248 research outputs found

    Understanding Conformational Regulation of the Integrin I-domain for Design of Chimeric Protein Switches

    Get PDF
    Within all complex biological processes intricate proteins are expressed to complete every niche and necessary task. Many express multiple allosterically regulated conformational states, with protein function regulated by effector molecules and other ligands. One such protein is the LFA-1 surface integrin protein and its inserted domain, the I-domain. We Isolated the I-domain for investigation of determining binding properties and understanding conformational regulations of affinity changes to its target ligand ICAM-1, for further use in chimeric protein switch design. A large change in binding affinity was found through the deletion of a sub-sequence of amino acids in I-domain known as the α7 helix. Our investigation shows that, when the α7 helix is deleted, I-domain converts into a permanent high affinity state in which binding affinity to ICAM-1 was increased, and this state can be reversed by co-expression with soluble α7 helix peptide. These results conclude that the α7 helix stabilizes the I domain in its low affinity conformation in a ligand-like manner, allowing relaxation to the high affinity conformation upon disruption of α7 helix interaction. While deletion of the α7 helix yields higher binding affinity in I-domain it cannot be applied in design of chimeric protein switches due to its permanent conformational state. Because of this, our switch design has a focus of allosterically regulating the I-domain and α7 helix through utilizing on/off switching of conformational states. I-domain is fused with EF3 and EF4 hands of calmodulin, which then regulates binding affinity to ICAM-1 through interaction with α7 helix, when the EF hands’ natural ligand peptides are present. Currently, mutant switches are being developed to alter EF hand binding specificity which, when bound to new target ligands, will cause an increase in I-domain-ICAM-1 binding affinity in switch molecules. The results of these allosteric regulations highlight the potential of chimeric protein switches for design of environmentally responsive targeting agents and suggest that, through directed evolution, regulated binding to a range of novel targets could be achieved for therapeutic intervention

    Review of developments in person-centred healthcare

    Get PDF
    Brendan McCormack - ORCID: 0000-0001-8525-8905 https://orcid.org/0000-0001-8525-8905Tanya McCance - ORCID: 0000-0002-9787-2627 https://orcid.org/0000-0002-9787-2627In recent years, there has been a shift in orientation towards person-centredness as part of a global move towards humanising and centralising the person within healthcare. Person-centredness, underpinned by robust philosophical and theoretical concepts, has an increasingly solid footprint in policy and practice, but research and education lag behind. This article considers the emergence of person-centredness, including person-centred care, and how it is positioned in healthcare policy around the world, while recognising a dominant philosophical positioning in Western philosophy, concepts and theories. Second, the evolution of person-centred healthcare over the past five years is reviewed. Published evidence of person-centred healthcare developments is drawn on, as well as information gathered from key stakeholders who engaged with the partner organisations in an Erasmus+ project to develop a European person-centred healthcare curriculum framework. Five themes are identified, which underpin the literature and stakeholder perspectives: Policy development for transformation Participatory strategies for public engagement Healthcare integration and coordination strategies Frameworks for practice Process and outcome measurement These themes reflect the World Health Organization’s global perspective on people-centred and integrated healthcare, and give some indication of development priorities as person-centred healthcare systems continue to be developed.https://doi.org/10.19043/ipdj.10Suppl2.00310pubpubSuppl

    Developing philosophical and pedagogical principles for a pan-European person-centred curriculum framework

    Get PDF
    Brendan McCormack - ORCID: 0000-0001-8525-8905 https://orcid.org/0000-0001-8525-8905Background: In the associated article in this special issue of the International Practice Development Journal, Phelan et al. (2020) offer an analysis of the global positioning of person-centredness from a strategic policy perspective. This second article, an international person-centred education curriculum development initiative, builds on that foundational work. It outlines the systematic, rigorous processes adopted by academics from five European countries to analyse stakeholder data, theoretically frame the data, and thereby identify philosophical and pedagogical principles to inform the development of person-centred curriculum frameworks.Aim: To identify key principles that have the potential to create an international curriculum framework for the education of person-centred healthcare practitioners.Methods: A hermeneutic praxis methodological approach was used, where multiple rounds of data analyses were conducted. These were initially undertaken in each country, then collaboratively with partners, while engaging with other forms of evidence.Findings: The project group generated a set of principles embedded in four philosophical dimensions: (i) transformative; (ii) co-constructed; (iii) relational; and (iv) pragmatic. The purpose of the curriculum was identified as being transformative, facilitating journeying through knowing, doing, being and becoming a competent and committed person-centred practitioner. A person-centred curriculum is built on a philosophy of pragmatism, adopts a co-constructionist approach to curriculum design and implementation, and encourages connectivity with self, other persons and contexts. Pedagogical principles, aligned to the four philosophical dimensions, identified the required learning environment, and the learning, teaching and assessment approaches required to educate person-centred healthcare practitioners.Conclusion: This article represents steps to foster a more focused and engaging way of implicitly and explicitly embedding person-centred care in curricula. Our theoretical framework has enabled us to consider the different layers of practice while staying true to the purpose of curriculum design. The presentation of the framework in this article makes it available for wider critique to those with an interest in this area of study.Implications for practice: The draft framework provides an opportunity for curriculum teams to critically reflect on and have dialogue around current curricula Person-centred curricula have the potential to improve service-user experiences of care Prepared person-centred practitioners will contribute to person-centred cultures Students and practitioners will experience person-centredness Practitioners will be bold and innovativehttps://doi.org/10.19043/ipdj.10Suppl2.00410pubpubSuppl

    Reconstructing ‘the Alcoholic’: Recovering from Alcohol Addiction and the Stigma this Entails

    Get PDF
    Public perception of alcohol addiction is frequently negative, whilst an important part of recovery is the construction of a positive sense of self. In order to explore how this might be achieved, we investigated how those who self-identify as in recovery from alcohol problems view themselves and their difficulties with alcohol and how they make sense of others’ responses to their addiction. Semi-structured interviews with six individuals who had been in recovery between 5 and 35 years and in contact with Alcoholics Anonymous were analysed using Interpretative Phenomenological Analysis. The participants were acutely aware of stigmatising images of ‘alcoholics’ and described having struggled with a considerable dilemma in accepting this identity themselves. However, to some extent they were able to resist stigma by conceiving of an ‘aware alcoholic self’ which was divorced from their previously unaware self and formed the basis for a new more knowing and valued identity

    Microdevices for extensional rheometry of low viscosity elastic liquids : a review

    Get PDF
    Extensional flows and the underlying stability/instability mechanisms are of extreme relevance to the efficient operation of inkjet printing, coating processes and drug delivery systems, as well as for the generation of micro droplets. The development of an extensional rheometer to characterize the extensional properties of low viscosity fluids has therefore stimulated great interest of researchers, particularly in the last decade. Microfluidics has proven to be an extraordinary working platform and different configurations of potential extensional microrheometers have been proposed. In this review, we present an overview of several successful designs, together with a critical assessment of their capabilities and limitations

    Somatic diseases in patients with schizophrenia in general practice: their prevalence and health care

    Get PDF
    BACKGROUND: Schizophrenia patients frequently develop somatic co-morbidity. Core tasks for GPs are the prevention and diagnosis of somatic diseases and the provision of care for patients with chronic diseases. Schizophrenia patients experience difficulties in recognizing and coping with their physical problems; however GPs have neither specific management policies nor guidelines for the diagnosis and treatment of somatic co-morbidity in schizophrenia patients. This paper systematically reviews the prevalence and treatment of somatic co-morbidity in schizophrenia patients in general practice. METHODS: The MEDLINE, EMBASE, PsycINFO data-bases and the Cochrane Library were searched and original research articles on somatic diseases of schizophrenia patients and their treatment in the primary care setting were selected. RESULTS: The results of this search show that the incidence of a wide range of diseases, such as diabetes mellitus, the metabolic syndrome, coronary heart diseases, and COPD is significantly higher in schizophrenia patients than in the normal population. The health of schizophrenic patients is less than optimal in several areas, partly due to their inadequate help-seeking behaviour. Current GP management of such patients appears not to take this fact into account. However, when schizophrenic patients seek the GP's help, they value the care provided. CONCLUSION: Schizophrenia patients are at risk of undetected somatic co-morbidity. They present physical complaints at a late, more serious stage. GPs should take this into account by adopting proactive behaviour. The development of a set of guidelines with a clear description of the GP's responsibilities would facilitate the desired changes in the management of somatic diseases in these patients

    Perceived neighborhood safety and incident mobility disability among elders: the hazards of poverty

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>We investigated whether lack of perceived neighborhood safety due to crime, or living in high crime neighborhoods was associated with incident mobility disability in elderly populations. We hypothesized that low-income elders and elders at retirement age (65 – 74) would be at greatest risk of mobility disability onset in the face of perceived or measured crime-related safety hazards.</p> <p>Methods</p> <p>We conducted the study in the New Haven Established Populations for Epidemiologic Studies of the Elderly (EPESE), a longitudinal cohort study of community-dwelling elders aged 65 and older who were residents of New Haven, Connecticut in 1982. Elders were interviewed beginning in 1982 to assess mobility (ability to climb stairs and walk a half mile), perceptions of their neighborhood safety due to crime, annual household income, lifestyle characteristics (smoking, alcohol use, physical activity), and the presence of chronic co-morbid conditions. Additionally, we collected baseline data on neighborhood crime events from the New Haven Register newspaper in 1982 to measure local area crime rates at the census tract level.</p> <p>Results</p> <p>At baseline in 1982, 1,884 elders were without mobility disability. After 8 years of follow-up, perceiving safety hazards was associated with increased risk of mobility disability among elders at retirement age whose incomes were below the federal poverty line (HR 1.56, 95% CI 1.02 – 2.37). No effect of perceived safety hazards was found among elders at retirement age whose incomes were above the poverty line. No effect of living in neighborhoods with high crime rates (measured by newspaper reports) was found in any sub-group.</p> <p>Conclusion</p> <p>Perceiving a safety hazard due to neighborhood crime was associated with increased risk of incident mobility disability among impoverished elders near retirement age. Consistent with prior literature, retirement age appears to be a vulnerable period with respect to the effect of neighborhood conditions on elder health. Community violence prevention activities should address perceived safety among vulnerable populations, such as low-income elders at retirement age, to reduce future risks of mobility disability.</p

    Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>The nuclear factor-κB (NF-κB) family is a set of transcription factors with key roles in the induction of the inflammatory response and may be the link between inflammation and cancer development. This pathway has been shown to influence ovarian epithelial tissue repair. Inhibitors of κB (IκB) prevent NF-κB activation by sequestering NF-κB proteins in the cytoplasm until IκB proteins are phosphorylated and degraded.</p> <p>Methods</p> <p>We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in <it>NFKBIA </it>and <it>NFKBIB </it>(the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.</p> <p>Results</p> <p>The minor allele for one synonymous SNP in <it>NFKBIA</it>, rs1957106, was associated with decreased risk (p = 0.03).</p> <p>Conclusion</p> <p>Considering the number of single-SNP tests performed and null gene-level results, we conclude that <it>NFKBIA </it>and <it>NFKBIB </it>are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.</p
    corecore