Holism and causal responsibility: the role of number and valence of event consequences

The present research examines the effect of holistic-analytic thinking style on causal responsibility. Across seven studies (N = 4,103), participants’ thinking style was either measured or manipulated. Then, the valence or number of consequences were varied in several scenarios involving a cause-consequence relationship. As a dependent measure, participants indicated the degree of responsibility attributed to the cause mentioned in each scenario. The results revealed that holistic (vs. analytic) participants assigned more responsibility to the cause when the consequences presented were a combination of positive and negative outcomes (vs. univalent), and when multiple consequences were triggered in the scenario (vs. single). To explore the explanatory factor for these results, a final study manipulated the complexity of the consequences, along with the number. The results of this research suggested that holistic (vs. analytic) individuals consider the degree of complexity of consequences to establish causal attributionThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded by the call “Proyectos de I+D para Jóvenes Doctores” from Comunidad Autónoma de Madrid and Universidad Autónoma de Madrid, referenced with the number SI3/PJI/2021-0019

Individual differences in thinking style and dealing with contradiction: The mediating role of mixed emotions

The present research examined how individuals' thinking style (holistic vs. analytic) is associated with the way they deal with contradictory information and whether experiencing mixed emotions can mediate this relationship. Participants first completed the thinking style measure and then were exposed to two contradictory pieces of information (Studies 1 and 2). In study 2, we also measured the experience of mixed emotions to test the mediating role of this variable. Across two studies, we found that individuals with a holistic thinking style were more able to reconcile contradictory information compared to individuals with an analytic thinking style. Study 2 showed that the relationship between thinking style and dealing with contradiction was mediated by the experience of mixed emotions. This research extends previous findings on confrontation of contradiction and mixed emotions by using an individual-differences rather than a cultural-differences approach, and establishes mixed emotions as a plausible mediating variable

Sistema de visión estereoscópica para navegación autónoma de vehículos no tripulados

La visión estereoscópica artificial es un campo muy amplio que forma parte de lo que se conoce como visión por computador. Técnicamente consiste en el procesamiento de dos imágenes obtenidas mediante sendas cámaras, a partir de una escena tridimensional 3D. Este procesamiento está orientado a reconstruir la escena en 3D a partir de las dos imágenes, izquierda y derecha. Un aspecto que cabe destacar es que las cámaras están desplazadas una cierta distancia, tal y como ocurre con nuestros ojos. El trabajo del computador consiste en identificar en ambas imágenes aquellos píxeles en las dos imágenes que se corresponden con la misma entidad física en la escena 3D, usando para ello algoritmos especializados. La distancia que separa estos píxeles se conoce como disparidad. La medida de la disparidad sirve para obtener la distancia a la que se sitúa físicamente ese objeto en la escena con respecto a las dos cámaras. La visión estereoscópica es un campo que tiene numerosas aplicaciones y en el que a día de hoy se están invirtiendo numerosos recursos en investigación. Concretamente, una de esas aplicaciones es la detección de obstáculos por parte de robots. Nuestro proyecto está orientado hacia esa aplicación práctica, si bien se centra exclusivamente en los aspectos relacionados con la correspondencia de los elementos homólogos en las imágenes. Para ello hemos implementado diversas técnicas y algoritmos de visión estereoscópica usando el lenguaje de programación C#. [ABSTRACT] Stereo vision is a broad eld that is part of computer vision. Technically, it consists of the processing of two images adquired by two cameras, from a given scenario. This processing is aimed to reconstruct the 3D scene from both images, namely left and right images. One thing that is worth mentioning is that the two cameras are shifted a certain distance, as it happens with our eyes. The computer basically identies in both images those pixels that match, using specialized algorithms. The distance that separates those pixels is known as disparity. Disparity is next used in the calculation of the distance between the object in the scene and the cameras. Stereo vision (also known as stereopsis) is a eld with multiple applications and in which it is invested many resources in research. One of those applications is the detection of obstacles by robots. Our project is oriented towards this practical application; although this work is focused only on the computation of the disparities, i.e. the correspondence between pixels in the images. We have implemented several stereo vision techniques and algorithms using the C# programming language

Lymphocytes in Alzheimer’s Disease Pathology: Altered Signaling Pathways

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including plaques, neurofibrillary tangles, and neuronal loss in brain regions linked to cognitive functions. Despite progress in uncovering many of the factors that contribute to the etiology of this disease, the cause of neuronal death is largely unknown. Neuroinflammation seems to play a critical role in the pathogenesis of AD. Inflammatory processes in the brain are mainly mediated by the intrinsic innate immune system consisting of astrocytes and microglial cells, and cytokine, chemokine, and growth factor signaling molecules. However mounting evidence suggest that the Central Nervous System (CNS) is accessible to lymphocytes and monocytes from the blood stream, indicating that there is an intense crosstalk between the immune and the CN systems. On the other hand, some AD-specific brain-derived proteins or metabolites may enter the plasma through a deficient blood-brain barrier, and exert some measurable signaling properties in peripheral cells. The goals of this review are: 1) to explore the evidences of changes in signaling pathways that could mediate both central and peripheral manifestations of AD, and 2) to explore whether changes in immune cells, particularly lymphocytes, could contribute to AD pathogenesis

Downregulation of ERK1/2 activity by CaMKII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients

11 páginas, 9 figuras, 2 tablas -- PAGS nros. 1090-1100Previously, we reported a Ca2+/calmodulin (CaM)-dependent impairment of apoptosis induced by serum deprivation in Alzheimer’s disease (AD) lymphoblasts. These cell lines showed downregulation of extracellular signal-regulated kinase (ERK)1/2 activity and elevated content of p21 compared with control cells. The aim of this study was to delineate the molecular mechanism underlying the distinct regulation of p21 content in AD cells. Quantitative reverse transcription polymerase chain reaction analysis demonstrated increased p21 messenger RNA (mRNA) levels in AD cells. The ERK1/2 inhibitor, PD98059, prevented death of control cells and enhanced p21 mRNA and protein levels. The CaM antagonist, calmidazolium, and the CaMKII inhibitor, KN-62, normalized the survival pattern of AD lymphoblasts by augmenting ERK1/2 activation and reducing p21 mRNA and protein levels. Upregulation of p21 transcription in AD cells appears to be the consequence of increased activity of forkhead box O3a (FOXO3a) as the result of diminished ERK1/2-mediated phosphorylation of this transcription factor, which in turn facilitates its nuclear accumulation. Murine double minute 2 (MDM2) protein levels were decreased in AD cells relative to control lymphoblasts, suggesting an impairment of FOXO3a degradationThis work has been supported by grants from Ministerio de Economía y Competitividad (SAF2007-624505, SAF2011-28603) and Fundación Ramón Areces to A.M.-R. N.E. holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia

[Background] Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c.709-1G > A). In this work, we have investigated the effects of two brain penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27) designed and synthetized in our laboratory on cell proliferation, TDP-43 phosphorylation and subcellular localization, as well as their effects on the known nuclear TDP-43 function repressing the expression of CDK6.[Results] We report here that both CK-1δ inhibitors (IGS-2.7 and IGS-3.27) normalized the proliferative activity of PGRN-deficient lymphoblasts by preventing the phosphorylation of TDP-43 fragments, its nucleo-cytosol translocation and the overactivation of the CDK6/pRb cascade. Moreover, ours results show neuroprotective effects of CK-1δ inhibitors in a neuronal cell model of induced TDP-43 phosphorylation.[Conclusions] Our results suggest that modulating CK-1δ activity could be considered a novel therapeutic approach for the treatment of FTLD-TDP and other TDP-43 proteinopathies.This work has been supported by grants from The Spanish Ministry of Economy and Competitiveness (projects SAF2012-37979-C03-01 to Ana Martinez and SAF2011-28603 to Angeles Martín-Requero). Moreover, Dr. Angeles Martín-Requero was supported by Ramón Areces foundation and Dr. López de Munain received research support from Ilundain Foundation.Peer reviewe

Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer's Disease Patients

Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer's disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD

TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients

IntroductionTDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.MethodologyWe have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.ResultsTDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.ConclusionTTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

athogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS