Thrombin Protease-activated Receptor-1 Signals through Gq- and G13-initiated MAPK Cascades Regulating c-Jun Expression to Induce Cell Transformation

Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Gi, Gq/11, and G12/13 transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Gq and Gi, and chimeric G protein subunits and murine fibroblasts deficient in Gq/11, and G12/13, we show here that, although coupling to Gi is sufficient to induce ERK activation, the ability to couple to Gq and/or G13 is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Gq and G13 can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1

Desenvolupament d'eines didàctiques per a l'aprenentatge de control de processos industrials

En els següent treball de final de grau s’estudia la possibilitat de realitzar unes pràctiques amb finalitats acadèmiques per al estudi del control automàtic en l’àmbit de la indústria química. Es treballarà en dues maquetes que representen dos processos bàsics i molt comuns en el control automàtic de la indústria química. La primera estació es centra en un control de nivell i per a la segona es planteja un control de pressió. Per tal de realitzar el guió de pràctiques és plantegen, s’apliquen i s’avaluen diverses tècniques de modelització de sistemes i sintonia d’estructures de control PID. Addicionalment es realitza una simulació amb l’eina Simulink del programa Matlab del comportament de les estacions en llaç obert i també, un cop s’ha establert l’estructura de control, del comportament en el llaç tancat amb el regulador instal·lat . Finalment es fa una proposta per al guió de pràctiques realitzant tenint en compte els resultats trobats en l’estudi de les estacions

Spaniens innere Blockaden: die Parlamentswahlen lassen nicht erwarten, dass sie überwunden werden

Am 28. April 2019 finden in Spanien vorgezogene Parlamentswahlen statt. Sie sind Ergebnis von drei Blockaden, mit denen das Land seit mehr als zehn Jahren konfron­tiert ist und die es unmöglich machen, stabile Regierungen zu bilden. Als Blockaden wirken eine politische Polarisierung, die zu einem Lagerdenken geführt hat, das keine übergreifenden Koalitionen zulässt; die Auswirkungen der Katalonien-Krise, die diese politischen Lager weiter verfestigt, und die innere Konfrontation als Folge des Migra­tionsdrucks aus Afrika, der massive innenpolitische Verwerfungen verursacht hat. Nach bisherigen Umfragen ist nicht zu erwarten, dass das Wählervotum dazu beitragen wird, die innere Spaltung zu überwinden und klare Mehrheitsverhältnisse zu schaf­fen. Den Regionalparteien könnte erneut eine Schlüsselrolle zufallen, womit Einzel­interessen wieder die Oberhand behielten. Als Folge würde die (nach einem möglichen Brexit) viertgrößte Volkswirtschaft der Europäischen Union (EU) auch in der kom­men­den Legislaturperiode durch innere Konflikte in ihrer Handlungsfähigkeit ein­geschränkt sein. Außerdem würde das Vorhaben, im europäischen Konzert eine grö­ßere Gestaltungsrolle zu spielen, an den politisch und regionalistisch geprägten Blockaden scheitern. (Autorenreferat

Evangelical Visitor- October 2, 1911. Vol. XXV. No. 20.

Evangelical Visitor published in Harrisburg, Pa., for the exposition of true, practical piety and devoted to the spread of evangelical truths and the unity of the church. Published in the interest of the church of the Brethren in Christ on October 2, 1911. Vol. XXV. No. 20

SEOM clinical guidelines in early stage breast cancer (2018)

Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20–30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy

Nurr1 protein is required for N-Methyl-d-aspartic Acid (NMDA) receptor-mediated neuronal survival

NMDA receptor (NMDAR) stimulation promotes neuronal survival during brain development. Cerebellar granule cells (CGCs) need NMDAR stimulation to survive and develop. These neurons differentiate and mature during its migration from the external granular layer to the internal granular layer, and lack of excitatory inputs triggers their apoptotic death. It is possible to mimic this process in vitro by culturing CGCs in low KCl concentrations (5 mm) in the presence or absence of NMDA. Using this experimental approach, we have obtained whole genome expression profiles after 3 and 8 h of NMDA addition to identify genes involved in NMDA-mediated survival of CGCs. One of the identified genes was Nurr1, a member of the orphan nuclear receptor subfamily Nr4a. Our results report a direct regulation of Nurr1 by CREB after NMDAR stimulation. ChIP assay confirmed CREB binding to Nurr1 promoter, whereas CREB shRNA blocked NMDA-mediated increase in Nurr1 expression. Moreover, we show that Nurr1 is important for NMDAR survival effect. We show that Nurr1 binds to Bdnf promoter IV and that silencing Nurr1 by shRNA leads to a decrease in brain-derived neurotrophic factor (BDNF) protein levels and a reduction of NMDA neuroprotective effect. Also, we report that Nurr1 and BDNF show a similar expression pattern during postnatal cerebellar development. Thus, we conclude that Nurr1 is a downstream target of CREB and that it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons

Correlació entre resposta radiològica i resposta patològica en pacients amb càncer de mama tractades amb quimioteràpia neoadjuvant

En pacients amb càncer de mama la ressonància magnètica és superior a altres exploracions per a monitoritzar la resposta a la quimioteràpia neoadjuvant. Analitzem la correlació entre resposta completa radiològica(RCr) valorada amb RM i resposta completa patològica (RCp), globalment i en funció dels diferents immunofenotips

In Situ LSPR Sensing of Secreted Insulin in Organ-on-Chip

Organ-on-a-chip (OOC) devices offer new approaches for metabolic disease modeling and drug discovery by providing biologically relevant models of tissues and organs in vitro with a high degree of control over experimental variables for high-content screening applications. Yet, to fully exploit the potential of these platforms, there is a need to interface them with integrated non-labeled sensing modules, capable of monitoring, in situ, their biochemical response to external stimuli, such as stress or drugs. In order to meet this need, we aim here to develop an integrated technology based on coupling a localized surface plasmon resonance (LSPR) sensing module to an OOC device to monitor the insulin in situ secretion in pancreatic islets, a key physiological event that is usually perturbed in metabolic diseases such as type 2 diabetes (T2D). As a proof of concept, we developed a biomimetic islet-on-a-chip (IOC) device composed of mouse pancreatic islets hosted in a cellulose-based scaffold as a novel approach. The IOC was interfaced with a state-of-the-art on-chip LSPR sensing platform to monitor the in situ insulin secretion. The developed platform offers a powerful tool to enable the in situ response study of microtissues to external stimuli for applications such as a drug-screening platform for human models, bypassing animal testing