Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents.

OBJECTIVE To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. STUDY DESIGN We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. RESULTS Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. CONCLUSIONS Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities.

Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner.

It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1β (IL-1β) may mediate this effect as it can affect glucoregulation, it is overexpressed in the 'healthy' brain during increased neuronal activity, and it supports high-energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL-1β-induced hypoglycemia. Here, we show that IL-1β adjusts glucoregulation by inducing its own production in the brain, and that IL-1β-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88)-dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1β stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1β effects on brain metabolism are most likely maintained by IL-1β auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity-dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1β to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1β production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.174.

Effects of two different memory training approaches in very pretermborn children

Background: Little research has been conducted to assess the effect of using memory training with school aged children who were born very preterm. This study aimed to determine whether two types of memory training approaches resulted in an improvement of trained functions and/or a generalization of the training effect to non-trained cognitive domains. Methods: Sixty-eight children born very preterm (7-12 years) were randomly allocated to a group undertaking memory strategy training (n=23), working memory training (n=22), or a waiting control group (n=23). Neuropsychological assessment was performed before and immediately after the training or waiting period, and at a six-month follow-up. Results: In both training groups, significant improvement of different memory domains occurred immediately after training (near transfer). Improvement of non-trained arithmetic performance was observed after strategy training (far transfer). At a six-month follow-up assessment, children in both training groups demonstrated better working memory, and their parents rated their memory functions to be better than controls. Performance level before the training was negatively associated with the training gain. Conclusions: These results highlight the importance of cognitive interventions, in particular the teaching of memory strategies, in very preterm-born children at early school age to strengthen cognitive performance and prevent problems at school.

The Five Senses in Medieval and Early Modern England

Edited by Annette Kern-Stähler, Beatrix Busse, and Wietse de Boer The essays collected in The Five Senses in Medieval and Early Modern England examine the interrelationships between sense perception and secular and Christian cultures in England from the medieval into the early modern periods. They address canonical texts and writers in the fields of poetry, drama, homiletics, martyrology and early scientific writing, and they espouse methods associated with the fields of corpus linguistics, disability studies, translation studies, art history and archaeology, as well as approaches derived from traditional literary studies. Together, these papers constitute a major contribution to the growing field of sensorial research that will be of interest to historians of perception and cognition as well as to historians with more generalist interests in medieval and early modern England.

Source Memory for Mental Imagery: Influences of the Stimuli’s Ease of Imagery.

The present study investigated how ease of imagery influences source monitoring accuracy. Two experiments were conducted in order to examine how ease of imagery influences the probability of source confusions of perceived and imagined completions of natural symmetric shapes. The stimuli consisted of binary pictures of natural objects, namely symmetric pictures of birds, butterflies, insects, and leaves. The ease of imagery (indicating the similarity of the sources) and the discriminability (indicating the similarity of the items) of each stimulus were estimated in a pretest and included as predictors of the memory performance for these stimuli. It was found that confusion of the sources becomes more likely when the imagery process was relatively easy. However, if the different processes of source monitoring-item memory, source memory and guessing biases-are disentangled, both experiments support the assumption that the effect of decreased source memory for easily imagined stimuli is due to decision processes and misinformation at retrieval rather than encoding processes and memory retention. The data were modeled with a Bayesian hierarchical implementation of the one high threshold source monitoring model.

Exploring the Impact of Decreased AMPK Pathway Activity on Brain Injury Outcome

Each year, 150 million people sustain a Traumatic Brain Injury (TBI). TBI results in life-long cognitive impairments for many survivors. One observed pathological alteration following TBI are changes in glucose metabolism. Altered glucose uptake occurs in the periphery as well as in the nervous system, with an acute increase in glucose uptake, followed by a prolonged metabolic suppression. Chronic, persistent suppression of brain glucose uptake occurs in TBI patients experiencing memory loss. Abberant post-injury activation of energy-sensing signaling cascades could result in perturbed cellular metabolism. AMP-activated kinase (AMPK) is a kinase that senses low ATP levels, and promotes efficient cell energy usage. AMPK promotes energy production through increasing glucose uptake via glucose transporter 4 (GLUT4). When AMPK is activated, it phosphorylates Akt Substrate of 160 kDa (AS160), a Rab GTPase activating protein that controls Glut4 translocation. Additionally, AMPK negatively regulates energy-consumption by inhibiting protein synthesis via the mechanistic Target of Rapamycin (mTOR) pathway. Given that metabolic suppression has been observed post-injury, we hypothesized that activity of the AMPK pathway is transiently decreased. As AMPK activation increases energy efficiency of the cell, we proposed that increasing AMPK activity to combat the post-injury energy crisis would improve cognitive outcome. Additionally, we expected that inhibiting AMPK targets would be detrimental. We first investigated the role of an existing state of hyperglycemia on TBI outcome, as hyperglycemia correlates with increased mortality and decreased cognitive outcome in clinical studies. Inducing hyperglycemia had no effect on outcome; however, we discovered that AMPK and AS160 phosphorylation were altered post-injury. We conducted vii work to characterize this period of AMPK suppression and found that AMPK phosphorylation was significantly decreased in the hippocampus and cortex between 24 hours and 3 days post-injury, and phosphorylation of its downstream targets was consistently altered. Based on this period of observed decreased AMPK activity, we administered an AMPK activator post-injury, and this improved cognitive outcome. Finally, to examine whether AMPK-regulated target Glut4 is involved in post-injury glucose metabolism, we applied an inhibitor and found this treatment impaired post-injury cognitive function. This work is significant, as AMPK activation may represent a new TBI therapeutic target.

T-CELL TREATMENTS FOR SOLID AND HEMATOLOGICAL TUMORS

Cell-based therapies have demonstrated potency and efficacy as cancer treatment modalities. T cells can be dichotomized by their T cell receptor (TCR) complexes where alpha/beta T cells (95% of T cells) and gamma/delta T cells (+T cells proliferated to clinically significant numbers and ROR1+ tumor cells were effectively targeted and killed by both ROR1-specific CAR+ T cell populations, although ROR1RCD137 were superior to ROR1RCD28 in clearance of leukemia xenografts in vivo. The second specific aim focused on generating bi-specific CD19-specific CAR+ gamma/delta T cells with polyclonal TCRgamma/delta repertoire on CD19+ artificial antigen presenting cells (aAPC). Enhanced cytolysis of CD19+ leukemia was observed by CAR+ gamma/delta T cells compared to CARneg gamma/delta T cells, and leukemia xenografts were significantly reduced compared to control mice in vivo. The third specific aim looked at the broad anti-tumor effects of polyclonal gamma/delta T cells expanded on aAPC without CAR+ T cells, where Vdelta1, Vdelta2, and Vdelta3 populations had naïve, effector memory, and central memory phenotypes and effector function strength in the following order: Vdelta2>Vdelta3>Vdelta1. Polyclonal gamma/delta T cells eliminated ovarian cancer xenografts in vivo and increased survival compared to control mice. Thus, translating these methodologies to clinical trials will provide cancer patients novel, safe, and effective options for their treatment.

Partial order and contextual net semantics for atomic and locally atomic CC programs

We present two concurrent semantics (i.e. semantics where concurrency is explicitely represented) for CC programs with atomic tells. One is based on simple partial orders of computation steps, while the other one is based on contextual nets and it is an extensión of a previous one for eventual CC programs. Both such semantics allow us to derive concurrency, dependency, and nondeterminism information for the considered languages. We prove some properties about the relation between the two semantics, and also about the relation between them and the operational semantics. Moreover, we discuss how to use the contextual net semantics in the context of CLP programs. More precisely, by interpreting concurrency as possible parallelism, our semantics can be useful for a safe parallelization of some CLP computation steps. Dually, the dependency information may also be interpreted as necessary sequentialization, thus possibly exploiting it for the task of scheduling CC programs. Moreover, our semantics is also suitable for CC programs with a new kind of atomic tell (called locally atomic tell), which checks for consistency only the constraints it depends on. Such a tell achieves a reasonable trade-off between efficiency and atomicity, since the checked constraints can be stored in a local memory and are thus easily accessible even in a distributed implementation.

Using attributed variables in the implementation of concurrent and parallel logic programming systems

Incorporating the possibility of attaching attributes to variables in a logic programming system has been shown to allow the addition of general constraint solving capabilities to it. This approach is very attractive in that by adding a few primitives any logic programming system can be turned into a generic constraint logic programming system in which constraint solving can be user deñned, and at source level - an extreme example of the "glass box" approach. In this paper we propose a different and novel use for the concept of attributed variables: developing a generic parallel/concurrent (constraint) logic programming system, using the same "glass box" flavor. We argüe that a system which implements attributed variables and a few additional primitives can be easily customized at source level to implement many of the languages and execution models of parallelism and concurrency currently proposed, in both shared memory and distributed systems. We illustrate this through examples and report on an implementation of our ideas.

On the uses of attributed variables in parallel and concurrent logic programming systems

Incorporating the possibility of attaching attributes to variables in a logic programming system has been shown to allow the addition of general constraint solving capabilities to it. This approach is very attractive in that by adding a few primitives any logic programming system can be turned into a generic constraint logic programming system in which constraint solving can be user defined, and at source level - an extreme example of the "glass box" approach. In this paper we propose a different and novel use for the concept of attributed variables: developing a generic parallel/concurrent (constraint) logic programming system, using the same "glass box" flavor. We argüe that a system which implements attributed variables and a few additional primitives can be easily customized at source level to implement many of the languages and execution models of parallelism and concurrency currently proposed, in both shared memory and distributed systems. We illustrate this through examples.

Memory isolation in many-core embedded systems

The current approach to developing mixed-criticality sys- tems is by partitioning the hardware resources (processors, memory and I/O devices) among the different applications. Partitions are isolated from each other both in the temporal and the spatial domain, so that low-criticality applications cannot compromise other applications with a higher level of criticality in case of misbehaviour. New architectures based on many-core processors open the way to highly parallel systems in which each partition can be allocated to a set of dedicated proces- sor cores, thus simplifying partition scheduling and temporal separation. Moreover, spatial isolation can also benefit from many-core architectures, by using simpler hardware mechanisms to protect the address spaces of different applications. This paper describes an architecture for many- core embedded partitioned systems, together with some implementation advice for spatial isolation.

La memoria en el proceso creativo de Juan Muñoz = Memory in the creative process of Juan Muñoz

Esta tesis integra un estudio reflexivo sobre la relación de dependencia entre la creación y la memoria a través del análisis de la última obra del escultor Juan Muñoz: Double Bind (Tate Modern, Londres, 2001). Desde esta posición es obligado replantear el análisis de la obra, lo que hace necesario su estudio cubriendo el mayor espectro posible de información accesible más allá de la obra en sí, para aproximarse a la convergencia entre memoria y creación. La perspectiva de análisis propuesta abre camino a nuevas consideraciones so¬bre la relevancia del conocimiento en el desarrollo del proceso creativo. Este análisis no debe tan sólo suponer una aportación al conocimiento del trabajo de Juan Muñoz. Debe también desprenderse de él la innegable participación y necesaria lectura del pasado en el presente. La amnesia de los tiempos pasados impide completar el atlas de imágenes en las que se apoya la creación impidiendo el conocimiento del origen de las fuentes de inspi¬ración y las bases de la creación de una determinada obra. Este hecho limita y distorsiona sus posibles interpretaciones. Pretendo un acercamiento al entendimiento de la forma de mirar y de crear a través del tiempo que es memoria. La memoria tiene un cometido de crucial importancia para la actividad mental y juega un papel fundamental en la conducta y en la creación. La obra es el resultado de la búsqueda de una idea que exprese algo que el creador no puede ex¬presar de otra manera. Es la necesidad de expresar las ideas mediante un lenguaje que se desarrolla en el tiempo y en el espacio, reflejo del ser que responde al pensamiento. Es una forma de experiencia donde subyacen las sendas del pasado y donde se plantea el futuro. Sólo el creador accede a la obra desde dentro, el observador llega a ella desde el exterior y mediante su propia subjetividad. Las obras son formas de experiencia de sus autores, comunicar el mensaje de dicha experiencia supone por tanto interpretar. Persiguiendo la necesidad de saber y entender, pretender explicar el sentido de una cosa implica una apreciación intencionada asociada al entendimiento del intérprete. Las obras son produc¬tos que portan un mensaje y que contienen en su estructura las trazas del tiempo vivido por su creador. Si se quiere adquirir un acercamiento que represente la posición de un autor, será necesario no solo mirar a través de ella, si no introducirse en el contexto de su historia. Mirar hacia atrás, hacia la profundidad del presente para tener conciencia del pensamiento presente y futuro. Recorrer de este modo la instalación Double Bind de Juan Muñoz proporciona una síntesis de sus preocupaciones e intereses a la vez que aporta un conocimiento no necesariamente inmediato, pero relevante y trascendente de la obra, su creador y la historia. ABSTRACT This thesis comprises a reflective study of the dependence relationship between creation and memory through the analysis of the latest work by the sculptor Juan Muñoz: Double Bind (Tate Modern, London, 2001). From this position, it is mandatory to rethink the analysis of the work, making it necessary to cover the widest possible range of information available beyond the work itself, in order to obtain a closer view of the convergence between memory and creation. The proposed analytical approach opens up new considerations on the relevance of knowledge during the development of the creative process. This analysis should not only make a contribution to the knowledge of the work of Juan Muñoz. It should also infer the undeniable involvement and the necessary reading of the past in the present. Amnesia regarding past makes it impossible to complete the atlas of images on which the creation is based, blocking knowledge of the origin of the sources of inspiration and the basis for the creation of a specific work. This fact limits and distorts its possible interpretations. My intention is an approach to how to understand memory as the way of looking and creating over time. Memory has a crucial role to mental activity and plays a key role in behaviour and creation. The work is the result of finding an idea that expresses something that the creator can not express otherwise. It is the need to express ideas by means of a language that develops throughout time and space, a reflection of the being that responds to the thought. It is a way of experience underlying the paths of the past and where the future is set out. Only the creator can access the work from the inside. The observer sees it from the outside and in accordance with his/her own subjectivity. The works form a part of the experience of their authors, thus implying the interpretation of the message of their experience being passed on. The pursuit of knowledge and understanding, and trying to explain the meaning of something implies a deliberate appreciation associated with the understanding of the interpreter. The works are products bearing a message and containing in their structure traces of the time lived by their creator. If one wants to come close to what the author’s posture represents, it will not only be necessary to penetrate it, but also to introduce oneself into the context of its history. Take a look back, towards the depth of the present in order to become aware of present and future thinking. To go across the installation of Double Bind by Juan Muñoz in this way offers a synthesis of his concerns and interests while also providing a not necessarily immediate knowledge, but one which is relevant and important to the work, its creator and history.

“O CRISTO AFOGADO: UMA NÃO-CRISTOLOGIA” RELIGIÃO, LITERATURA E PÓS-COLONIALISMO

O objetivo dessa tese é aprofundar, a partir do discurso pós-colonial, uma crise na perspectiva teológica da libertação. Esta promoveu, na década de 1970, uma reviravolta nos estudos teológicos no terceiro mundo. Para tanto, leremos um conto de Gabriel García Márquez chamado “El ahogado más hermosodel mundo” (1968) analizando e avaliando as estratégias políticas e culturais ali inscritas. Para levar a frente tal avaliação é preciso ampliar o escopo de uma visão que divide o mundo em secular/religioso, ou em ideias/práticas religiosas e não religiosas, para dar passo a uma visão unificada que compreende a mundanalidade, tanto do que é catalogado como ‘religioso’ quanto do que se pretende ‘não religioso’. A teologia/ciências da religião, como discurso científico sobre a economia das trocas que lidam com visões, compreensões e práticas de mundo marcadas pelo reconhecimento do mistério que lhes é inerente, possuem um papel fundamental na compreensão, explicitação, articulação e disponibilização de tais forças culturais. A percepção de existirem elementos no conto que se relacionam com os símbolos sobre Jesus/Cristo nos ofereceu um vetor de análise; entretanto, não nos deixamos limitar pelos grilhões disciplinares que essa simbologia implica. Ao mesmo tempo, esse vínculo, compreendido desde a relação imperial/colonial inerente aos discursos e imagens sobre Jesus-Cristo, embora sem centralizar a análise, não poderia ficar intocado. Partimos para a construção de uma estrutura teórica que explicitasse os valores, gestos, e horizontes mundanos do conto, cristológicos e não-cristológicos, contribuindo assim para uma desestabilização dos quadros tradicionais a partir dos quais se concebem a teologia e as ciências da religião, a obra de García Márquez como literatura, e a geografia imperial/colonial que postula o realismo ficcional de territórios como “América Latina”. Abrimos, assim, um espaço de significação que lê o conto como uma “não-cristologia”, deslocando o aprisionamento disciplinar e classificatório dos elementos envolvidos na análise. O discurso crítico de Edward Said, Homi Bhabha e GayatriSpivak soma-se à prática teórica de teólogas críticas feministas da Ásia, da África e da América Latina para formular o cenário político emancipatório que denominaremos teologia crítica secular.

Inter- and intraspecies polymorphisms in the cholecystokinin-B/gastrin receptor alter drug efficacy

The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E → K). When examined using the 288E → K receptor, the efficacies of both PD135,158 and L-740,093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.