Showing papers by "Imperial College London published in 2009"
TL;DR: It is concluded that the full repertoire of functional networks utilized by the brain in action is continuously and dynamically “active” even when at “rest.”
Abstract: Neural connections, providing the substrate for functional networks, exist whether or not they are functionally active at any given moment. However, it is not known to what extent brain regions are continuously interacting when the brain is “at rest.” In this work, we identify the major explicit activation networks by carrying out an image-based activation network analysis of thousands of separate activation maps derived from the BrainMap database of functional imaging studies, involving nearly 30,000 human subjects. Independently, we extract the major covarying networks in the resting brain, as imaged with functional magnetic resonance imaging in 36 subjects at rest. The sets of major brain networks, and their decompositions into subnetworks, show close correspondence between the independent analyses of resting and activation brain dynamics. We conclude that the full repertoire of functional networks utilized by the brain in action is continuously and dynamically “active” even when at “rest.”
4,768 citations
TL;DR: This protocol provides a guide to interpreting the output of structure prediction servers in general and one such tool in particular, the protein homology/analogy recognition engine (Phyre), which can reliably detect up to twice as many remote homologies as standard sequence-profile searching.
Abstract: Determining the structure and function of a novel protein is a cornerstone of many aspects of modern biology. Over the past decades, a number of computational tools for structure prediction have been developed. It is critical that the biological community is aware of such tools and is able to interpret their results in an informed way. This protocol provides a guide to interpreting the output of structure prediction servers in general and one such tool in particular, the protein homology/analogy recognition engine (Phyre). New profile–profile matching algorithms have improved structure prediction considerably in recent years. Although the performance of Phyre is typical of many structure prediction systems using such algorithms, all these systems can reliably detect up to twice as many remote homologies as standard sequence-profile searching. Phyre is widely used by the biological community, with >150 submissions per day, and provides a simple interface to results. Phyre takes 30 min to predict the structure of a 250-residue protein.
4,403 citations
National Institutes of Health1, Imperial College London2, Boston Children's Hospital3, University of Alberta4, Royal Prince Alfred Hospital5, University of Sydney6, University of Giessen7, Amrita Institute of Medical Sciences and Research Centre8, University of Illinois at Urbana–Champaign9, Medical University of Graz10, Vanderbilt University Medical Center11, University of São Paulo12
TL;DR: In this paper, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches, and the main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups.
4,135 citations
TL;DR: Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer, despite cigarette consumption per smoker varying little with BMI.
3,847 citations
TL;DR: In this paper, the authors discuss human emotion perception from a psychological perspective, examine available approaches to solving the problem of machine understanding of human affective behavior, and discuss important issues like the collection and availability of training and test data.
Abstract: Automated analysis of human affective behavior has attracted increasing attention from researchers in psychology, computer science, linguistics, neuroscience, and related disciplines. However, the existing methods typically handle only deliberately displayed and exaggerated expressions of prototypical emotions despite the fact that deliberate behaviour differs in visual appearance, audio profile, and timing from spontaneously occurring behaviour. To address this problem, efforts to develop algorithms that can process naturally occurring human affective behaviour have recently emerged. Moreover, an increasing number of efforts are reported toward multimodal fusion for human affect analysis including audiovisual fusion, linguistic and paralinguistic fusion, and multi-cue visual fusion based on facial expressions, head movements, and body gestures. This paper introduces and surveys these recent advances. We first discuss human emotion perception from a psychological perspective. Next we examine available approaches to solving the problem of machine understanding of human affective behavior, and discuss important issues like the collection and availability of training and test data. We finally outline some of the scientific and engineering challenges to advancing human affect sensing technology.
2,503 citations
TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
2,373 citations
TL;DR: How Bayesian techniques have made a significant impact in tackling problems such as neuroimaging problems, particularly in regards to the analysis tools in the FMRIB Software Library (FSL), is described.
2,269 citations
Royal Botanic Garden Edinburgh1, National Institutes of Health2, University of Guelph3, University of Johannesburg4, Royal Botanic Gardens5, Smithsonian Institution6, University of British Columbia7, Natural History Museum8, Korea University9, University of Toronto10, State University of Feira de Santana11, University of Costa Rica12, Columbus State University13, University of Wisconsin-Madison14, New York Botanical Garden15, University of the Andes16, University of Cape Town17, Seoul National University18, Hallym University19, National Autonomous University of Mexico20, Imperial College London21
TL;DR: The 2-locus combination of rbcL+matK will provide a universal framework for the routine use of DNA sequence data to identify specimens and contribute toward the discovery of overlooked species of land plants.
Abstract: DNA barcoding involves sequencing a standard region of DNA as a tool for species identification. However, there has been no agreement on which region(s) should be used for barcoding land plants. To provide a community recommendation on a standard plant barcode, we have compared the performance of 7 leading candidate plastid DNA regions (atpF–atpH spacer, matK gene, rbcL gene, rpoB gene, rpoC1 gene, psbK–psbI spacer, and trnH–psbA spacer). Based on assessments of recoverability, sequence quality, and levels of species discrimination, we recommend the 2-locus combination of rbcL+matK as the plant barcode. This core 2-locus barcode will provide a universal framework for the routine use of DNA sequence data to identify specimens and contribute toward the discovery of overlooked species of land plants.
2,255 citations
Columbia University1, University of Oxford2, Nathan Kline Institute for Psychiatric Research3, New York University4, University College London5, University of Pennsylvania6, University of California, Los Angeles7, University of Iowa8, McGill University9, French Institute for Research in Computer Science and Automation10, French Institute of Health and Medical Research11, John Radcliffe Hospital12, Imperial College London13, Mauna Kea Technologies14
TL;DR: This study is the largest evaluation of nonlinear deformation algorithms applied to brain image registration ever conducted and suggests that the findings are generalizable to new subject populations that are labeled or evaluated using different labeling protocols.
2,214 citations
TL;DR: It is shown that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry, the strongest and most significant genetic effect associated with natural clearance ofHCV.
Abstract: Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
2,079 citations
TL;DR: It can be anticipated that a considerable proportion of the non-smoking adult population has urinary cadmium concentrations of 0.5 microg/g creatinine or higher in non-exposed areas, and for smokers this proportion is considerably higher, which implies no margin of safety between the point of departure and the exposure levels in the general population.
TL;DR: Transmissibility is substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics, by analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, which makes an early assessment of transmissibility and severity.
Abstract: A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults ( /=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.
TL;DR: A balanced critical appraisal of the BUGS software is provided, highlighting how various ideas have led to unprecedented flexibility while at the same time producing negative side effects.
Abstract: BUGS is a software package for Bayesian inference using Gibbs sampling. The software has been instrumental in raising awareness of Bayesian modelling among both academic and commercial communities internationally, and has enjoyed considerable success over its 20-year life span. Despite this, the software has a number of shortcomings and a principal aim of this paper is to provide a balanced critical appraisal, in particular highlighting how various ideas have led to unprecedented flexibility while at the same time producing negative side effects. We also present a historical overview of the BUGS project and some future perspectives. Copyright © 2009 John Wiley & Sons, Ltd.
Cristen J. Willer, Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Ruth J. F. Loos +163 more•Institutions (36)
TL;DR: Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
Woolcock Institute of Medical Research1, University of Otago2, University of Cape Town3, Creighton University4, University of Arizona5, University of Groningen6, University of Edinburgh7, McMaster University8, Imperial College London9, University of Leicester10, University of Amsterdam11, University of Washington12, University of Aberdeen13, University of Pittsburgh14
TL;DR: New definitions for asthma control, severity, and exacerbations are developed, based on current treatment principles and clinical and research relevance, to provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.
Abstract: Background: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.Purpose: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.Methods: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.Results: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge ...
Autonomous University of Barcelona1, National and Kapodistrian University of Athens2, Lund University3, University of Bergen4, Hannover Medical School5, University of Zurich6, Russian National Research Medical University7, SOCAR8, University of London9, Imperial College London10, Wrocław Medical University11
TL;DR: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable.
Abstract: BACKGROUND Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. METHODS We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 μg per liter or between 100 and 299 μg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. RESULTS Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780.)
TL;DR: The molecular and physical information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering, and exciting developments are likely to help reconcile the clinical and commercial pressures on tissue engineering.
Abstract: The molecular and physical information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cell-instructive scaffolds, while others remain largely unexplored. Yet for commercial success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of production. This is spurring interest in recreating extracellular influences in simplified forms, from the reduction of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clinical and commercial pressures on tissue engineering.
TL;DR: The APOE ε4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes and could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow.
Abstract: The APOE epsilon4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE epsilon4-carriers and 18 matched noncarriers (age range: 20-35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased "default mode network" (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in epsilon4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in epsilon4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE epsilon4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.
TL;DR: This paper discusses and applies an ABC method based on sequential Monte Carlo (SMC) to estimate parameters of dynamical models and develops ABC SMC as a tool for model selection; given a range of different mathematical descriptions, it is able to choose the best model using the standard Bayesian model selection apparatus.
Abstract: Approximate Bayesian computation (ABC) methods can be used to evaluate posterior distributions without having to calculate likelihoods. In this paper, we discuss and apply an ABC method based on sequential Monte Carlo (SMC) to estimate parameters of dynamical models. We show that ABC SMC provides information about the inferability of parameters and model sensitivity to changes in parameters, and tends to perform better than other ABC approaches. The algorithm is applied to several well-known biological systems, for which parameters and their credible intervals are inferred. Moreover, we develop ABC SMC as a tool for model selection; given a range of different mathematical descriptions, ABC SMC is able to choose the best model using the standard Bayesian model selection apparatus.
TL;DR: Can PSII be exploited through increased use of biomass as an energy source and, more importantly, can the energy/CO2 problem be addressed by developing new photochemical technologies which mimic the natural system?
Abstract: Photosystem II (PSII) is the water splitting enzyme of photosynthesis. Its appearance during evolution dramatically changed the chemical composition of our planet and set in motion an unprecedented explosion in biological activity. Powered by sunlight, PSII supplies biology with the ‘hydrogen’ needed to convert carbon dioxide into organic molecules. The questions now are can we continue to exploit this photosynthetic process through increased use of biomass as an energy source and, more importantly, can we address the energy/CO2 problem by developing new photochemical technologies which mimic the natural system? (Critical review, 82 references)
TL;DR: Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors.
Abstract: Background Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. Methods We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5°C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. Results Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of su...
TL;DR: Rather than one or two domestication events leading to the extant baker’s yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
Abstract: Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
TL;DR: PanTHERIA as mentioned in this paper is a species-level data set compiled for analysis of life history, ecology, and geography of all known extant and recently extinct mammalian species, collected over a period of three years by 20 individuals.
Abstract: Analyses of life-history, ecological, and geographic trait differences among species, their causes, correlates, and likely consequences are increasingly important for understanding and conserving biodiversity in the face of rapid global change. Assembling multispecies trait data from diverse literature sources into a single comprehensive data set requires detailed consideration of methods to reliably compile data for particular species, and to derive single estimates from multiple sources based on different techniques and definitions. Here we describe PanTHERIA, a species-level data set compiled for analysis of life history, ecology, and geography of all known extant and recently extinct mammals. PanTHERIA is derived from a database capable of holding multiple geo-referenced values for variables within a species containing 100 740 lines of biological data for extant and recently extinct mammalian species, collected over a period of three years by 20 individuals. PanTHERIA also includes spatial databases o...
Harvard University1, Boston University2, Massachusetts Institute of Technology3, University of Michigan4, Merck & Co.5, University of Oxford6, National Institutes of Health7, French Institute of Health and Medical Research8, University of Eastern Finland9, University of Southern California10, National Institute for Health and Welfare11, Imperial College London12, Lund University13, University of Helsinki14, Wellcome Trust Sanger Institute15, Tufts University16, University of North Carolina at Chapel Hill17
TL;DR: The results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Abstract: Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
TL;DR: The biology of latent tuberculosis is discussed as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria.
Abstract: Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.
TL;DR: The dynamics and stability of thin liquid films have fascinated scientists over many decades: the observations of regular wave patterns in film flows along a windowpane or along guttering, the patterning of dewetting droplets, and the fingering of viscous flows down a slope are all examples that are familiar in daily life.
Abstract: The dynamics and stability of thin liquid films have fascinated scientists over many decades: the observations of regular wave patterns in film flows down a windowpane or along guttering, the patterning of dewetting droplets, and the fingering of viscous flows down a slope are all examples that are familiar in daily life. Thin film flows occur over a wide range of length scales and are central to numerous areas of engineering, geophysics, and biophysics; these include nanofluidics and microfluidics, coating flows, intensive processing, lava flows, dynamics of continental ice sheets, tear-film rupture, and surfactant replacement therapy. These flows have attracted considerable attention in the literature, which have resulted in many significant developments in experimental, analytical, and numerical research in this area. These include advances in understanding dewetting, thermocapillary- and surfactant-driven films, falling films and films flowing over structured, compliant, and rapidly rotating substrates, and evaporating films as well as those manipulated via use of electric fields to produce nanoscale patterns. These developments are reviewed in this paper and open problems and exciting research avenues in this thriving area of fluid mechanics are also highlighted.
Christopher Newton-Cheh1, Christopher Newton-Cheh2, Toby Johnson3, Toby Johnson4 +359 more•Institutions (64)
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
Christine G. Elsik1, Christine G. Elsik2, Christine G. Elsik3, Ross L. Tellam1 +325 more•Institutions (65)
TL;DR: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage and provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
Abstract: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
TL;DR: If policies for salt reduction at the population level are to be effective, policy development and implementation needs to target the main source of dietary sodium in the various populations.
Abstract: Background High levels of dietary sodium (consumed as common salt, sodium chloride) are associated with raised blood pressure and adverse cardiovascular health. Despite this, public health efforts to reduce sodium consumption remain limited to a few countries. Comprehensive, contemporaneous sodium intake data from around the world are needed to inform national/international public health initiatives to reduce sodium consumption. Methods Use of standardized 24-h sodium excretion estimates for adults from the international INTERSALT (1985–87) and INTERMAP (1996–99) studies, and recent dietary and urinary sodium data from observational or interventional studies—identified by a comprehensive search of peer-reviewed and ‘grey’ literature—presented separately for adults and children. Review of methods for the estimation of sodium intake/ excretion. Main food sources of sodium are presented for several Asian, European and Northern American countries, including previously unpublished INTERMAP data.
TL;DR: It is shown in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity.
Abstract: Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)–activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.