Hyperglycemia triggers HIPK2 protein degradation

Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2. We focused on the effect of high glucose (HG) on HIPK2 protein stability and the underlying mechanisms. We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2-induced p53 apoptotic activity. HG-triggered HIPK2 protein downregulation was rescued by both proteasome inhibitor MG132 and by protein phosphatase inhibitors Calyculin A (CL-A) and Okadaic Acid (OA). Looking for the phosphatase involved, we found that protein phosphatase 2A (PP2A) induced HIPK2 degradation, as evidenced by directly activating PP2A with FTY720 or by silencing PP2A with siRNA in HG condition. The effect of PP2A on HIPK2 protein degradation could be in part due to hypoxia-inducible factor-1 (HIF-1) activity which has been previously shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases. Validation analysed performed with HIF-1α dominant negative or with silencing of Siah2 ubiquitin ligase clearly showed rescue of HG-induced HIPK2 degradation. These findings demonstrate how hyperglycemia, through a complex protein cascade, induced HIPK2 downregulation and consequently impaired p53 apoptotic activity, revealing a novel link between diabetes/obesity and tumor resistance to therapies

An Innovative Cloud-based Supervision System for the Integration of RPAS in Urban Environments

This paper proposes the outline of a Cloud-based supervision system for Remotely Piloted Aircraft Systems (RPAS), which are operating in urban environments. The novelty of this proposed concept is dual: (i) a Cloud-based supervision system focusing on safety and robustness, (ii) the definition of technical requirements allowing the RPAS to fly over urban areas, as a possible evolution of drone use in future smart cities. A new concept for the regulatory issues is also proposed, compared with existing worldwide regulations. The Cloud framework is intended to be an automated system for path planning and control of RPAS flying under its coverage, and not limited to conventional remote control as if supervised by a human pilot. Future works will be based on the experimental validation of the proposed concept in an urban area of Turin (Italy)

Regulation of G protein-coupled receptor kinase subtypes by calcium sensor proteins

AbstractG protein-coupled receptor homologous desensitization is intrinsically related to the function of a class of S/T kinases named G protein-coupled receptor kinases (GRK). The GRK family is composed of six cloned members, named GRK1 to 6. Studies from different laboratories have demonstrated that different calcium sensor proteins (CSP) can selectively regulate the activity of GRK subtypes. In the presence of calcium, rhodopsin kinase (GRK1) is inhibited by the photoreceptor-specific CSP recoverin through direct binding. Several other recoverin homologues (including NCS 1, VILIP 1 and hippocalcin) are also able to inhibit GRK1. The ubiquitous calcium-binding protein calmodulin (CaM) can inhibit GRK5 with a high affinity (IC50=40–50 nM). A direct interaction between GRK5 and Ca2+/CaM was documented and this binding does not influence the catalytic activity of the kinase, but rather reduced GRK5 binding to the membrane. These studies suggest that CSP act as functional analogues in mediating the regulation of different GRK subtypes by Ca2+. This mechanism is, however, highly selective with respect to the GRK subtypes: while GRK1, but not GRK2 and GRK5, is regulated by recoverin and other NCS, GRK4, 5 and 6, that belong to the GRK4 subfamily, are potently inhibited by CaM, which had little or no effect on members of other GRK subfamilies

The theory of the four discourses: a kaleidoscopic tool

Este artículo presenta los primeros resultados alcanzados en el marco de la investigación “La inclusión escolar desde la perspectiva de la teoría de los discursos”, dirigida por la Lic. Laura Kiel en la Universidad Nacional Tres de Febrero. Propone un abordaje lógico del lazo social en las escuelas. Se presenta un desarrollo teórico sobre los cuatro discursos. Queda planteada la hipótesis de trabajo sobre los efectos de la generalización del discurso universitario en el campo social y las consecuencias de que este discurso haya quedado funcionando solo en los ámbitos escolares. A partir de la rotación de discursos, se define la noción de “entrevenir discursivo” entendido como la maniobra por la cual un discurso da lugar a otro.This paper presents the first results achieved within the framework of the research “School inclusion from the perspective of the theory of discourses”, directed by Laura Kiel at the Tres de Febrero National University. It proposes a logical approach to the social bond in schools, while presenting a theoretical development on the four discourses. It establishes a hypothesis on the consequences that the generalization of the university discourse in the social field entailed in the schools and the educational bond. From the rotation of discourses, the notion of “discursive in-tervene” is defined as the maneuver by which one discourse gives rise to another.Fil: Danelinck, Daniela Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani". Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani"; Argentina. Universidad Nacional de Tres de Febrero; ArgentinaFil: Ledesma, Natalia. Universidad Nacional de Tres de Febrero; ArgentinaFil: Cuomo, Gabriela. Universidad Nacional de Tres de Febrero; ArgentinaFil: Kiel, Laura Mirta. Universidad Nacional de Tres de Febrero; Argentin

Problemas actuales de la luz real y representada

La actualidad de las artes visuales requiere que se replanteen las estrategias de enseñanza vinculadas al estudio y a la utilización del valor lumínico en la construcción espacial de la imagen bidimensional, sea ésta figurativa o abstracta, y que se reconozcan sus alcances y sus limitaciones. A continuación se detallan algunas de las problemáticas que acarrea esta concepción y luego se proponen ciertas posibilidades que habilitan nuevos abordajes al momento de trabajar y de definir el contenido en el aula.Facultad de Arte

COVID-19 vaccine immunogenicity in 16 patients with autoimmune systemic diseases. Lack of both humoral and cellular response to booster dose and ongoing disease modifying therapies

Patients with autoimmune systemic diseases (ASDs) represent a frail population during the ongoing COVID-19 pandemic. The vaccination is the major preventive measure; however, a significant number of ASD patients show an impaired production of anti-COVID-19 neutralizing antibodies (NAb), possibly counterbalanced by adequate T-cell response. The present study aimed at evaluating both humoral and cellular response to COVID-19 vaccine booster dose in this particular setting

Bibliometric Network Analysis on Rapid-Onset Opioids for Breakthrough Cancer Pain Treatment

Background and Objectives. Proper breakthrough cancer pain (BTcP) management is of pivotal importance. Although rapid-acting, oral and nasal transmucosal, fentanyl formulations (rapid-onset opioids, ROOs) are licensed for BTcP treatment, not all guidelines recommend their use. Presumably, some research gaps need to be bridged to produce solid evidence. We present a bibliometric network analysis on ROOs for BTcP treatment.Methods. Documents were retrieved from the Web of Science (WOS) online database. The string was "rapid onset opioids" or "transmucosal fentanyl" and "breakthrough cancer pain". Year of publication, journal metrics (impact factor and quartile), title, document type, topic, and clinical setting (in-patients, outpatients, and palliative care) were extracted. The software tool VOSviewer (version 1.6.17) was used to analyze the semantic network analyzes, bibliographic coupling, journals analysis, and research networks.Results. 502 articles were found in WOS. A declining trend in published articles from 2014 to 2021 was observed. Approximately 50% of documents regard top quartile (Q1) journals. Most articles focused on ROOs efficacy, but abuse and misuse issues are poorly addressed. With respect to article type, we calculated 132 clinical investigations. The semantic network analysis found interconnections between the terms "breakthrough cancer pain," "opioids," and "cancers." The top co-cited article was published in 2000 and addressed pain assessment. The largest number of partnerships regarded the United States, Italy, and England.Conclusion. In this research area, most articles are published in top-ranked journals. Nevertheless, paramount topics should be better addressed, and the implementation of research networks is needed. (C) 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved

The dynamical state of bars in cluster dwarf galaxies: The cases of NGC 4483 and NGC 4516

Dwarf barred galaxies are the perfect candidates for hosting slowly-rotating bars. They are common in dense environments and they have a relatively shallow potential well, making them prone to heating by interactions. When an interaction induces bar formation, the bar should rotate slowly. They reside in massive and centrally-concentrated dark matter halos, which slow down the bar rotation through dynamical friction. While predictions suggest that slow bars should be common, measurements of bar pattern speed, using the Tremaine-Weinberg method, show that bars are mostly fast in the local Universe. We present a photometric and kinematic characterisation of bars hosted by two dwarf galaxies in the Virgo Cluster, NGC 4483 and NGC 4516. We derive the bar length and strength using the Next Generation Virgo Survey imaging and the circular velocity, bar pattern speed, and rotation rate using spectroscopy from the Multi Unit Spectroscopic Explorer. Including the previously studied galaxy IC 3167, we compare the bar properties of the three dwarf galaxies with those of their massive counterparts from literature. Bars in the dwarf galaxies are shorter and weaker, and rotate slightly slower with respect to those in massive galaxies. This could be due to a different bar formation mechanism and/or to a large dark matter fraction in the centre of dwarf galaxies. We show that it is possible to push the application of the Tremaine-Weinberg method to the galaxy low mass regime