Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance

The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core domain and negate the p53 sequence-specific DNA binding. Moreover, these mutations exhibit a dominant negative effect on the remaining wild-type p53. Here, we report the cryo electron microscopy structure of the full-length p53 tetramer bound to a DNA-encoding transcription factor response element (RE) at a resolution of 21 Å. While two core domains from both dimers of the p53 tetramer interact with DNA within the complex, the other two core domains remain available for binding another DNA site. This finding helps to explain the dominant negative effect of p53 mutants based on the fact that p53 dimers are formed co-translationally before the whole tetramer assembles; therefore, a single mutant dimer would prevent the p53 tetramer from binding DNA. The structure indicates that the Achilles’ heel of p53 is in its dimer-of-dimers organization, thus the tetramer activity can be negated by mutation in only one allele followed by tumourigenesis

The NIHR collaboration for leadership in applied health research and care (CLAHRC) for greater manchester: combining empirical, theoretical and experiential evidence to design and evaluate a large-scale implementation strategy

Background: In response to policy recommendations, nine National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRCs) were established in England in 2008, aiming to create closer working between the health service and higher education and narrow the gap between research and its implementation in practice. The Greater Manchester (GM) CLAHRC is a partnership between the University of Manchester and twenty National Health Service (NHS) trusts, with a five-year mission to improve healthcare and reduce health inequalities for people with cardiovascular conditions. This paper outlines the GM CLAHRC approach to designing and evaluating a large-scale, evidence- and theory-informed, context-sensitive implementation programme. Discussion: The paper makes a case for embedding evaluation within the design of the implementation strategy. Empirical, theoretical, and experiential evidence relating to implementation science and methods has been synthesised to formulate eight core principles of the GM CLAHRC implementation strategy, recognising the multi-faceted nature of evidence, the complexity of the implementation process, and the corresponding need to apply approaches that are situationally relevant, responsive, flexible, and collaborative. In turn, these core principles inform the selection of four interrelated building blocks upon which the GM CLAHRC approach to implementation is founded. These determine the organizational processes, structures, and roles utilised by specific GM CLAHRC implementation projects, as well as the approach to researching implementation, and comprise: the Promoting Action on Research Implementation in Health Services (PARIHS) framework; a modified version of the Model for Improvement; multiprofessional teams with designated roles to lead, facilitate, and support the implementation process; and embedded evaluation and learning. Summary: Designing and evaluating a large-scale implementation strategy that can cope with and respond to the local complexities of implementing research evidence into practice is itself complex and challenging. We present an argument for adopting an integrative, co-production approach to planning and evaluating the implementation of research into practice, drawing on an eclectic range of evidence sources.Gill Harvey, Louise Fitzgerald, Sandra Fielden, Anne McBride, Heather Waterman, David Bamford, Roman Kislo and Ruth Boade

MOPAT: a graph-based method to predict recurrent cis-regulatory modules from known motifs

The identification of cis-regulatory modules (CRMs) can greatly advance our understanding of eukaryotic regulatory mechanism. Current methods to predict CRMs from known motifs either depend on multiple alignments or can only deal with a small number of known motifs provided by users. These methods are problematic when binding sites are not well aligned in multiple alignments or when the number of input known motifs is large. We thus developed a new CRM identification method MOPAT (motif pair tree), which identifies CRMs through the identification of motif modules, groups of motifs co-ccurring in multiple CRMs. It can identify ‘orthologous’ CRMs without multiple alignments. It can also find CRMs given a large number of known motifs. We have applied this method to mouse developmental genes, and have evaluated the predicted CRMs and motif modules by microarray expression data and known interacting motif pairs. We show that the expression profiles of the genes containing CRMs of the same motif module correlate significantly better than those of a random set of genes do. We also show that the known interacting motif pairs are significantly included in our predictions. Compared with several current methods, our method shows better performance in identifying meaningful CRMs

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

C–H Functionalization Reactivity of a Nickel–Imide

This article discusses C-H functionalization reactivity of a Nickel-Imide

Evolving the theory and praxis of knowledge translation through social interaction: a social phenomenological study

Background: As an inherently human process fraught with subjectivity, dynamic interaction, and change, social interaction knowledge translation (KT) invites implementation scientists to explore what might be learned from adopting the academic tradition of social constructivism and an interpretive research approach. This paper presents phenomenological investigation of the second cycle of a participatory action KT intervention in the home care sector to answer the question: What is the nature of the process of implementing KT through social interaction? Methods: Social phenomenology was selected to capture how the social processes of the KT intervention were experienced, with the aim of representing these as typical socially-constituted patterns. Participants (n = 203), including service providers, case managers, administrators, and researchers organized into nine geographically-determined multi-disciplinary action groups, purposefully selected and audiotaped three meetings per group to capture their enactment of the KT process at early, middle, and end-of-cycle timeframes. Data, comprised of 36 hours of transcribed audiotapes augmented by researchers\u27 field notes, were analyzed using social phenomenology strategies and authenticated through member checking and peer review. Results: Four patterns of social interaction representing organization, team, and individual interests were identified: overcoming barriers and optimizing facilitators; integrating \u27science push\u27 and \u27demand pull\u27 approaches within the social interaction process; synthesizing the research evidence with tacit professional craft and experiential knowledge; and integrating knowledge creation, transfer, and uptake throughout everyday work. Achieved through relational transformative leadership constituted simultaneously by both structure and agency, in keeping with social phenomenology analysis approaches, these four patterns are represented holistically in a typical construction, specifically, a participatory action KT (PAKT) model. Conclusion: Study findings suggest the relevance of principles and foci from the field of process evaluation related to intervention implementation, further illuminating KT as a structuration process facilitated by evolving transformative leadership in an active and integrated context. The model provides guidance for proactively constructing a \u27fit\u27 between content, context, and facilitation in the translation of evidence informing professional craft knowledge

What Do We Know About Neuropsychological Aspects Of Schizophrenia?

Application of a neuropsychological perspective to the study of schizophrenia has established a number of important facts about this disorder. Some of the key findings from the existing literature are that, while neurocognitive impairment is present in most, if not all, persons with schizophrenia, there is both substantial interpatient heterogeneity and remarkable within-patient stability of cognitive function over the long-term course of the illness. Such findings have contributed to the firm establishment of neurobiologic models of schizophrenia, and thereby help to reduce the social stigma that was sometimes associated with purely psychogenic models popular during parts of the 20th century. Neuropsychological studies in recent decades have established the primacy of cognitive functions over psychopathologic symptoms as determinants of functional capacity and independence in everyday functioning. Although the cognitive benefits of both conventional and even second generation antipsychotic medications appear marginal at best, recognition of the primacy of cognitive deficits as determinants of functional disability in schizophrenia has catalyzed recent efforts to develop targeted treatments for the cognitive deficits of this disorder. Despite these accomplishments, however, some issues remain to be resolved. Efforts to firmly establish the specific neurocognitive/neuropathologic systems responsible for schizophrenia remain elusive, as do efforts to definitively demonstrate the specific cognitive deficits underlying specific forms of functional impairment. Further progress may be fostered by recent initiatives to integrate neuropsychological studies with experimental neuroscience, perhaps leading to measures of deficits in cognitive processes more clearly associated with specific, identifiable brain systems