Showing papers by "University of Cambridge published in 2010"
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TL;DR: The PHENIX software for macromolecular structure determination is described and its uses and benefits are described.
Abstract: Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
18,531 citations
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TL;DR: Graphene has high mobility and optical transparency, in addition to flexibility, robustness and environmental stability as discussed by the authors, and its true potential lies in photonics and optoelectronics, where the combination of its unique optical and electronic properties can be fully exploited, even in the absence of a bandgap, and the linear dispersion of the Dirac electrons enables ultrawideband tunability.
Abstract: The richness of optical and electronic properties of graphene attracts enormous interest. Graphene has high mobility and optical transparency, in addition to flexibility, robustness and environmental stability. So far, the main focus has been on fundamental physics and electronic devices. However, we believe its true potential lies in photonics and optoelectronics, where the combination of its unique optical and electronic properties can be fully exploited, even in the absence of a bandgap, and the linear dispersion of the Dirac electrons enables ultrawideband tunability. The rise of graphene in photonics and optoelectronics is shown by several recent results, ranging from solar cells and light-emitting devices to touch screens, photodetectors and ultrafast lasers. Here we review the state-of-the-art in this emerging field.
6,863 citations
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TL;DR: This work develops an approach to detect noncovalent interactions in real space, based on the electron density and its derivatives, which provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids.
Abstract: Molecular structure does not easily identify the intricate noncovalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron density and its derivatives. Our approach reveals the underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.
5,731 citations
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Wageningen University and Research Centre1, University of Cambridge2, North Carolina State University3, University of Göttingen4, Cornell University5, Leibniz Institute for Neurobiology6, Queen Mary University of London7, Northwestern University8, Georgia Institute of Technology9, University of Southern Mississippi10, Université de Montréal11, Duke University12, Clemson University13, Clarkson University14
TL;DR: This work reviews recent advances and challenges in the developments towards applications of stimuli-responsive polymeric materials that are self-assembled from nanostructured building blocks and provides a critical outline of emerging developments.
Abstract: Responsive polymer materials can adapt to surrounding environments, regulate transport of ions and molecules, change wettability and adhesion of different species on external stimuli, or convert chemical and biochemical signals into optical, electrical, thermal and mechanical signals, and vice versa. These materials are playing an increasingly important part in a diverse range of applications, such as drug delivery, diagnostics, tissue engineering and 'smart' optical systems, as well as biosensors, microelectromechanical systems, coatings and textiles. We review recent advances and challenges in the developments towards applications of stimuli-responsive polymeric materials that are self-assembled from nanostructured building blocks. We also provide a critical outline of emerging developments.
4,908 citations
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United Nations Environment Programme1, BirdLife International2, Zoological Society of London3, Statistics Netherlands4, University of North Carolina at Chapel Hill5, Old Dominion University6, Conservation International7, Food and Agriculture Organization8, University of Virginia9, Royal Society for the Protection of Birds10, University of Queensland11, University of Cambridge12, National Center for Atmospheric Research13, World Wide Fund for Nature14, South African National Parks15, UNESCO16, University of British Columbia17, Tata Institute of Fundamental Research18, The Nature Conservancy19, Patuxent Wildlife Research Center20, American Bird Conservancy21, Stellenbosch University22, International Union for Conservation of Nature and Natural Resources23
TL;DR: Most indicators of the state of biodiversity showed declines, with no significant recent reductions in rate, whereas indicators of pressures on biodiversity showed increases, indicating that the Convention on Biological Diversity’s 2010 targets have not been met.
Abstract: In 2002, world leaders committed, through the Convention on Biological Diversity, to achieve a significant reduction in the rate of biodiversity loss by 2010. We compiled 31 indicators to report on progress toward this target. Most indicators of the state of biodiversity (covering species' population trends, extinction risk, habitat extent and condition, and community composition) showed declines, with no significant recent reductions in rate, whereas indicators of pressures on biodiversity (including resource consumption, invasive alien species, nitrogen pollution, overexploitation, and climate change impacts) showed increases. Despite some local successes and increasing responses (including extent and biodiversity coverage of protected areas, sustainable forest management, policy responses to invasive alien species, and biodiversity-related aid), the rate of biodiversity loss does not appear to be slowing.
3,993 citations
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TL;DR: A meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration found diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors.
3,568 citations
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TL;DR: The Bat Algorithm as mentioned in this paper is based on the echolocation behavior of bats and combines the advantages of existing algorithms into the new bat algorithm to solve many tough optimization problems.
Abstract: Metaheuristic algorithms such as particle swarm optimization, firefly algorithm and harmony search are now becoming powerful methods for solving many tough optimization problems. In this paper, we propose a new metaheuristic method, the Bat Algorithm, based on the echolocation behaviour of bats. We also intend to combine the advantages of existing algorithms into the new bat algorithm. After a detailed formulation and explanation of its implementation, we will then compare the proposed algorithm with other existing algorithms, including genetic algorithms and particle swarm optimization. Simulations show that the proposed algorithm seems much superior to other algorithms, and further studies are also discussed.
3,528 citations
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Tanya M. Teslovich1, Kiran Musunuru, Albert V. Smith2, Andrew C. Edmondson3 +215 more•Institutions (46)
TL;DR: The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
3,469 citations
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23 Apr 2010TL;DR: The Bat Algorithm as mentioned in this paper is based on the echolocation behavior of bats and combines the advantages of existing algorithms into the new bat algorithm to solve many tough optimization problems.
Abstract: Metaheuristic algorithms such as particle swarm optimization, firefly algorithm and harmony search are now becoming powerful methods for solving many tough optimization problems. In this paper, we propose a new metaheuristic method, the Bat Algorithm, based on the echolocation behaviour of bats. We also intend to combine the advantages of existing algorithms into the new bat algorithm. After a detailed formulation and explanation of its implementation, we will then compare the proposed algorithm with other existing algorithms, including genetic algorithms and particle swarm optimization. Simulations show that the proposed algorithm seems much superior to other algorithms, and further studies are also discussed.
3,162 citations
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TL;DR: In this article, a biennial review summarizes much of particle physics using data from previous editions, plus 2158 new measurements from 551 papers, they list, evaluate and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.
2,788 citations
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Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Cristen J. Willer3, Sonja I. Berndt +410 more•Institutions (86)
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.
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University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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TL;DR: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype, which has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity.
Abstract: BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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TL;DR: This work has provided a solid foundation for studying the regulation of translation initiation by mechanisms that include the modulation of initiation factor activity and through sequence-specific RNA-binding proteins and microRNAs (which affect individual mRNAs).
Abstract: Protein synthesis is principally regulated at the initiation stage (rather than during elongation or termination), allowing rapid, reversible and spatial control of gene expression. Progress over recent years in determining the structures and activities of initiation factors, and in mapping their interactions in ribosomal initiation complexes, have advanced our understanding of the complex translation initiation process. These developments have provided a solid foundation for studying the regulation of translation initiation by mechanisms that include the modulation of initiation factor activity (which affects almost all scanning-dependent initiation) and through sequence-specific RNA-binding proteins and microRNAs (which affect individual mRNAs).
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Anthony Nolan1, University of Oxford2, Biomedical Primate Research Centre3, Kettering University4, Hoffmann-La Roche5, University of Texas MD Anderson Cancer Center6, Fred Hutchinson Cancer Research Center7, University of Washington8, University of California, Los Angeles9, Hallym University10, University of Geneva11, National Marrow Donor Program12, Medical University of Vienna13, Stanford University14, Harvard University15, University of Cambridge16
TL;DR: This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports.
Abstract: The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).
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TL;DR: The network-based statistic (NBS) is introduced for the first time and its power is evaluated with the use of receiver operating characteristic (ROC) curves to demonstrate its utility with application to a real case-control study involving a group of people with schizophrenia for which resting-state functional MRI data were acquired.
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15 Apr 2010
TL;DR: Systematic studies of more than 25,000 cancer genomes will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Abstract: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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TL;DR: It is demonstrated that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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TL;DR: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size.
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TL;DR: A meta-analysis of published and unpublished data found that statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events.
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TL;DR: A class of interatomic potential models that can be automatically generated from data consisting of the energies and forces experienced by atoms, as derived from quantum mechanical calculations, are introduced.
Abstract: We introduce a class of interatomic potential models that can be automatically generated from data consisting of the energies and forces experienced by atoms, as derived from quantum mechanical calculations. The models do not have a fixed functional form and hence are capable of modeling complex potential energy landscapes. They are systematically improvable with more data. We apply the method to bulk crystals, and test it by calculating properties at high temperatures. Using the interatomic potential to generate the long molecular dynamics trajectories required for such calculations saves orders of magnitude in computational cost.
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TL;DR: This paper shows how to use the recently developed firefly algorithm to solve non-linear design problems and proposes a few new test functions with either singularity or stochastic components but with known global optimality and thus they can be used to validate new optimisation algorithms.
Abstract: Modern optimisation algorithms are often metaheuristic, and they are very promising in solving NP-hard optimisation problems. In this paper, we show how to use the recently developed firefly algorithm to solve non-linear design problems. For the standard pressure vessel design optimisation, the optimal solution found by FA is far better than the best solution obtained previously in the literature. In addition, we also propose a few new test functions with either singularity or stochastic components but with known global optimality and thus they can be used to validate new optimisation algorithms. Possible topics for further research are also discussed.
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TL;DR: The optoelectronic properties of graphene are exploited to realize an ultrafast laser and pave the way to graphene-based photonics.
Abstract: Graphene is at the center of a significant research effort Near-ballistic transport at room temperature and high mobility make it a potential material for nanoelectronics Its electronic and mechanical properties are also ideal for micro- and nanomechanical systems, thin-film transistors, and transparent and conductive composites and electrodes Here we exploit the optoelectronic properties of graphene to realize an ultrafast laser A graphene-polymer composite is fabricated using wet-chemistry techniques Pauli blocking following intense illumination results in saturable absorption, independent of wavelength This is used to passively mode-lock an erbium-doped fiber laser working at 1559 nm, with a 524 nm spectral bandwidth and approximately 460 fs pulse duration, paving the way to graphene-based photonics
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National Institutes of Health1, Mayo Clinic2, Harvard University3, American Cancer Society4, University of Cambridge5, University of Melbourne6, University of California, Irvine7, Loma Linda University8, Johns Hopkins University9, University of Minnesota10, Cancer Council Victoria11, Karolinska Institutet12, City of Hope National Medical Center13, New York University14, University of Washington15, The Queen's Medical Center16
TL;DR: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality and the hazard ratios for the men were similar.
Abstract: BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.
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TL;DR: In this article, the authors used the Firefly Algorithm to solve nonlinear design problems and showed that the optimal solution found by FA is far better than the best solution obtained previously in literature.
Abstract: Modern optimisation algorithms are often metaheuristic, and they are very promising in solving NP-hard optimization problems. In this paper, we show how to use the recently developed Firefly Algorithm to solve nonlinear design problems. For the standard pressure vessel design optimisation, the optimal solution found by FA is far better than the best solution obtained previously in literature. In addition, we also propose a few new test functions with either singularity or stochastic components but with known global optimality, and thus they can be used to validate new optimisation algorithms. Possible topics for further research are also discussed.
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TL;DR: A new heuristic for feature detection is presented and, using machine learning, a feature detector is derived from this which can fully process live PAL video using less than 5 percent of the available processing time.
Abstract: The repeatability and efficiency of a corner detector determines how likely it is to be useful in a real-world application. The repeatability is important because the same scene viewed from different positions should yield features which correspond to the same real-world 3D locations. The efficiency is important because this determines whether the detector combined with further processing can operate at frame rate. Three advances are described in this paper. First, we present a new heuristic for feature detection and, using machine learning, we derive a feature detector from this which can fully process live PAL video using less than 5 percent of the available processing time. By comparison, most other detectors cannot even operate at frame rate (Harris detector 115 percent, SIFT 195 percent). Second, we generalize the detector, allowing it to be optimized for repeatability, with little loss of efficiency. Third, we carry out a rigorous comparison of corner detectors based on the above repeatability criterion applied to 3D scenes. We show that, despite being principally constructed for speed, on these stringent tests, our heuristic detector significantly outperforms existing feature detectors. Finally, the comparison demonstrates that using machine learning produces significant improvements in repeatability, yielding a detector that is both very fast and of very high quality.
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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.
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TL;DR: This review focuses on mammalian autophagy, and an overview of the understanding of its machinery and the signaling cascades that regulate it is given, and the possibility of autophagic upregulation as a therapeutic approach for various conditions is considered.
Abstract: (Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.
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University of Glasgow1, University of Salerno2, Max Planck Society3, University of Southampton4, University of Paris-Sud5, Paris Diderot University6, VU University Amsterdam7, University of Nice Sophia Antipolis8, Washington State University9, University of Warsaw10, University of Birmingham11, Cardiff University12, University of Rome Tor Vergata13, Moscow State University14, California Institute of Technology15, fondazione bruno kessler16, Centre national de la recherche scientifique17, University of Cambridge18, University of Tübingen19, University of Urbino20, University of Vienna21, University of Minnesota22, University of Jena23, Albert Einstein Institution24, Northwestern University25, University of Savoy26, Pennsylvania State University27, University of Pisa28, Sapienza University of Rome29, University of Florence30
TL;DR: The third-generation ground-based observatory Einstein Telescope (ET) project as discussed by the authors is currently in its design study phase, and it can be seen as the first step in this direction.
Abstract: Advanced gravitational wave interferometers, currently under realization, will soon permit the detection of gravitational waves from astronomical sources. To open the era of precision gravitational wave astronomy, a further substantial improvement in sensitivity is required. The future space-based Laser Interferometer Space Antenna and the third-generation ground-based observatory Einstein Telescope (ET) promise to achieve the required sensitivity improvements in frequency ranges. The vastly improved sensitivity of the third generation of gravitational wave observatories could permit detailed measurements of the sources' physical parameters and could complement, in a multi-messenger approach, the observation of signals emitted by cosmological sources obtained through other kinds of telescopes. This paper describes the progress of the ET project which is currently in its design study phase.
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Erasmus University Rotterdam1, University of Cambridge2, University of Paris3, University of Copenhagen4, Aarhus University5, Ghent University6, National and Kapodistrian University of Athens7, French Institute of Health and Medical Research8, University of Upper Alsace9, VU University Amsterdam10, Maastricht University11, University of Manchester12, Manchester Royal Infirmary13, University of Brescia14, Charles University in Prague15
TL;DR: In this paper, the authors established reference and normal values for Carotid-femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, based on a large European population.
Abstract: Aims: Carotid-femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results: We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion: The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.