Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors.

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

Insularity and the evolution of melanism, sexual dichromatism and body size in the worldwide-distributed barn owl.

Abstract Island biogeography has provided fundamental hypotheses in population genetics, ecology and evolutionary biology. Insular populations usually face different feeding conditions, predation pressure, intraspecific and interspecific competition than continental populations. This so-called island syndrome can promote the evolution of specific phenotypes like a small (or large) body size and a light (or dark) colouration as well as influence the evolution of sexual dimorphism. To examine whether insularity leads to phenotypic differentiation in a consistent way in a worldwide-distributed nonmigratory species, we compared body size, body shape and colouration between insular and continental barn owl (Tyto alba) populations by controlling indirectly for phylogeny. This species is suitable because it varies in pheomelanin-based colouration from reddish-brown to white, and it displays eumelanic black spots for which the number and size vary between individuals, populations and species. Females are on average darker pheomelanic and display more and larger eumelanic spots than males. Our results show that on islands barn owls exhibited smaller and fewer eumelanic spots and lighter pheomelanic colouration, and shorter wings than on continents. Sexual dimorphism in pheomelanin-based colouration was less pronounced on islands than continents (i.e. on islands males tended to be as pheomelanic as females), and on small islands owls were redder pheomelanic and smaller in size than owls living on larger islands. Sexual dimorphism in the size of eumelanic spots was more pronounced (i.e. females displayed much larger spots than males) in barn owls living on islands located further away from a continent. Our study indicates that insular conditions drive the evolution towards a lower degree of eumelanism, smaller body size and affects the evolution of sexual dichromatism in melanin-based colour traits. The effect of insularity was more pronounced on body size and shape than on melanic traits.

How do the different components of episodic memory develop? Role of executive functions and short-term feature-binding abilities.

This study investigated the development of all 3 components of episodic memory (EM), as defined by Tulving, namely, core factual content, spatial context, and temporal context. To this end, a novel, ecologically valid test was administered to 109 participants aged 4-16 years. Results showed that each EM component develops at a different rate. Ability to memorize factual content emerges early, whereas context retrieval abilities continue to improve until adolescence, due to persistent encoding difficulties (isolated by comparing results on free recall and recognition tasks). Exploration of links with other cognitive functions revealed that short-term feature-binding abilities contribute to all EM components, and executive functions to temporal and spatial context, although ability to memorize temporal context is predicted mainly by age.

Astrocytes: powering memory.

Creating long-term memory requires a cellular program in neurons involving gene expression, protein synthesis, and formation of new synaptic connections. Suzuki et al. (2011) show that astrocytes, glial cells of the brain, play a necessary role in this program by converting glycogen to lactate and transporting it to neurons.

Age-related differences on event-related potentials and brain rhythm oscillations during working memory activation.

Previous functional imaging studies have pointed to the compensatory recruitment of cortical circuits in old age in order to counterbalance the loss of neural efficiency and preserve cognitive performance. Recent electroencephalographic (EEG) analyses reported age-related deficits in the amplitude of an early positive-negative working memory (PN(wm)) component as well as changes in working memory (WM)-load related brain oscillations during the successful performance of the n-back task. To explore the age-related differences of EEG activation in the face of increasing WM demands, we assessed the PN(wm) component area, parietal alpha event-related synchronization (ERS) as well as frontal theta ERS in 32 young and 32 elderly healthy individuals who successfully performed a highly WM demanding 3-back task. PN(wm) area increased with higher memory loads (3- and 2-back > 0-back tasks) in younger subjects. Older subjects reached the maximal values for this EEG parameter during the less WM demanding 0-back task. They showed a rapid development of an alpha ERS that reached its maximal amplitude at around 800 ms after stimulus onset. In younger subjects, the late alpha ERS occurred between 1,200 and 2,000 ms and its amplitude was significantly higher compared with elders. Frontal theta ERS culmination peak decreased in a task-independent manner in older compared with younger cases. Only in younger individuals, there was a significant decrease in the phasic frontal theta ERS amplitude in the 2- and 3-back tasks compared with the detection and 0-back tasks. These observations suggest that older adults display a rapid mobilization of their neural generators within the parietal cortex to manage very low demanding WM tasks. Moreover, they are less able to activate frontal theta generators during attentional tasks compared with younger persons.

Memory-based scheduling of scientific computing clusters

This study looks at how increased memory utilisation affects throughput and energy consumption in scientific computing, especially in high-energy physics. Our aim is to minimise energy consumed by a set of jobs without increasing the processing time. The earlier tests indicated that, especially in data analysis, throughput can increase over 100% and energy consumption decrease 50% by processing multiple jobs in parallel per CPU core. Since jobs are heterogeneous, it is not possible to find an optimum value for the number of parallel jobs. A better solution is based on memory utilisation, but finding an optimum memory threshold is not straightforward. Therefore, a fuzzy logic-based algorithm was developed that can dynamically adapt the memory threshold based on the overall load. In this way, it is possible to keep memory consumption stable with different workloads while achieving significantly higher throughput and energy-efficiency than using a traditional fixed number of jobs or fixed memory threshold approaches.

NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells.

Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.

Santé en milieu pénitentiaire: vulnérabilité partagée entre détenus et professionnels de la santé [Health in prison: shared vulnerability between detainees and health professionals]

In prison, the health professional has to take the sanitary needs of a temporary of chronically vulnerable population. His practice has to meet laws and recommendations, as well as the field reality and its numerous constraints. This puts him in a "shared vulnerability and stigmatization". He attempts to maintain or restore a health status in a deteriorating environment, at least psychologically. He is in the penitentiary world's eye which he depends upon in many ways to achieve his mandate. His activity is scarcely known and recognised by his peers from whom he can be very out of touch. To ensure a humanistic, efficient and equivalent-of-care practice, the health professional must rely on sound knowledge of general healthcare, ethics, deontology and medical laws. Basic and continuous training is a mainspring, like networking and development of federal recommendations.

The neuronal monocarboxylate transporter MCT2: its regulation by BDNF and its role in learning and memory

Glucose has been considered the major, if not the exclusive, energy substrate for the brain. But under certain physiological and pathological conditions other substrates, namely monocarboxylates (lactate, pyruvate and ketone bodies), can contribute significantly to satisfy brain energy demands. These monocarboxylates need to be transported across the blood-brain barrier or out of astrocytes into the extracellular space and taken up into neurons. It has been shown that monocarboxylates are transported by a family of proton-linked transporters called monocarboxylate transporters (MCTs). In the central nervous system, MCT2 is the predominant neuronal isoform and little is known about the regulation of its expression. Noradrenaline (NA), insulin and IGF-1 were previously shown to enhance the expression of MCT2 in cultured cortical neurons via a translational mechanism. Here we demonstrate that the well known brain neurotrophic factor BDNF enhances MCT2 protein expression in cultured cortical neurons and in synaptoneurosome preparations in a time- and concentrationdependent manner without affecting MCT2 mRNA levels. We observed that BDNF induced MCT2 expression by activation of MAPK as well as PI3K/Akt/mTOR signaling pathways. Furthermore, we investigated the possible post-transcriptional regulation of MCT2 expression by a neuronal miRNA. Then, we demonstrated that BDNF enhanced MCT2 expression in the hippocampus in vivo, in parallel with some post-synaptic proteins such as PSD95 and AMPA receptor GluR2/3 subunits, and two immediate early genes Arc and Zif268 known to be expressed in conditions related to synaptic plasticity. In the last part, we demonstrated in vivo that a downregulation of hippocampal MCT2 via silencing with an appropriate lentiviral vector in mice caused an impairment of working memory without reference memory deficit. In conclusion, these results suggest that regulation of neuronal monocarboxylate transporter MCT2 expression could be a key event in the context of synaptic plasticity, allowing an adequate energy substrate supply in situations of altered synaptic efficacy. - Le glucose représente le substrat énergétique majeur pour le cerveau. Cependant, dans certaines conditions physiologiques ou pathologiques, le cerveau a la capacité d'utiliser des substrats énergéiques appartenant à la classe des monocarboxylates (lactate, pyruvate et corps cétoniques) afin de satisfaire ses besoins énergétiques. Ces monocarboxylates doivent être transportés à travers la barrière hématoencéphalique mais aussi hors des astrocytes vers l'espace extracellulaire puis re-captés par les neurones. Leur transport est assuré par une famillle de transporteurs aux monocarboxylates (MCTs). Dans le système nerveux central, les neurones expriment principalement l'isoforme MCT2 mais peu d'informations sont disponibles concernant la régulation de son expression. Il a été montré que la noradrénaline, l'insuline et l'IGF-1 induisent l'expression de MCT2 dans des cultures de neurones corticaux par un mécanisme traductionnel. Dans cette étude nous démontrons dans un premier temps que le facteur neurotrophique BDNF augmente l'expression de MCT2 à la fois dans des cultures de neurones corticaux et dans les préparations synaptoneurosomales selon un décours temporel et une gamme de concentrations propre. Aucun changement n'a été observé concernant les niveaux d'ARNm de MCT2. Nous avons observé que le BDNF induisait l'expression de MCT2 par l'activation simultanée des voies de signalisation MAPK et PI3K/Akt/mTOR. De plus, nous nous sommes intéressés à une potentielle régulation par les micro-ARNs de la synthèse de MCT2. Ensuite, nous avons démontré que le BDNF induit aussi l'expression de MCT2 dans l'hippocampe de la souris en parallèle avec d'autres protéines post-synaptiques telles que PSD95 et GluR2/3 et avec deux « immediate early genes » tels que Arc et Zif268 connus pour être exprimés dans des conditions de plasticité synaptique. Dans un dernier temps, nous avons démontré qu'une diminution d'expression de MCT2 induite par le biais d'un siRNA exprimé via un vecteur lentiviral dans l'hippocampe de souris générait des déficits de mémoire de travail sans affecter la mémoire de référence. En conclusion, ces résultats nous suggèrent que le transporteur aux monocarboxylates neuronal MCT2 serait essentiel pour l'apport énergétique du lactate pour les neurones dans des conditions de haute activité neuronale comme c'est le cas pendant les processus de plasticité synaptique.

Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases

AbstractBACKGROUND: Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult.PRINCIPAL FINDINGS: We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell.CONCLUSIONS: For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases.AVAILABILITY: The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download

Language Resources Factory: case study on the acquisition of Translation Memories

This paper demonstrates a novel distributed architecture to facilitate the acquisition of Language Resources. We build a factory that automates the stages involved in the acquisition, production, updating and maintenance of these resources. The factory is designed as a platform where functionalities are deployed as web services, which can be combined in complex acquisition chains using workflows. We show a case study, which acquires a Translation Memory for a given pair of languages and a domain using web services for crawling, sentence alignment and conversion to TMX.

Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses.

Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6.