Membrane targeting of palmitoylated Wnt and Hedgehog revealed by chemical probes

AbstractPalmitoylation of the Wnt and Hedgehog proteins is critical for maintaining their physiological functions. To date, there are no reported studies that characterize the cellular distribution of the palmitoylated forms of these proteins. Here, we describe the subcellular localization of palmitoylated Wnt and Sonic Hedgehog by using a highly sensitive and non-radioactive labeling method that utilizes alkynyl palmitic acid. We show that palmitoylated Wnt and Sonic Hedgehog localize to cellular membrane fractions only, highlighting a role for palmitoylation in the membrane association of these proteins. The method described herein has the utility to validate inhibitors of Wnt and Hedgehog acyltransferases in drug discovery, and enables further investigations of the role of palmitoylation in the secretion and signaling of these proteins

Criterios de implementación ISO 14001:2015 caso estudio sector industrial.

Criterios de implementación ISO 14001:2015 caso estudio sector industrial.El siguiente estudio de caso, corresponde al análisis de los diferentes procesos y etapas según la norma ISO 14001:2015 de una empresa ibaguereña dedicada al procesamiento y comercialización de Feldespato. La organización es pionera a nivel local y regional en la gestión y control ambiental, implementando nuevos procesos y tecnologías limpias eficientes con el ambiente. El plan de gestión ambiental de la empresa, se caracteriza por disponer de un sistema de calidad encaminado en la protección de los recursos naturales de la zona aledaña a la mina y la mitigación de impactos ambientales producidos en las diferentes etapas que se desarrollan a lo largo de la extracción, procesamiento y distribución del feldespato (alimentación, trituración, molienda, transporte, captación de finos y separación magnética). Los resultados, a partir del análisis detallado de los procesos y etapas de la empresa, evidencian que esta cumple con la mayor parte de los requerimientos establecidos en la norma ISO 14001 de 2015, respecto al sistema de gestión ambiental SGA, ya que tiene como objetivo, proteger el medio ambiente y mitigar los impactos ambientales causados a lo largo de sus diferentes procesos en el área de influencia. Por otro lado, cada una de las dependencias que conforman la organización, tienen dentro de sus políticas de calidad de gestión y control, implementar planes de mejoramiento, con el fin de afianzar el ciclo PHVA institucional, estableciendo un mejoramiento continuo de diferentes procesos. Palabras claves: Industria, Feldespato, ISO 14001 de 2015, SGA, Ciclo PHVAThe following study of case, it corresponds to the analysis of the different processes and stages according to the ISO norm 14001:2015 of a company ibaguereña dedicated to the processing and commercialization of Feldspar. The organization is pioneering to local and regional level in the management and environmental control, implementing new processes and clean efficient technologies with the environment. The plan of environmental management of the company, it is characterized for having a qualit system directed in the protection of the natural resources of the bordering zone to the mine and the mitigation of environmental impacts produced in the different stages that develop along the extraction, processing and distribution of the feldspar (supply, crushing, grinding, transport, capture of thin and magnetic separation). The results, from the detailed analysis of the processes and stages of the company, demonstrate that this one fulfills with most of the requirements established in the ISO norm 14001 of 2015, with regard to the system of environmental management SGA, since it has as aim, to protect the environment and to mitigate the environmental impacts caused along his different processes in the area of influence. On the other hand, each of the dependences that shape the organization, have inside his policies of quality of management and control, implement plans of improvement, in order to guarantee the cycle institutional PHVA, establishing a constant improvement of different processes. Key words: Industry, Feldspar, ISO 14001 of 2015, SGA, Cycle PHV

First Colombian Multicentric Newborn Screening for Congenital Toxoplasmosis

Congenital toxoplasmosis can result in permanent sequel as blindness or neurological damage in children and it seems to be more severe in South America than in other continents. There is a lack of information about this frequency in Colombia, where no control program is established, although it is a recognized cause of potentially preventable congenital blindness. We propose the first Colombian multicentric study to determine the frequency and impact of congenital toxoplasmosis. More than 15,000 newborns in seven cities were studied. Newborns were tested at birth by doing a cord blood test for toxoplasmosis. Additionally, children from mothers with history of toxoplasmosis acquired during pregnancy were recalled for a follow-up. The program identified fifteen children otherwise undiagnosed; three of these children died as consequence of congenital toxoplasmosis. The frequency of the congenital infection varied significantly between cities, being higher in Armenia and Florencia, intermediate in Bogota, Bucaramanga and Barranquilla and very low in western cities such as Cucuta and Riohacha. For the first time a significant correlation was found between mean rainfall at the city and the incidence of this congenital infection

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

Interleukin-2: biology, design and application

Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating anti-tumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation

Development of a novel class of interleukin-2 immunotherapies for metastatic cancer

Tumour immunotherapy, and particularly immue checkpoint inhibitors, have resulted in considerable response rates in patients with metastatic cancer. However, most of these approaches are limited to immunogenic tumours. Based on its ability to stimulate cytotoxic T cells, interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and metastatic kidney cancer. Clinical efficacy achieved through high doses is countered by severe adverse effects on vascular endothelial cells and various organs, a short in vivo half-life, and the stimulation of regulatory T cells that counteract antitumour immune responses. Accumulating evidence suggests that IL-2 receptor β (CD122)-biased IL-2 formulations address the shortcomings of IL-2 cancer immunotherapy. This knowledge stems from studies using CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2 complexes), which preferentially stimulate CD8+ T cells, while interaction with regulatory T cells and vascular endothelial cells is disfavoured by the anti-IL-2 antibody used. CD122-biased IL-2 complexes, when assessed in different mouse cancer models, cause stronger antitumour effects and significantly less adverse effects than high-dose IL-2. A recently developed and characterised anti-human IL-2 antibody, termed NARA1, forms human CD122-biased IL-2 complexes. Alternative strategies based on this concept, such as site-directed pegylation and mutation of IL-2, have also been pursued. Moreover, recent data have shown that a combination of CD122-biased IL-2 formulations with immune checkpoint inhibitors, antigen-specific immunotherapy and epigenetic modifying drugs results in synergistic anti-cancer effects in various tumour models. Thus, CD122-biased IL-2 approaches constitute a novel class of immunotherapy for metastatic cancer that has the potential to complement and increase the efficacy of other antitumour strategies

Epigenetic mechanisms of tumor resistance to immunotherapy

The recent impact of cancer immunotherapies has firmly established the ability and importance of the immune system to fight malignancies. However, the intimate interaction between the highly dynamic tumor and immune cells leads to a selection process driven by genetic and epigenetic processes. As the molecular pathways of cancer resistance mechanisms to immunotherapy become increasingly known, novel therapeutic targets are being tested in combination with immune-stimulating approaches. We here review recent insights into the molecular mechanisms of tumor resistance with particular emphasis on epigenetic processes and place these in the context of previous models

Endogenous polyclonal anti-IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation

BACKGROUND Particular neutralizing mAbs to certain cytokines act as agonists in vivo through protection of the cytokine's active site and prolongation of its half-life. Although this principle might be useful for targeted immunotherapy, its role in the pathogenesis of inflammation and autoimmunity is unclear. OBJECTIVE We sought to determine whether slight, structurally nonrelevant modifications of the prototypic proinflammatory cytokine IL-1β during an immune response could elicit polyclonal anti-IL-1β antibody responses that modulated IL-1β's in vivo activity. METHODS We engineered 2 different IL-1β variants, thereby mimicking the process of cytokine modification occurring during inflammation, and conjugated them to virus-like particles, followed by immunization of mice. The resulting polyclonal anti-IL-1β antibody responses were assessed by using in vitro and in vivo assays, as well as 2 relevant (auto-) inflammatory murine models. RESULTS Although antibody responses generated to one variant were potently inhibiting IL-1β, antibody responses induced by the other variant even potentiated the in vivo effects of IL-1β; the latter led to enhanced morbidity in 2 different IL-1β-mediated mouse models, including a model of inflammatory bowel disease and an inflammatory arthritis model. CONCLUSION These data demonstrate that endogenous polyclonal anti-cytokine antibody responses can enhance the cytokine's activity in inflammatory and autoimmune diseases