ERK Signals: Scaffolding Scaffolds?

ERK1/2 MAP Kinases become activated in response to multiple intra- and extra-cellular stimuli through a signaling module composed of sequential tiers of cytoplasmic kinases. Scaffold proteins regulate ERK signals by connecting the different components of the module into a multi-enzymatic complex by which signal amplitude and duration are fine-tuned, and also provide signal fidelity by isolating this complex from external interferences. In addition, scaffold proteins play a central role as spatial regulators of ERKs signals. In this respect, depending on the subcellular localization from which the activating signals emanate, defined scaffolds specify which substrates are amenable to be phosphorylated. Recent evidence has unveiled direct interactions among different scaffold protein species. These scaffold-scaffold macro-complexes could constitute an additional level of regulation for ERK signals and may serve as nodes for the integration of incoming signals and the subsequent diversification of the outgoing signals with respect to substrate engagement.PC lab is supported by grants BFU2011-23807 and SAF-2015 63638R (MINECO/FERDER, UE) from the Spanish Ministry of Economy – Fondos FEDER; by the Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD/12/0036/0033), Spanish Ministry of Health and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113. BC is a CSIC JAE-Doc program postdoctoral fellow supported by the European Social Fund.Peer reviewedPeer Reviewe

Análisis evolutivo de las secuelas neurocognitivas en los niños nacidos con una edad gestacional inferior a 32 semanas y/o peso al nacer menos de 1500 gramos

Los avances clínicos y de investigación llevados a cabo en los últimos años no han impedido que los índices de prematuridad continúen aumentando en los países desarrollados. La importancia de conocer mejor este tipo de nacimientos radica tanto en la supervivencia de los neonatos como en la gran preocupación por su morbilidad. Las secuelas sensoriales y neurológicas son frecuentes y conocidas por los profesionales sanitarios, sin embargo las alteraciones neurocognitivas que sufren estos niños y que parecen ser inversamente proporcionales a la edad gestacional y peso al nacer han adquirido una notable trascendencia. Los trastornos del neurodesarrollo se consideran alteraciones vinculadas a la maduración cerebral. Por ello, se inician en la infancia y se expresan de forma diferente en distintas etapas del crecimiento. Son alteraciones que evolucionan de acuerdo con la formación del sistema nervioso central y que regulan las funciones motoras, sensitivas, cognitivas y emocionales que permiten la adaptación al medio. Los niños nacidos de forma prematura son vulnerables a padecer trastornos del neurodesarrollo por contar con un cerebro inmaduro y un tipo especifico de vascularización que la hace especialmente sensible a sufrir lesiones cerebrales. Además la maduración cerebral en un ambiente extrauterino puede ser objeto de importantes modificaciones lo que podría derivar en anomalías cerebrales no estructurales que contribuirían a explicar los problemas cognitivos, conductuales y emocionales que pueden aparecer en los niños nacidos con una edad gestacional menor a 37 semanas y/o peso inferior a 2.500 gramos..

User-centred design of a digital advisory service: enhancing public agricultural extension for sustainable intensification in Tanzania

Sustainable intensification (SI) is promoted as a rural development paradigm for sub-Saharan Africa. Achieving SI requires smallholder farmers to have access to information that is context-specific, increases their decision-making capacities, and adapts to changing environments. Current extension services often struggle to address these needs. New mobile phone-based services can help. In order to enhance the public extension service in Tanzania, we created a digital service that addresses smallholder farmers’ different information needs for implementing SI. Using a co-design methodology – User-Centered Design – we elicited feedback from farmers and extension agents in Tanzania to create a new digital information service, called Ushauri. This automated hotline gives farmers access to a set of pre-recorded messages. Additionally, farmers can ask questions in a mailbox. Extension agents then listen to these questions through an online platform, where they record and send replies via automated push-calls. A test with 97 farmers in Tanzania showed that farmers actively engaged with the service to access agricultural advice. Extension agents were able to answer questions with reduced workload compared to conventional communication channels. This study illustrates how User-Centered Design can be used to develop information services for complex and resource-restricted smallholder farming contexts

Probabilistic scenario planning in agriculture: balancing risks through data-driven forecasting

Probabilistic scenario planning in agriculture is a procedure that uses available data and expert estimates to inform decision-making across the food system in a way that minimizes economic risk

Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope

Sequestration of c-Fos at the nuclear envelope (NE) through interaction with A-type lamins suppresses AP-1–dependent transcription. We show here that c-Fos accumulation within the extraction-resistant nuclear fraction (ERNF) and its interaction with lamin A are reduced and enhanced by gain-of and loss-of ERK1/2 activity, respectively. Moreover, hindering ERK1/2-dependent phosphorylation of c-Fos attenuates its release from the ERNF induced by serum and promotes its interaction with lamin A. Accordingly, serum stimulation rapidly releases preexisting c-Fos from the NE via ERK1/2-dependent phosphorylation, leading to a fast activation of AP-1 before de novo c-Fos synthesis. Moreover, lamin A–null cells exhibit increased AP-1 activity and reduced levels of c-Fos phosphorylation. We also find that active ERK1/2 interacts with lamin A and colocalizes with c-Fos and A-type lamins at the NE. Thus, NE-bound ERK1/2 functions as a molecular switch for rapid mitogen-dependent AP-1 activation through phosphorylation-induced release of preexisting c-Fos from its inhibitory interaction with lamin A/C

Método para predecir la respuesta terapéutica a fármacos inhibidores de la serina-treonina kinasa BRAF

La presente invención se refiere a un método in vitro que permite predecir la respuesta terapéutica al tratamiento con fármacos inhibidores de BRAF, tales como vemurafenib, en pacientes de cáncer asociado a mutaciones oncogénicas en dicha kinasa, tal como melanoma BRAF positivo. Dicho método se basa en la medición de los niveles de ERK1/2 citoplasmática, a través de la detección y cuantificación de ERK1/2 fosforiladas en serina 301/284 respectivamente, en una muestra biológica aislada del paciente. La invención también proporciona un anticuerpo específico frente a ERK1/2 fosforiladas en serina 301/284 y un kit que lo comprende, los cuales son de utilidad en el método descrito.Solicitud: 201930419 (13.05.2019)Nº Pub. de Solicitud: ES2793801A1 (16.11.2020

Ras subcellular localization inversely regulates thyroid tumor growth and dissemination

RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under-or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS sitespecific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.PC lab is supported by grant RTI2018-096658B-100 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE). Santisteban, Riesco and Crespo Laboratories are supported jointly by grants from Asociación Española Contra el Cancer (AECC; GCB141423113) and CIBERONC from the Instituto de Salud Carlos III (ISCIII). PS acknowledges support from: SAF2016-75531-R (MINECO/FEDER, UE); B2017/BMD-3724 Tironet2 (Comunidad de Madrid) and PID2019-105303RB-I00/AEI/10.13039/501100011033 from Ministerio de Ciencia e Innovación (MICIN). B.C is funded by Retos Jóvenes Investigadores grant SAF2015-73364-JIN (MICIU/AEI/FEDER, UE), a PIE grant from Consejo Superior de Investigaciones Científicas (CSIC)- MICIU and the Ramón y Cajal Research Program (MICIU, RYC2018-024004-I)

Designing gender-inclusive digital solutions for agricultural development: An introductory guide and toolkit

Digital tools play an increasingly important role in agricultural research for development. Often, they fall short in fulfilling their promises for women or other marginalized groups. Adoption across these groups is often low. One key reason for this is a narrow and techno-centric perspective on digital tool design. Human Centered Design brings a change in perspective on digital innovations towards more inclusive design processes. This practical guide and toolkit for gender-inclusive digital design is directed at people in CGIAR working in digital agriculture who are interested in creating gender-inclusive, sustainable solutions. This guide aims to 1) introduce the concepts of design thinking and inclusive design, 2) describe the design process and provide relevant tools for the differentsteps of the process, and 3) provide links for further readings to deepen the understanding on this topic

Tapping the full potential of the digital revolution for agricultural extension: an emerging innovation agenda

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Participatory design of digital innovation in agricultural research-for-development: insights from practice

Digital development is becoming mainstream in research-for-development. Applying participatory design methodologies in digital development projects can help develop more user-centered innovation. But these processes require new skills and methods from researchers, and research-for-development project context can create challenges for participatory design. This article presents lessons learned from practical experiences within participatory design projects for digital solutions