbury of New Zealand9
TL;DR: In this paper, the authors present a review of the financial costs of alien species in Europe, as the first step toward calculating an estimate of the economic consequences of extraterrestrial species.
Abstract: Recent comprehensive data provided through the DAISIE project (www.europe-aliens.org) have facilitated the development of the first pan-European assessment of the impacts of alien plants, vertebrates, and invertebrates – in terrestrial, freshwater, and marine environments – on ecosystem services. There are 1094 species with documented ecological impacts and 1347 with economic impacts. The two taxonomic groups with the most species causing impacts are terrestrial invertebrates and terrestrial plants. The North Sea is the maritime region that suffers the most impacts. Across taxa and regions, ecological and economic impacts are highly correlated. Terrestrial invertebrates create greater economic impacts than ecological impacts, while the reverse is true for terrestrial plants. Alien species from all taxonomic groups affect “supporting”, “provisioning”, “regulating”, and “cultural” services and interfere with human well-being. Terrestrial vertebrates are responsible for the greatest range of impacts, and these are widely distributed across Europe. Here, we present a review of the financial costs, as the first step toward calculating an estimate of the economic consequences of alien species in Europe.
985 citations
TL;DR: The risk index based on seven objective, easily assessed factors has excellent discriminative ability and can be used to assess individual risk of PPC and focus further research on measures to improve patient care.
Abstract: Background: Current knowledge of the risk for postoperative pulmonary complications (PPCs) rests on studies that narrowly selected patients and procedures. Hypothesizing thatPPCoccurrencecouldbepredictedfromareducedsetof perioperative variables, we aimed to develop a predictive index for a broad surgical population. Methods: Patients undergoing surgical procedures given general, neuraxial, or regional anesthesia in 59 hospitals were randomly selected for this prospective, multicenter study. The main outcome was the development of at least one of the following:respiratoryinfection,respiratoryfailure,bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. The cohort was randomly divided into a development subsample to construct a logistic regression model and a validation subsample. A PPC predictive index was constructed. Results: Of 2,464 patients studied, 252 events were observed in 123 (5%). Thirty-day mortality was higher in patients with a PPC (19.5%; 95% [CI], 12.5–26.5%) than in those without a PPC (0.5%; 95% CI, 0.2–0.8%). Regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infectionduringthepreviousmonth,age,preoperativeanemia, upper abdominal or intrathoracic surgery, surgical duration of at least 2 h, and emergency surgery. The area under the receiver operating characteristic curve was 90% (95% CI, 85–94%) for the development subsample and 88% (95% CI, 84–93%) for the validation subsample. Conclusion: The risk index based on seven objective, easily assessed factors has excellent discriminative ability. The index can be used to assess individual risk of PPC and focus further research on measures to improve patient care.
905 citations
TL;DR: The eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody, which synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
875 citations
John H. Werren1, Stephen Richards2, Christopher A. Desjardins1, Oliver Niehuis3 +158 more•Institutions (58)
TL;DR: Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation.
Abstract: We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N. giraulti, and N. longicornis. Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
838 citations
TL;DR: The Quality Of Reporting Of Metaanalysis (QUOROMA) as discussed by the authors is a lista of comprobación for revistas, revisores, editores, and revistas en Medicina Clinica.
Abstract: En el ano 1999, despues de 3 anos de trabajo, se publico la declaracion QUOROM, cuyo objetivo era establecer unas normas para mejorar la calidad de la presentacion de los metaanalisis de ensayos clinicos aleatorizados. Se publico un comentario de este documento en un monografico sobre listas de comprobacion para autores, revisores y editores de revistas medicas en Medicina Clinica. En resumen, la declaracion Quality Of Reporting Of Metaanalysis (QUOROM) incluye una lista de comprobacion estructurada con 18 items que los autores de un metaanalisis, y tambien los editores de revistas, deberian considerar a la hora de publicar su trabajo en forma de articulo en una revista medica. Ademas, incluye un diagrama de flujo que describe todo el proceso, desde la identificacion inicial de los estudios potencialmente relevantes hasta la seleccion definitiva de estos. La finalidad de QUOROM era animar a los autores a que proporcionaran toda aquella informacion que resulta esencial para interpretar y utilizar adecuadamente los resultados de un metaanalisis. Numerosos estudios realizados con posterioridad a la publicacion de QUOROM han mostrado que la calidad de los metaanalisis publicados en revistas medicas todavia es deficiente. A pesar de esto, y a diferencia de otras iniciativas similares como CONSORT (dirigida a ensayos clinicos), la declaracion QUOROM no parece
Autonomous University of Barcelona1, St George's Hospital2, Trinity College, Dublin3, Oslo University Hospital4, Tel Aviv University5, University of Lisbon6, Hannover Medical School7, Université libre de Bruxelles8, University of Florence9, National and Kapodistrian University of Athens10, Lund University11, The Catholic University of America12, King's College London13
TL;DR: This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated.
Abstract: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.
TL;DR: It is shown that freeze-dried bacterial cellulose nanofibril aerogels can be used as templates for making lightweight porous magnetic aerogel, which can be compacted into a stiff magnetic nanopaper.
Abstract: Nanostructured biological materials inspire the creation of materials with tunable mechanical properties. Strong cellulose nanofibrils derived from bacteria or wood can form ductile or tough networks that are suitable as functional materials. Here, we show that freeze-dried bacterial cellulose nanofibril aerogels can be used as templates for making lightweight porous magnetic aerogels, which can be compacted into a stiff magnetic nanopaper. The 20-70-nm-thick cellulose nanofibrils act as templates for the non-agglomerated growth of ferromagnetic cobalt ferrite nanoparticles (diameter, 40-120 nm). Unlike solvent-swollen gels and ferrogels, our magnetic aerogel is dry, lightweight, porous (98%), flexible, and can be actuated by a small household magnet. Moreover, it can absorb water and release it upon compression. Owing to their flexibility, high porosity and surface area, these aerogels are expected to be useful in microfluidics devices and as electronic actuators.
University of Alberta1, Cedars-Sinai Medical Center2, Harvard University3, Johns Hopkins University4, Cleveland Clinic5, University of Arizona6, Hannover Medical School7, Mayo Clinic8, University of Pittsburgh9, University of Maryland, Baltimore10, University of Paris11, Washington University in St. Louis12, University of Alabama13, Westmead Hospital14, University of North Carolina at Chapel Hill15, University of Vienna16, Autonomous University of Barcelona17, NewYork–Presbyterian Hospital18, Cornell University19
TL;DR: The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance.
TL;DR: A review of the emerging literature on sustainable degrowth can be found in this article, where Hueting, d'Alessandro, van den Bergh, Kerschner, Spangenberg and Alcott discuss whether current growth patterns are (un)sustainable and offer different perspectives on what degrowth might mean, and whether and under what conditions it might be desirable.
TL;DR: Present-day species richness of long-lived vascular plant specialists was better explained by past than current landscape patterns, indicating an extinction debt, while short-lived butterfly specialists showed no evidence for an extinction Debt at a time scale of c.
Abstract: Intensification or abandonment of agricultural land use has led to a severe decline of semi-natural habitats across Europe. This can cause immediate loss of species but also time-delayed extinctions, known as the extinction debt. In a pan-European study of 147 fragmented grassland remnants, we found differences in the extinction debt of species from different trophic levels. Present-day species richness of long-lived vascular plant specialists was better explained by past than current landscape patterns, indicating an extinction debt. In contrast, short-lived butterfly specialists showed no evidence for an extinction debt at a time scale of c. 40 years. Our results indicate that management strategies maintaining the status quo of fragmented habitats are insufficient, as time-delayed extinctions and associated co-extinctions will lead to further biodiversity loss in the future.
TL;DR: This review summarizes the available clinicopathological data on uterine sarcomas classified by the WHO diagnostic criteria and concludes that immunohistochemical studies of oncoproteins as well as molecular analysis of non-random translocations will lead to an accurate and prognostically relevant classification of these rare tumors.
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.
TL;DR: Current knowledge on the alteration of BVOC emission rates due to climate and global changes: warming, drought, land use changes, high atmospheric CO(2) concentrations, ozone and enhanced UV radiation is reviewed.
TL;DR: How well-established risk factors for CVD can originate from inflammation in other tissues is discussed, and possible mechanistic links between skin inflammation and increased risks of obesity or metabolic alterations and CVD are considered.
TL;DR: Results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation, and the ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
Abstract: Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
TL;DR: A continuous analogue of the theorems of [F. Cucker and S. Smale, IEEE Trans. Automat. Control, 52 (2007), pp. 852–862] is shown to hold for the solutions on the kinetic model, which means that the solutions will concentrate exponentially fast in velocity to the mean velocity of the initial condition, while in space they will converge towards a translational flocking solution.
Abstract: In this paper, we analyze the asymptotic behavior of solutions of the continuous kinetic version of flocking by Cucker and Smale [IEEE Trans. Automat. Control, 52 (2007), pp. 852–862], which describes the collective behavior of an ensemble of organisms, animals, or devices. This kinetic version introduced in [S.-Y. Ha and E. Tadmor, Kinet. Relat. Models, 1 (2008), pp. 415–435] is here obtained starting from a Boltzmann-type equation. The large-time behavior of the distribution in phase space is subsequently studied by means of particle approximations and a stability property in distances between measures. A continuous analogue of the theorems of [F. Cucker and S. Smale, IEEE Trans. Automat. Control, 52 (2007), pp. 852–862] is shown to hold for the solutions on the kinetic model. More precisely, the solutions will concentrate exponentially fast in velocity to the mean velocity of the initial condition, while in space they will converge towards a translational flocking solution.
TL;DR: The concept of sustainable de-growth was introduced by mapping some of the main intellectual influences from these fields, with special focus on the Francophone and Anglophone thinking about this emergent notion as mentioned in this paper.
TL;DR: In this article, the authors study the hydrodynamics of bubble growth in first-order phase transitions and predict the size of the gravity wave signal resulting from bubble collisions, which depends on both the bubble wall velocity and the plasma fluid velocity.
Abstract: The study of the hydrodynamics of bubble growth in first-order phase transitions is very relevant for electroweak baryogenesis, as the baryon asymmetry depends sensitively on the bubble wall velocity, and also for predicting the size of the gravity wave signal resulting from bubble collisions, which depends on both the bubble wall velocity and the plasma fluid velocity. We perform such study in different bubble expansion regimes, namely deflagrations, detonations, hybrids (steady states) and runaway solutions (accelerating wall), without relying on a specific particle physics model. We compute the efficiency of the transfer of vacuum energy to the bubble wall and the plasma in all regimes. We clarify the condition determining the runaway regime and stress that in most models of strong first-order phase transitions this will modify expectations for the gravity wave signal. Indeed, in this case, most of the kinetic energy is concentrated in the wall and almost no turbulent fluid motions are expected since the surrounding fluid is kept mostly at rest.
TL;DR: A cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche is identified, which confer poor prognosis in GBM patients.
TL;DR: DFT calculations and kinetic experiments suggest a mechanism for homogeneous iridium-catalyzed water oxidation and contribute to the determination of the rate-determining step.
Abstract: Iridium half-sandwich complexes of the types Cp*Ir(N−C)X, [Cp*Ir(N−N)X]X, and [CpIr(N−N)X]X are catalyst precursors for the homogeneous oxidation of water to dioxygen. Kinetic studies with cerium(IV) ammonium nitrate as primary oxidant show that oxygen evolution is rapid and continues over many hours. In addition, [Cp*Ir(H2O)3]SO4 and [(Cp*Ir)2(μ-OH)3]OH can show even higher turnover frequencies (up to 20 min−1 at pH 0.89). Aqueous electrochemical studies on the cationic complexes having chelate ligands show catalytic oxidation at pH > 7; conversely, at low pH, there are no oxidation waves up to 1.5 V vs NHE for the complexes. H218O isotope incorporation studies demonstrate that water is the source of oxygen atoms during cerium(IV)-driven catalysis. DFT calculations and kinetic experiments, including kinetic-isotope-effect studies, suggest a mechanism for homogeneous iridium-catalyzed water oxidation and contribute to the determination of the rate-determining step. The kinetic experiments also help distin...
University of Pennsylvania1, Autonomous University of Barcelona2, Mayo Clinic3, University of Manchester4, Erasmus University Rotterdam5, VU University Amsterdam6, Indiana University – Purdue University Indianapolis7, University of Siena8, National Institutes of Health9, Neuroscience Research Australia10, University of Cambridge11, University of Michigan12, Oregon Health & Science University13, Northwestern University14, King's College London15, University of Texas at Dallas16, University of Texas Southwestern Medical Center17, University of Barcelona18, University of Zurich19, Ludwig Maximilian University of Munich20, Duke University21, University of California, San Francisco22, Boston University23, Veterans Health Administration24, Emory University25, University College London26, University of British Columbia27, University of Pittsburgh28, University of Virginia29, University of Antwerp30, Flanders Institute for Biotechnology31, Columbia University32, Johns Hopkins University33, University of Sydney34, University of New South Wales35, University of Washington36, University of Sheffield37, Washington University in St. Louis38, Alfred Hospital39, University of California, Davis40, Harvard University41, Icahn School of Medicine at Mount Sinai42, Rush University Medical Center43, University of Arizona44, University of California, Los Angeles45, University of Southern California46, University of Eastern Finland47, Uppsala University48, Pierre-and-Marie-Curie University49, University of California, San Diego50, University of California, Irvine51, University of Toronto52, University of Alabama at Birmingham53, University of Würzburg54, Karolinska Institutet55
TL;DR: It is found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM 106B, which implicate variants in TMEM106B as a strong risk factor for FTLD, suggesting an underlying pathogenic mechanism.
Abstract: Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
Carlos III Health Institute1, University of Chieti-Pescara2, Spanish National Research Council3, Autonomous University of Barcelona4, Tufts University5, University of Seville6, Marche Polytechnic University7, University of Naples Federico II8, University of Jaén9, Mario Negri Institute for Pharmacological Research10, French Institute of Health and Medical Research11, University of Zaragoza12, National and Kapodistrian University of Athens13, University of Córdoba (Spain)14, University of Copenhagen15, University of Granada16, University of Las Palmas de Gran Canaria17, University of Bari18, University of Paris19
TL;DR: Results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk, and the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity is consistent.
Abstract: Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).
TL;DR: NMR spectroscopy is used to demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity.
Abstract: G-protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters, and these membrane proteins are the largest group of therapeutic targets for a broad range of diseases. It is very difficult to obtain high-resolution X-ray crystal structures of GPCRs; little is known about the functional role(s) of the extracellular surface in receptor activation or about the conformational coupling of the extracellular surface to the native ligand-binding pocket. In this study, Bokoch et al. used NMR spectroscopy to investigate ligand-specific conformational changes around a salt bridge linking extracellular loops 2 and 3 of the β2 adrenergic receptor. They found that drugs that bind within the transmembrane core (and exhibit different efficacies towards G-protein activation) stabilize distinct conformations of the extracellular surface. New therapeutic agents that target this diverse surface could function as allosteric modulators with high subtype selectivity. G-protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters and are the largest group of therapeutic targets for a range of diseases. The extracellular surface (ECS) of GPCRs is diverse and therefore an ideal target for the discovery of subtype-selective drugs. Here, NMR spectroscopy is used to investigate ligand-specific conformational changes around a central structural feature in the ECS of a GPCR. G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs1,2,3,4,5 have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the β2 adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.
TL;DR: In this article, the authors describe the methodology and data used to determine greenhouse gas (GHG) emissions attributable to ten cities or city-regions: Los Angeles County, Denver City and County, Greater Toronto, New York City, Greater London, Geneva Canton, Greater Prague, Barcelona, Cape Town and Bangkok.