Sterile inflammation can be initiated by innate immune recognition of markers of tissue injury termed damage-associated molecular patterns (DAMPs). DAMP recognition by dendritic cells (DCs) has also ...been postulated to lead to T cell responses to foreign antigens in tumors or allografts. Many DAMPs represent intracellular contents that are released upon cell damage, notably after necrosis. In this regard, we have previously described DNGR-1 (CLEC9A) as a DC-restricted receptor specific for an unidentified DAMP that is exposed by necrotic cells and is necessary for efficient priming of cytotoxic T cells against dead cell-associated antigens. Here, we have shown that the DNGR-1 ligand is preserved from yeast to man and corresponds to the F-actin component of the cellular cytoskeleton. The identification of F-actin as a DNGR-1 ligand suggests that cytoskeletal exposure is a universal sign of cell damage that can be targeted by the innate immune system to initiate immunity.
► DNGR-1 recognizes a cell-associated ligand conserved from yeast to man ► F-actin is the ligand for DNGR-1 ► F-actin exposure permits DNGR-1 recognition of necrotic cells
DNGR-1 is a C-type lectin receptor that binds F-actin exposed by dying cells and facilitates cross-presentation of dead cell-associated antigens by dendritic cells. Here we present the structure of ...DNGR-1 bound to F-actin at 7.7 Å resolution. Unusually for F-actin binding proteins, the DNGR-1 ligand binding domain contacts three actin subunits helically arranged in the actin filament, bridging over two protofilaments, as well as two neighboring actin subunits along one protofilament. Mutation of residues predicted to mediate ligand binding led to loss of DNGR-1-dependent cross-presentation of dead cell-associated antigens, formally demonstrating that the latter depends on F-actin recognition. Notably, DNGR-1 has relatively modest affinity for F-actin but multivalent interactions allow a marked increase in binding strength. Our findings shed light on modes of actin binding by cellular proteins and reveal how extracellular detection of cytoskeletal components by dedicated receptors allows immune monitoring of loss of cellular integrity.
•DNGR-1 binds to a site formed by three actin filament subunits•DNGR-1 binding site is distinct among F-actin binding proteins•Avidity allows DNGR-1 to efficiently respond to F-actin•Binding to F-actin fully accounts for DNGR-1-mediated cross-presentation
DNGR-1 is a dendritic cell receptor that binds F-actin exposed on dead cells and promotes cross-presentation of associated antigens. Reis e Sousa and colleagues solved the structure of the DNGR-1:F-actin complex and analyzed the biophysics of receptor-ligand interaction, providing insights into innate immune recognition of cell death.
Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the ...receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to
triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the
orthologue of Syk, and Src42A, a
Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes the evolution of adaptive immunity.
Damage-associated molecular patterns (DAMPs) are molecules exposed or released by dead cells that trigger or modulate immunity and tissue repair. In vertebrates, the cytoskeletal component F-actin is ...a DAMP specifically recognised by DNGR-1, an innate immune receptor. Previously we suggested that actin is also a DAMP in
by inducing STAT-dependent genes (<xref ref-type="bibr" rid="bib10">Srinivasan et al., 2016 ). Here, we revise that conclusion and report that α-actinin is far more potent than actin at inducing the same STAT response and can be found in trace amounts in actin preparations. Recombinant expression of actin or α-actinin in bacteria demonstrated that only α-actinin could drive the expression of STAT target genes in
. The response to injected α-actinin required the same signalling cascade that we had identified in our previous work using actin preparations. Taken together, these data indicate that α-actinin rather than actin drives STAT activation when injected into
.
Patient satisfaction is viewed as a significant indicator of quality of care. More specifically, improving patient satisfaction related to communication about medications and potential side effects ...can improve healthcare outcomes. Patient satisfaction scores related to medication side effects on a neuro-medical surgical unit were monitored following a quality improvement program. These patients frequently experience cognitive impairment and functional difficulties that can affect the way they understand and handle medications. The purpose of this quality improvement practice change was to (a) develop an educational approach for post acute neurosurgical patients and (b) evaluate whether the use of the approach is successful in improving patient satisfaction scores related to medication education on side effects. The quality improvement program interventions included (a) patient informational handouts inserted into admission folders, (b) nurse education about the importance of providing education on side effects to patient and discussion of their involvement with the program, (c) unit flyers with nurse education, and (d) various communications with bedside nurses through personal work mail and emails. The primary focus was for nurses to employ the "teach back" method to review and reinforce the medication side-effect teaching with patients. Evaluation of the data showed an increase in patient satisfaction after the implementation of the "Always Ask" program.
A new era in the ICU: the case for telemedicine Yeo, Will; Ahrens, Susan L Grass; Wright, Tim
Critical care nursing quarterly,
2012 Oct-Dec, 2012-10-00, 20121001, Letnik:
35, Številka:
4
Journal Article
Recenzirano
Management of the patient in the intensive care unit requires constant vigilance and monitoring. The nursing staff, and physicians must be readily available to alter therapy in response to adverse ...physiological changes and life-threatening events. In the face of limited staffing and overwhelming workloads, telemedicine has become a mainstay in ensuring safety for the critically ill patient. Nurses must respond to the challenge to utilize every aspect of this technology, and to become an active partner in improving the utilization of this tool for accessing physician interface and ensuring support when decision-making and immediate actions are required for optimum clinical outcomes.
To what extent does soccer increase the capability of the homeless and those living on the street? This study addresses this question by focusing on the ways in which the Homeless World Cup and ...Street Soccer (Scotland) have impacted upon the lives of some individuals. Primary source data obtained from a series of interviews are situated within Sen's capability approach to social choice theory. The implications of the study contribute to policy by supporting the idea that sport can contribute as a resource of hope through the development of capability that impacts upon life chances and choices. It adds to a growing number of applied studies of sport that have critically used the work of Sen and it advances the way in which this body of work has been utilized in sport and related areas.
There is a continuing debate about the contribution of sport and sport for development and peace (SDP) to both the theory and practice of social justice. At the same time the policy world is showing ...strong indications that it is seeking politically smarter ways of understanding what it means to foster social justice, development, and inclusive peace processes. This position statement is committed to sport actively being seen to be playing a part in addressing the challenges that face humanity in the 21st century. The proposition is that sport and SDP are served well by a capability approach (CA) as a framework that enables the construction of the common good. The article considers a CA for social justice prior to a discussion of sport, capability, and the common good, which positions sport as a resource of hope in fostering politically smarter cultural relations.
Whereas mechanical stimulation is essential for bone homeostasis, straining of larger magnitude promotes bone regeneration by directing cell differentiation and proliferation and influencing the gene ...expression patterns of osteoblasts, which play a vital role in fracture healing by producing and mineralizing osteoid matrix. To elucidate the molecular mechanisms underlying the response of osteoblasts to mechanical strains comparable to those occurring during bone regeneration, MC3T3 S4 (MC4) osteoblast‐like cells were stretched in vitro. Analysis based on microarray expression profiling during the first 8 h after straining showed 674 differentially expressed genes. The response to mechanical strain can be divided in an immediate‐early response (IER) and later responses. Examination of the ∼40 genes differentially expressed within the first 60 min, including 11 involved in regulating gene transcription, showed both promiscuous IER genes such as Fos that are upregulated by multiple extracellular stimuli, as well as a number of genes previously shown in neurons to be induced preferentially by depolarization (IPD‐IER). Selected differentially expressed genes were validated after mechanical straining and KCl‐induced depolarization. The effects of inhibitors for protein kinase A, mitogen‐activated protein kinase, and calcineurin pathways were assessed in separate experiments by quantitative RT‐PCR and shown to have differential effects on the response of MC4 cells and primary calvaria osteoblasts to both mechanical straining and KCl‐induced depolarization. Therefore, our results showed the existence of two distinct pathways that mediate the IER of osteoblasts to large‐magnitude mechanical straining and suggest that the IER to depolarizing stimuli is conserved in cell types as different as osteoblasts and neurons.
Originating from Florence Nightingale's work, using evidence to determine the best patient care has been the ethos for nursing practice. Evidence-based practice (EBP) requires structures and ...processes "to evaluate existing nursing practice" and "translate new knowledge into nursing practice" for positive patient outcomes. This reflects Donabedian's quality improvement framework of structure, process, and outcomes. One essential structure for promoting effective EBP use by nurses is strong leadership. The nurse executive team at a Midwestern 350-bed community hospital conducted a gap analysis to determine EBP application in the nursing department and found a glaring deficit. hi a large nationwide EBP study, nurses reported they lacked literacy skills to search and interpret research. This illustrates that leaders' verbal support alone is insufficient. No EBP projects were in production by nurse leaders before the program, creating an opportunity to promote design and completion of evidence-based protocols. Demographic data indicated 74% of leaders reported 16 or more years' nursing experience, and all had some exposure to EBP.
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