Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells

Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells

Reducing the time-lag between onset of chest pain and seeking professional medical help: a theory-based review

Background: Research suggests that there are a number of factors which can be associated with delay in a patient seeking professional help following chest pain, including demographic and social factors. These factors may have an adverse impact on the efficacy of interventions which to date have had limited success in improving patient action times. Theory-based methods of review are becoming increasingly recognised as important additions to conventional systematic review methods. They can be useful to gain additional insights into the characteristics of effective interventions by uncovering complex underlying mechanisms. Methods: This paper describes the further analysis of research papers identified in a conventional systematic review of published evidence. The aim of this work was to investigate the theoretical frameworks underpinning studies exploring the issue of why people having a heart attack delay seeking professional medical help. The study used standard review methods to identify papers meeting the inclusion criterion, and carried out a synthesis of data relating to theoretical underpinnings. Results: Thirty six papers from the 53 in the original systematic review referred to a particular theoretical perspective, or contained data which related to theoretical assumptions. The most frequently mentioned theory was the self-regulatory model of illness behaviour. Papers reported the potential significance of aspects of this model including different coping mechanisms, strategies of denial and varying models of treatment seeking. Studies also drew attention to the potential role of belief systems, applied elements of attachment theory, and referred to models of maintaining integrity, ways of knowing, and the influence of gender. Conclusions: The review highlights the need to examine an individual’s subjective experience of and response to health threats, and confirms the gap between knowledge and changed behaviour. Interventions face key challenges if they are to influence patient perceptions regarding seriousness of symptoms; varying processes of coping; and obstacles created by patient perceptions of their role and responsibilities. A theoretical approach to review of these papers provides additional insight into the assumptions underpinning interventions, and illuminates factors which may impact on their efficacy. The method thus offers a useful supplement to conventional systematic review methods

An in vivo humanized model to study homing and sequestration of plasmodium falciparum transmission stages in the bone marrow

Introduction Recent evidence suggests that the bone marrow (BM) plays a key role in the diffusion of P. falciparum malaria by providing a "niche" for the maturation of the parasite gametocytes, responsible for human-to-mosquito transmission. Suitable humanized in vivo models to study the mechanisms of the interplay between the parasite and the human BM components are still missing. MethodsWe report a novel experimental system based on the infusion of immature P. falciparum gametocytes into immunocompromised mice carrying chimeric ectopic ossicles whose stromal and bone compartments derive from human osteoprogenitor cells. ResultsWe demonstrate that immature gametocytes home within minutes to the ossicles and reach the extravascular regions, where they are retained in contact with different human BM stromal cell types. DiscussionOur model represents a powerful tool to study BM function and the interplay essential for parasite transmission in P. falciparum malaria and can be extended to study other infections in which the human BM plays a role

Exposure to b‐LED light while exerting antimicrobial activity on Gram‐negative and ‐positive bacteria promotes transient EMT‐like changes and growth arrest in keratinocytes

While blue LED (b‐LED) light is increasingly being studied for its cytotoxic activity towards bacteria in therapy of skin‐related infections, its effects on eukaryotic cells plasticity are less well characterized. Moreover, since different protocols are often used, comparing the effect of b‐LED towards both microorganisms and epithelial surfaces may be difficult. The aim of this study was to analyze, in the same experimental setting, both the bactericidal activity and the effects on human keratinocytes. Exposure to b‐LED induced an intense cytocidal activity against Grampositive (i.e, Staphylococcus aureus) and Gram‐negative (i.e., Pseudomonas aeruginosa) bacteria associated with catheter‐related infections. Treatment with b‐LED of a human keratinocyte cell line induced a transient cell cycle arrest. At the molecular level, exposure to b‐LED induced a transient downregulation of Cyclin D1 and an upregulation of p21, but not signs of apoptosis. Interestingly, a transient induction of phosphor‐histone γ‐H2Ax, which is associated with genotoxic damages, was observed. At the same time, keratinocytes underwent a transient epithelial to mesenchymal transition (EMT)‐like phenotype, characterized by E‐cadherin downregulation and SNAIL/SLUG induction. As a functional readout of EMT induction, a scratch assay was performed. Surprisingly, b‐LED treatment provoked a delay in the scratch closure. In conclusion, we demonstrated that b‐ LED microbicidal activity is associated with complex responses in keratinocytes that certainly deserve further analysis

La percepción del paciente crítico sobre los cuidados enfermeros: una aproximación al concepto de satisfacción

Introducción: El grado de satisfacción es un indicador fundamental de la calidad asistencial. Existen numerosos instrumentos que miden la satisfacción con los cuidados enfermeros, aunque no responden a la realidad del paciente crítico ni a nuestro contexto. Objetivos: Explorar y comprender la satisfacción de los pacientes ingresados en Cuidados Intensivos de un hospital nivel iii con los cuidados enfermeros, para definir e identificar las dimensiones del concepto de satisfacción desde su punto de vista. Material y métodos: Estudio cualitativo según la teoría fundamentada en 3 unidades de Cuidados Intensivos de 34 boxes individuales. Muestreo teórico. La muestra, tras la saturación de datos, fue de 19 participantes. La recogida de datos fue a través de la entrevista en profundidad y diario de campo. Análisis de contenido según teoría fundamentada. Se siguieron los criterios de rigor de Guba y Lincoln. Informe favorable del comité de ética del centro y consentimiento informado. Resultados: Emergen 4 categorías: definición y dimensiones del concepto de satisfacción, expectativas y vivencias. Los participantes incluyen en su definición de satisfacción las dimensiones: competencias profesionales, cuidados humanos, técnicos y continuados. La combinación de estos elementos produce sentimientos de seguridad, tranquilidad, estar vigilado, sentirse persona, percibiendo una relación cercana y de confianza con la enfermera que realiza cuidados individualizados. Conclusiones: La definición y las dimensiones del concepto de satisfacción desde el punto de vista del paciente muestran los aspectos importantes para la persona además de clarificar sus dimensiones, permitiendo la construcción de instrumentos más acordes con el contexto y su percepción real

Incentive-based Approaches to Sustainable Fisheries

The failures of traditional target-species management have led many to propose an ecosystem approach to fisheries to promote sustainability. The ecosystem approach is necessary, especially to account for fishery-ecosystem interactions, but by itself is not sufficient to address two important factors contributing to unsustainable fisheries: inappropriate incentives bearing on fishers and the ineffective governance that frequently exists in commercial, developed fisheries managed primarily by total-harvest limits and input controls. We contend that much greater emphasis must be placed on fisher motivation when managing fisheries. Using evidence from more than a dozen natural experiments in commercial fisheries, we argue that incentive-based approaches that better specify community and individual harvest or territorial rights and price ecosystem services and that are coupled with public research, monitoring, and effective oversight promote sustainable fisheries

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses