Showing papers by "University College London published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.

Abstract: Objective The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. Methods The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. Results Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). Conclusion The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or antidouble-stranded DNA antibodies. (Less)

Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease

Abstract: A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Validation of the theoretical domains framework for use in behaviour change and implementation research

Abstract: An integrative theoretical framework, developed for cross-disciplinary implementation and other behaviour change research, has been applied across a wide range of clinical situations. This study tests the validity of this framework. Validity was investigated by behavioural experts sorting 112 unique theoretical constructs using closed and open sort tasks. The extent of replication was tested by Discriminant Content Validation and Fuzzy Cluster Analysis. There was good support for a refinement of the framework comprising 14 domains of theoretical constructs (average silhouette value 0.29): ‘Knowledge’, ‘Skills’, ‘Social/Professional Role and Identity’, ‘Beliefs about Capabilities’, ‘Optimism’, ‘Beliefs about Consequences’, ‘Reinforcement’, ‘Intentions’, ‘Goals’, ‘Memory, Attention and Decision Processes’, ‘Environmental Context and Resources’, ‘Social Influences’, ‘Emotions’, and ‘Behavioural Regulation’. The refined Theoretical Domains Framework has a strengthened empirical base and provides a method for theoretically assessing implementation problems, as well as professional and other health-related behaviours as a basis for intervention development.

Psychological correlates of university students' academic performance: a systematic review and meta-analysis

Abstract: A review of 13 years of research into antecedents of university students' grade point average (GPA) scores generated the following: a comprehensive, conceptual map of known correlates of tertiary GPA; assessment of the magnitude of average, weighted correlations with GPA; and tests of multivariate models of GPA correlates within and across research domains. A systematic search of PsycINFO and Web of Knowledge databases between 1997 and 2010 identified 7,167 English-language articles yielding 241 data sets, which reported on 50 conceptually distinct correlates of GPA, including 3 demographic factors and 5 traditional measures of cognitive capacity or prior academic performance. In addition, 42 non-intellective constructs were identified from 5 conceptually overlapping but distinct research domains: (a) personality traits, (b) motivational factors, (c) self-regulatory learning strategies, (d) students' approaches to learning, and (e) psychosocial contextual influences. We retrieved 1,105 independent correlations and analyzed data using hypothesis-driven, random-effects meta-analyses. Significant average, weighted correlations were found for 41 of 50 measures. Univariate analyses revealed that demographic and psychosocial contextual factors generated, at best, small correlations with GPA. Medium-sized correlations were observed for high school GPA, SAT, ACT, and A level scores. Three non-intellective constructs also showed medium-sized correlations with GPA: academic self-efficacy, grade goal, and effort regulation. A large correlation was observed for performance self-efficacy, which was the strongest correlate (of 50 measures) followed by high school GPA, ACT, and grade goal. Implications for future research, student assessment, and intervention design are discussed.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease

Abstract: Objective: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. Methods: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/ Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. Results: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLADQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. Conclusions: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively. (JPGN 2012;54: 136–160)

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

Mechanochemistry: opportunities for new and cleaner synthesis

Abstract: The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

The clustering of galaxies in the sdss-iii baryon oscillation spectroscopic survey: Baryon acoustic oscillations in the data release 9 spectroscopic galaxy sample

Abstract: We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III). Our results come from the Data Release 11 (DR11) sample, containing nearly one million galaxies and covering approximately $8\,500$ square degrees and the redshift range $0.2

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Normalization as a canonical neural computation.

Abstract: There is increasing evidence that the brain relies on a set of canonical neural computations, repeating them across brain regions and modalities to apply similar operations to different problems. A promising candidate for such a computation is normalization, in which the responses of neurons are divided by a common factor that typically includes the summed activity of a pool of neurons. Normalization was developed to explain responses in the primary visual cortex and is now thought to operate throughout the visual system, and in many other sensory modalities and brain regions. Normalization may underlie operations such as the representation of odours, the modulatory effects of visual attention, the encoding of value and the integration of multisensory information. Its presence in such a diversity of neural systems in multiple species, from invertebrates to mammals, suggests that it serves as a canonical neural computation.

Smart cities of the future

Abstract: Here we sketch the rudiments of what constitutes a smart city which we define as a city in which ICT is merged with traditional infrastructures, coordinated and integrated using new digital technologies. We first sketch our vision defining seven goals which concern: developing a new understanding of urban problems; effective and feasible ways to coordinate urban technologies; models and methods for using urban data across spatial and temporal scales; developing new technologies for communication and dissemination; developing new forms of urban governance and organisation; defining critical problems relating to cities, transport, and energy; and identifying risk, uncertainty, and hazards in the smart city. To this, we add six research challenges: to relate the infrastructure of smart cities to their operational functioning and planning through management, control and optimisation; to explore the notion of the city as a laboratory for innovation; to provide portfolios of urban simulation which inform future designs; to develop technologies that ensure equity, fairness and realise a better quality of city life; to develop technologies that ensure informed participation and create shared knowledge for democratic city governance; and to ensure greater and more effective mobility and access to opportunities for urban populations. We begin by defining the state of the art, explaining the science of smart cities. We define six scenarios based on new cities badging themselves as smart, older cities regenerating themselves as smart, the development of science parks, tech cities, and technopoles focused on high technologies, the development of urban services using contemporary ICT, the use of ICT to develop new urban intelligence functions, and the development of online and mobile forms of participation. Seven project areas are then proposed: Integrated Databases for the Smart City, Sensing, Networking and the Impact of New Social Media, Modelling Network Performance, Mobility and Travel Behaviour, Modelling Urban Land Use, Transport and Economic Interactions, Modelling Urban Transactional Activities in Labour and Housing Markets, Decision Support as Urban Intelligence, Participatory Governance and Planning Structures for the Smart City. Finally we anticipate the paradigm shifts that will occur in this research and define a series of key demonstrators which we believe are important to progressing a science of smart cities.

Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.

Abstract: randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P = 0.75). CONCLUSIONS Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.)

Bayesian Reasoning and Machine Learning

Abstract: Machine learning methods extract value from vast data sets quickly and with modest resources They are established tools in a wide range of industrial applications, including search engines, DNA sequencing, stock market analysis, and robot locomotion, and their use is spreading rapidly People who know the methods have their choice of rewarding jobs This hands-on text opens these opportunities to computer science students with modest mathematical backgrounds It is designed for final-year undergraduates and master's students with limited background in linear algebra and calculus Comprehensive and coherent, it develops everything from basic reasoning to advanced techniques within the framework of graphical models Students learn more than a menu of techniques, they develop analytical and problem-solving skills that equip them for the real world Numerous examples and exercises, both computer based and theoretical, are included in every chapter Resources for students and instructors, including a MATLAB toolbox, are available online

Psychological therapies for the management of chronic pain (excluding headache) in adults

Abstract: Background Psychological treatments are designed to treat pain, distress and disability, and are in common practice. This review updates and extends the 2009 version of this systematic review. Objectives To evaluate the effectiveness of psychological therapies for chronic pain (excluding headache) in adults, compared with treatment as usual, waiting list control, or placebo control, for pain, disability, mood and catastrophic thinking. Search methods We identified randomised controlled trials (RCTs) of psychological therapy by searching CENTRAL, MEDLINE, EMBASE and Psychlit from the beginning of each abstracting service until September 2011. We identified additional studies from the reference lists of retrieved papers and from discussion with investigators. Selection criteria Full publications of RCTs of psychological treatments compared with an active treatment, waiting list or treatment as usual. We excluded studies if the pain was primarily headache, or was associated with a malignant disease. We also excluded studies if the number of patients in any treatment arm was less than 20. Data collection and analysis Forty-two studies met our criteria and 35 (4788 participants) provided data. Two authors rated all studies. We coded risk of bias as well as both the quality of the treatments and the methods using a scale designed for the purpose. We compared two main classes of treatment (cognitive behavioural therapy(CBT) and behaviour therapy) with two control conditions (treatment as usual; active control) at two assessment points (immediately following treatment and six months or more following treatment), giving eight comparisons. For each comparison, we assessed treatment effectiveness on four outcomes: pain, disability, mood and catastrophic thinking, giving a total of 32 possible analyses, of which there were data for 25. Main results Overall there is an absence of evidence for behaviour therapy, except a small improvement in mood immediately following treatment when compared with an active control. CBT has small positive effects on disability and catastrophising, but not on pain or mood, when compared with active controls. CBT has small to moderate effects on pain, disability, mood and catastrophising immediately post-treatment when compared with treatment as usual/waiting list, but all except a small effect on mood had disappeared at follow-up. At present there are insufficient data on the quality or content of treatment to investigate their influence on outcome. The quality of the trial design has improved over time but the quality of treatments has not. Authors' conclusions Benefits of CBT emerged almost entirely from comparisons with treatment as usual/waiting list, not with active controls. CBT but not behaviour therapy has weak effects in improving pain, but only immediately post-treatment and when compared with treatment as usual/waiting list. CBT but not behaviour therapy has small effects on disability associated with chronic pain, with some maintenance at six months. CBT is effective in altering mood and catastrophising outcomes, when compared with treatment as usual/waiting list, with some evidence that this is maintained at six months. Behaviour therapy has no effects on mood, but showed an effect on catastrophising immediately post-treatment. CBT is a useful approach to the management of chronic pain. There is no need for more general RCTs reporting group means: rather, different types of studies and analyses are needed to identify which components of CBT work for which type of patient on which outcome/s, and to try to understand why.

A reconciled estimate of ice-sheet mass balance

Abstract: We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic adjustment to estimate the mass balance of Earth’s polar ice sheets. We find that there is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by –142 ± 49, +14 ± 43, –65 ± 26, and –20 ± 14 gigatonnes year−1, respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year−1 to the rate of global sea-level rise.

Socioeconomic status and smoking: a review

Abstract: Smoking prevalence is higher among disadvantaged groups, and disadvantaged smokers may face higher exposure to tobacco's harms. Uptake may also be higher among those with low socioeconomic status (SES), and quit attempts are less likely to be successful. Studies have suggested that this may be the result of reduced social support for quitting, low motivation to quit, stronger addiction to tobacco, increased likelihood of not completing courses of pharmacotherapy or behavioral support sessions, psychological differences such as lack of self-efficacy, and tobacco industry marketing. Evidence of interventions that work among lower socioeconomic groups is sparse. Raising the price of tobacco products appears to be the tobacco control intervention with the most potential to reduce health inequalities from tobacco. Targeted cessation programs and mass media interventions can also contribute to reducing inequalities. To tackle the high prevalence of smoking among disadvantaged groups, a combination of tobacco control measures is required, and these should be delivered in conjunction with wider attempts to address inequalities in health.

Analyses of pig genomes provide insight into porcine demography and evolution

Abstract: For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars ∼1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.