562 research outputs found

    A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

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    BACKGROUND: Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. METHODS: We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. RESULTS: We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. CONCLUSIONS: Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases

    A comparative framework: how broadly applicable is a 'rigorous' critical junctures framework?

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    The paper tests Hogan and Doyle's (2007, 2008) framework for examining critical junctures. This framework sought to incorporate the concept of ideational change in understanding critical junctures. Until its development, frameworks utilized in identifying critical junctures were subjective, seeking only to identify crisis, and subsequent policy changes, arguing that one invariably led to the other, as both occurred around the same time. Hogan and Doyle (2007, 2008) hypothesized ideational change as an intermediating variable in their framework, determining if, and when, a crisis leads to radical policy change. Here we test this framework on cases similar to, but different from, those employed in developing the exemplar. This will enable us determine whether the framework's relegation of ideational change to a condition of crisis holds, or, if ideational change has more importance than is ascribed to it by this framework. This will also enable us determined if the framework itself is robust, and fit for the purposes it was designed to perform — identifying the nature of policy change

    UK survey of occupational therapist’s and physiotherapist’s experiences and attitudes towards hip replacement precautions and equipment

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    Background: Total hip replacement (THR) is one of the most common orthopaedic procedures in the United Kingdom (UK). Historically, people following THR have been provided with hip precautions and equipment such as: raised toilet seats and furniture rises, in order to reduce the risks of dislocation post-operation. The purpose of this study was to determine current practices in the provision of these interventions in the UK for people following primary THR. Methods: A 27-question, self-administered online survey was developed and distributed to UK physiotherapists and occupational therapists involved in the management of people following primary THR (target respondents). The survey included questions regarding the current practices in the provision of equipment and hip precautions for THR patients, and physiotherapist’s and occupational therapist’s attitudes towards these practices. The survey was disseminated through print and web-based/social media channels. Results: 170 health professionals (87 physiotherapists and 83 occupational therapists), responded to the survey. Commonly prescribed equipment in respondent’s health trusts were raised toilet seats (95%), toilet frames and rails (88%), furniture raises (79%), helping hands/grabbers (77%), perching stools (75%) and long-handled shoe horns (75%). Hip precautions were routinely prescribed by 97% of respondents. Hip precautions were most frequently taught in a pre-operative group (52% of respondents). Similarly equipment was most frequently provided pre-operatively (61% respondents), and most commonly by occupational therapists (74% respondents). There was variability in the advice provided on the duration of hip precautions and equipment from up to six weeks post-operatively to life-time usage. Conclusions: Current practice on hip precautions and provision of equipment is not full representative of clinician’s perceptions of best care after THR. Future research is warranted to determine whether and to whom hip precautions and equipment should be prescribed post-THR as opposed to the current ‘blanket’ provision of equipment and movement restriction provided in UK practice

    Photoswitchable diacylglycerols enable optical control of protein kinase C.

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    Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

    Early Vegetation Development on an Exposed Reservoir: Implications for Dam Removal

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    The 4-year drawdown of Horsetooth Reservoir, Colorado, for dam maintenance, provides a case study analog of vegetation response on sediment that might be exposed from removal of a tall dam. Early vegetation recovery on the exposed reservoir bottom was a combination of (1) vegetation colonization on bare, moist substrates typical of riparian zones and reservoir sediment of shallow dams and (2) a shift in moisture status from mesic to the xeric conditions associated with the pre-impoundment upland position of most of the drawdown zone. Plant communities changed rapidly during the first four years of exposure, but were still substantially different from the background upland plant community. Predictions from the recruitment box model about the locations of Populus deltoides subsp. monilifera (plains cottonwood) seedlings relative to the water surface were qualitatively confirmed with respect to optimum locations. However, the extreme vertical range of water surface elevations produced cottonwood seed regeneration well outside the predicted limits of drawdown rate and height above late summer stage. The establishment and survival of cottonwood at high elevations and the differences between the upland plant community and the community that had developed after four years of exposure suggest that vegetation recovery following tall dam removal will follow a trajectory very different from a simple reversal of the response to dam construction, involving not only long time scales of establishment and growth of upland vegetation, but also possibly decades of persistence of legacy vegetation established during the reservoir to upland transition

    Historical institutionalism and the politics of sustainable energy transitions: a research agenda

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    Improving the understanding of the politics of sustainable energy transitions has become a major focus for research. This paper builds on recent interest in institutionalist approaches to consider in some depth the agenda arising from a historical institutionalist perspective on such transitions. It is argued that historical institutionalism is a valuable complement to socio-technical systems approaches, offering tools for the explicit analysis of institutional dynamics that are present but implicit in the latter framework, opening up new questions and providing useful empirical material relevant for the study of the wider political contexts within which transitions are emerging. Deploying a number of core concepts including veto players, power, unintended consequences, and positive and negative feedback in a variety of ways, the paper explores research agendas in two broad areas: understanding diversity in transition outcomes in terms of the effects of different institutional arrangements, and the understanding of transitions in terms of institutional development and change. A range of issues are explored, including: the roles of electoral and political institutions, regulatory agencies, the creation of politically credible commitment to transition policies, power and incumbency, institutional systems and varieties of capitalism, sources of regime stability and instability, policy feedback effects, and types of gradual institutional change. The paper concludes with some observations on the potential and limitations of historical institutionalism, and briefly considers the question of whether there may be specific institutional configurations that would facilitate more rapid sustainable energy transitions

    An unusual presentation of Castleman's Disease:a case report

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    BACKGROUND: Castleman's disease (CD), a rare condition of uncertain etiology, involves a massive proliferation of lymphoid tissues and typically presents as mediastinal masses. We describe a patient with CD who presented with diffuse adenopathy involving the inguinal, paratracheal, retroperitoneal, axillary, and pelvic regions. CASE PRESENTATION: Case report describing presentation, work-up, management and clinical course of a patient with Castleman's disease in the setting of a county hospital in metropolitan area. Patient was treated with chemotherapeutic agents. CONCLUSIONS: To our knowledge, this represents the first case of CD involving an HIV-positive patient with a negative Human Herpes Virus (HHV-8) viral panel. Because patients with similar clinical histories are at high risk for the development of non-Hodgkin's lymphoma and Kaposi sarcoma, regular medical surveillance is recommended
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