The complement inhibitor low molecular weight dextran sulfate prevents TLR4-induced phenotypic and functional maturation of human dendritic cells.

Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1beta, IL-6, IL-12p70, and TNF-alpha. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of IkappaB-alpha and activation of NF-kappaB. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.

Infections and functional impairment in nursing home residents: a reciprocal relationship.

OBJECTIVES: To determine the relationship between infections and functional impairment in nursing home residents. DESIGN: Prospective cohort study (follow-up period, 6 months). SETTING: Thirty-nine nursing homes in western Switzerland. PARTICIPANTS: A total of 1,324 residents aged 65 and older (mean age 85.7; 76.6% female) who agreed to participate, or their proxies, by oral informed consent. MEASUREMENTS: Functional status measured every 3 months. Two different outcomes were used: (a) functional decline defined as death or decreased function at follow-up and (b) functional status score using a standardized measure. RESULTS: At the end of follow-up, mortality was 14.6%, not different for those with and without infection (16.2% vs 13.1%, P=.11). During both 3-month periods, subjects with infection had higher odds of functional decline, even after adjustment for baseline characteristics and occurrence of a new illness (adjusted odds ratio (AOR)=1.6, 95% confidence interval (CI)=1.2-2.2, P=.002, and AOR=1.5, 95% CI=1.1-2.0, P=.008, respectively). The odds of decline increased in a stepwise fashion in patients with zero, one, and two or more infections. The analyses predicting functional status score (restricted to subjects who survived) gave similar results. A survival analysis predicting time to first infection confirmed a stepwise greater likelihood of infection in subjects with moderate and severe impairment at baseline than in subjects with no or mild functional impairment at baseline. CONCLUSION: Infections appear to be both a cause and a consequence of functional impairment in nursing home residents. Further studies should be undertaken to investigate whether effective infection control programs can also contribute to preventing functional decline, an important component of these residents' quality of life.

Refined asymptotics for the subcritical Keller-Segel system and related functional inequalities

We analyze the rate of convergence towards self-similarity for the subcritical Keller-Segel system in the radially symmetric two-dimensional case and in the corresponding one-dimensional case for logarithmic interaction. We measure convergence in Wasserstein distance. The rate of convergence towards self-similarity does not degenerate as we approach the critical case. As a byproduct, we obtain a proof of the logarithmic Hardy-Littlewood-Sobolev inequality in the one dimensional and radially symmetric two dimensional case based on optimal transport arguments. In addition we prove that the onedimensional equation is a contraction with respect to Fourier distance in the subcritical case.

Morphological Studies on the Triatoma brasiliensis Neiva, 1911 (Hemiptera, Reduviidae, Triatominae) Genital Structures and Eggs of Different Chromatic Forms

Triatoma brasiliensis is considered one of the most important Chagas disease vectors being a widespread species in semiarid areas of northeastern Brazil. The species displays distinct chromatic patterns of the cuticle in different localities. Four populations were analyzed in this study: 1-Caicó, Rio Grande do Norte, it will be called the brasiliensis population; 2-Espinosa, Minas Gerais, the melanica population; 3-Petrolina, Pernambuco, the macromelasoma population, and 4-Juazeiro, Bahia, the darker one in overall cuticle coloration, the Juazeiro population. In order to differentiate the four populations of T. brasiliensis, a comparative morphological analysis of external genital structures and of eggs were carried out. The analysis of the male genital structures evidenced minor individual structural variations that did not correlate with chromatic differences or the geographical origins, emphasizing the importance of examining sufficiently large and representative samples before using minor genital variations for taxonomic diagnosis. By scanning electron microscopy of the egg exochorion, each chromatic population presented a distinct ornamentation pattern. The melanica population differed mainly from the other populations studied since it had about 40.6%, 69.6% and 76.6% more perforations, on each cell exochorion, than the brasiliensis, the Juazeiro and the macromelasoma populations respectively. In the melanica population the perforation layout is also peculiar, with densely distributed perforations over all the egg surface. Morphometric measures of the eggs showed statistically significant differences: the macromelasoma population presented the longest length (2.43 mm) while the shortest was recorded in the brasiliensis population (2.29 mm).

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

High-field (3T) magnetic resonance defecography with functional assessment of the evacuation phase : a pictorial essay : P10

Purpose: Dynamic high-field magnetic resonance (MR) defecography including the evacuation phase is a promising tool for the assessment of functional pelvic disorders, nowadays seen with increasing frequency in elderly women in particular. Learning objectives: 1. To describe the adequate technique of dynamic high-field MRI (3T) in assessing pelvic floor disorders. 2. To provide an overview of the most common pathologies occurring during the evacuation phase, especially in comparison with results of conventional defecography. Methods and materials: After description of the ideal technical parameters of MR defecography performed in supine position after gel rectal filling with a 3 Tesla unit and including the evacuation phase we stress the importance of using a standardized evaluation system for the exact assessment of pelvic floor pathophysiology. Results: The typical pelvic floor disorders occurring before and/or during the evacuation phase, such as sphincter insufficiency, vaginal vault and/or uterine prolapse, cystourethrocele, peritoneo-/ entero-/ sigmoïdocele or rectal prolapse, are demonstrated. The difference between the terms "pelvic floor descent" and "pelvic floor relaxation" are pictorially outlined. MR results are compared with these of conventional defecography. Conclusion: Exact knowledge about the correct technique including the evacuation phase and the use of a standardized evaluation system in assessing pelvic floor disorders by dynamic high-field MRI is mandatory for accurate and reproducible diagnosis.

Role of Immune Complexes from Pacients with Different Clinical Forms of Schistosomiasis in the Modulation of In Vitro Granuloma Reaction

Schistosomiasis is a disease whose pathology is strongly related to the granulomatous reaction formed around parasite eggs trapped in host tissues. Studies have shown that the chronic intestinal form (INT) of this infection is associated with a variety of immunoregulatory mechanisms which lead to a diminished granulomatous reaction. Using an in vitro model of granuloma reaction, we show that immune complexes (IC) isolated from sera of INT patients are able to reduce granulomatous reaction developed by peripheral blood mononuclear cells (PBMC) from acute (AC), INT and hepatosplenic (HE) patients to soluble egg antigen (SEA)-conjugated polyacrylamide beads (PB-SEA). This inhibitory activity is also observed in cell proliferation assay of PBMC from INT and HE patients stimulated with SEA and adult worm antigen (SWAP). Furthermore, IC isolated from sera of patients with different clinical forms of the disease are also able to suppress INT patients PBMC reactivity. Therefore, our results show that circulating IC present in sera of patients with different clinical forms of schistosomiasis may down-regulate PBMC reactivity to parasite antigens resulting in a diminished granuloma reaction to parasite eggs

Structural and functional interaction sites between Na,K-ATPase and FXYD proteins.

Several members of the FXYD protein family are tissue-specific regulators of Na,K-ATPase that produce distinct effects on its apparent K(+) and Na(+) affinity. Little is known about the interaction sites between the Na,K-ATPase alpha subunit and FXYD proteins that mediate the efficient association and/or the functional effects of FXYD proteins. In this study, we have analyzed the role of the transmembrane segment TM9 of the Na,K-ATPase alpha subunit in the structural and functional interaction with FXYD2, FXYD4, and FXYD7. Mutational analysis combined with expression in Xenopus oocytes reveals that Phe(956), Glu(960), Leu(964), and Phe(967) in TM9 of the Na,K-ATPase alpha subunit represent one face interacting with the three FXYD proteins. Leu(964) and Phe(967) contribute to the efficient association of FXYD proteins with the Na,K-ATPase alpha subunit, whereas Phe(956) and Glu(960) are essential for the transmission of the functional effect of FXYD proteins on the apparent K(+) affinity of Na,K-ATPase. The relative contribution of Phe(956) and Glu(960) to the K(+) effect differs for different FXYD proteins, probably reflecting the intrinsic differences of FXYD proteins on the apparent K(+) affinity of Na,K-ATPase. In contrast to the effect on the apparent K(+) affinity, Phe(956) and Glu(960) are not involved in the effect of FXYD2 and FXYD4 on the apparent Na(+) affinity of Na,K-ATPase. The mutational analysis is in good agreement with a docking model of the Na,K-ATPase/FXYD7 complex, which also predicts the importance of Phe(956), Glu(960), Leu(964), and Phe(967) in subunit interaction. In conclusion, by using mutational analysis and modeling, we show that TM9 of the Na,K-ATPase alpha subunit exposes one face of the helix that interacts with FXYD proteins and contributes to the stable interaction with FXYD proteins, as well as mediating the effect of FXYD proteins on the apparent K(+) affinity of Na,K-ATPase.

Exploration of immune competencies of viral-specific CD8+T cells in MS patients using tetramers and functional CTL assays

Introduction: Epstein-Barr Virus(EBV) has been repeatedly associatedwith multiple sclerosis (MS). Wehave previously shown that there is ahigh peripheral as well as intrathecalactivation of EBV-, but not cytomegalovirus(CMV)-specific CD8+ Tcells, early in the course of MS,strengthening the link between EBVand MS. However, the trigger of thisincreased EBV-specific CD8+ T cellresponse remains obscure. It could resultfrom a higher EBV viral load. Alternatively,it could be due to an intrinsicallydeficient EBV-specificCTL response, cytotoxic granulesmediated.Thus, we performed anin-depth study of the phenotype of exvivo EBV- and CMV-specific CD8+T cells in MS patients and control patients,assessing their cytotoxic activity.Methods:We analyzed the profileof cytotoxic granules in EBV- andCMV-specific CD8+ T cells in a cohortof 13 early MS patients, 20 lateMS, 30 other neurological diseases(OND) patients and 7 healthy controlsubjects. Ex vivo analysis of EBV- orCMV-specific CD8+ T cells was performedusing HLA class I/tetramercomplexes coupled to CCR7 andCD57 markers in conjunction withperforin, granzymes A, BandKstaining.In a sub-cohort of MS patientsand controls, cytotoxic activity ofEBV- and CMV-specific CD8+ Tcells was investigated using a functionalCFSE CTL assay. Results: UsingHLA Class I tetramers for EBVand CMV, we found that the frequencyof EBV- or CMV-specificCD8+ T cells were similar in all studysubjects. Most of EBV- and CMVspecificCD8+Tcells were highly differentiated(CCR7-) and a variousproportion expressed the exhaustionmarker CD57. MS and OND patientshad increased perforin expression inEBV-specific CD8+ T cells. Most importantly,we found that MS patientswith longer disease duration tended tohave lower CTL cytotoxicity as comparedto earlyMSpatients or controls.Conclusions: Effector EBV-specificCD8+ T cells are increased in earlyMS, however their cytotoxic granuleprofile does not seem to be fully alteredand the cytotoxic activity ofthese cells is normal. However, thecytotoxic activity of CTL decreasedin late MS patients suggesting an exhaustionof EBV-specific CD8+ Tcells possibly due to EBV reactivation.This work was supported by theSwiss National Foundation PP00B3-124893, the Swiss Society for MS,and the Biaggi Foundation to RADP.

Facilitated glucose transporters in epithelial cells.

The molecular cloning of facilitated sugar transporters has led to the identification of a family of transport molecules having similar functions, but possessing specific kinetic and regulatory properties. These transporter isoforms are characterized by different primary structures, specific tissue localization, and polarized expression within the same epithelial cells. The use of Xenopus oocytes for the functional expression of different members of this transporter family has been of considerable value in defining the kinetic properties and sugar specificities of the different isoforms. The expression of chimeric or variously mutated transporters should, in the near future, permit the determination of the structural basis for their kinetic properties and sugar specificities. cDNA probes and antipeptide antibodies specific for each isoform are now being used to determine their specific regulation during development and in different states of altered glucose homeostasis. The variety of molecular forms implicated in the apparently simple task of sugar uptake or transepithelial transport has been surprising. With the available molecular tools now in hand, it will be possible to study these mechanisms in much greater detail.

Explicit methods for Hilbert modular forms

We exhibit algorithms to compute systems of Hecke eigenvalues for spaces of Hilbert modular forms over a totally real field. We provide many explicit examples as well as applications to modularity and Galois representations.

MEVA-Ambiental: MEtodologia per a la Valoració de l'Aprenentatge. Centrada en l'educació ambiental

Aquest projecte abasta el disseny i el desenvolupament d’un model prototípic de Metodologia per a la Valoració de l’Aprenentatge Ambiental, a la qual anomenem “MEVA-Ambiental”. Per a fer possible aquesta fita ens hem basat en fonaments ontològics i constructivistes per representar i analitzar el coneixement a fi de poder quantificar l’Increment de Coneixement (IC). Per nosaltres l’IC esdevé un indicador socio-educatiu que ens servirà per a determinar l’efectivitat dels tallers d’educació ambiental en percentatge. En procedir d’aquesta manera, les qualificacions resultats poden es poden prendre com punt de partida per a desenvolupar estudis en el temps i comprendre com “s’ancora” el nou coneixement a l’estructura cognitiva dels aprenents. Més enllà del plantejament teòric de mètode, també proveïm la solució tècnica que mostra com n’és de funcional i d’aplicable la part empírica metodològica. A aquesta solució que hem anomenat “MEVA-Tool”, és una eina virtual que automatitza la recollida i tractament de dades amb una estructura dinàmica basada en “qüestionaris web” que han d’emplenar els estudiants, una “base de dades” que acumula la informació i en permet un filtratge selectiu, i més “Llibre Excel” que en fa el tractament informatiu, la representació gràfica dels resultats, l’anàlisi i conclusions.

Evolution of decision-making and learning under fluctuating social environments

The capacity to learn to associate sensory perceptions with appropriate motor actions underlies the success of many animal species, from insects to humans. The evolutionary significance of learning has long been a subject of interest for evolutionary biologists who emphasize the bene¬fit yielded by learning under changing environmental conditions, where it is required to flexibly switch from one behavior to another. However, two unsolved questions are particularly impor¬tant for improving our knowledge of the evolutionary advantages provided by learning, and are addressed in the present work. First, because it is possible to learn the wrong behavior when a task is too complex, the learning rules and their underlying psychological characteristics that generate truly adaptive behavior must be identified with greater precision, and must be linked to the specific ecological problems faced by each species. A framework for predicting behavior from the definition of a learning rule is developed here. Learning rules capture cognitive features such as the tendency to explore, or the ability to infer rewards associated to unchosen actions. It is shown that these features interact in a non-intuitive way to generate adaptive behavior in social interactions where individuals affect each other's fitness. Such behavioral predictions are used in an evolutionary model to demonstrate that, surprisingly, simple trial-and-error learn¬ing is not always outcompeted by more computationally demanding inference-based learning, when population members interact in pairwise social interactions. A second question in the evolution of learning is its link with and relative advantage compared to other simpler forms of phenotypic plasticity. After providing a conceptual clarification on the distinction between genetically determined vs. learned responses to environmental stimuli, a new factor in the evo¬lution of learning is proposed: environmental complexity. A simple mathematical model shows that a measure of environmental complexity, the number of possible stimuli in one's environ¬ment, is critical for the evolution of learning. In conclusion, this work opens roads for modeling interactions between evolving species and their environment in order to predict how natural se¬lection shapes animals' cognitive abilities. - La capacité d'apprendre à associer des sensations perceptives à des actions motrices appropriées est sous-jacente au succès évolutif de nombreuses espèces, depuis les insectes jusqu'aux êtres hu¬mains. L'importance évolutive de l'apprentissage est depuis longtemps un sujet d'intérêt pour les biologistes de l'évolution, et ces derniers mettent l'accent sur le bénéfice de l'apprentissage lorsque les conditions environnementales sont changeantes, car dans ce cas il est nécessaire de passer de manière flexible d'un comportement à l'autre. Cependant, deux questions non résolues sont importantes afin d'améliorer notre savoir quant aux avantages évolutifs procurés par l'apprentissage. Premièrement, puisqu'il est possible d'apprendre un comportement incorrect quand une tâche est trop complexe, les règles d'apprentissage qui permettent d'atteindre un com¬portement réellement adaptatif doivent être identifiées avec une plus grande précision, et doivent être mises en relation avec les problèmes écologiques spécifiques rencontrés par chaque espèce. Un cadre théorique ayant pour but de prédire le comportement à partir de la définition d'une règle d'apprentissage est développé ici. Il est démontré que les caractéristiques cognitives, telles que la tendance à explorer ou la capacité d'inférer les récompenses liées à des actions non ex¬périmentées, interagissent de manière non-intuitive dans les interactions sociales pour produire des comportements adaptatifs. Ces prédictions comportementales sont utilisées dans un modèle évolutif afin de démontrer que, de manière surprenante, l'apprentissage simple par essai-et-erreur n'est pas toujours battu par l'apprentissage basé sur l'inférence qui est pourtant plus exigeant en puissance de calcul, lorsque les membres d'une population interagissent socialement par pair. Une deuxième question quant à l'évolution de l'apprentissage concerne son lien et son avantage relatif vis-à-vis d'autres formes plus simples de plasticité phénotypique. Après avoir clarifié la distinction entre réponses aux stimuli génétiquement déterminées ou apprises, un nouveau fac¬teur favorisant l'évolution de l'apprentissage est proposé : la complexité environnementale. Un modèle mathématique permet de montrer qu'une mesure de la complexité environnementale - le nombre de stimuli rencontrés dans l'environnement - a un rôle fondamental pour l'évolution de l'apprentissage. En conclusion, ce travail ouvre de nombreuses perspectives quant à la mo¬délisation des interactions entre les espèces en évolution et leur environnement, dans le but de comprendre comment la sélection naturelle façonne les capacités cognitives des animaux.