Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) affects vascular barrier function and thus increases vessel permeability. This phenomenon may be exploited to facilitate targeted drug delivery and may lead to a new clinical application of photodynamic therapy. Here, we investigate the role of leukocyte recruitment for PDT-induced vascular permeabilization. STUDY DESIGN/MATERIAL AND METHODS: Fluorescein isothiocyanate dextran (FITC-D, 2,000 kDa) was injected intravenously 120 minutes after focal PDT on striated muscle in nude mice bearing dorsal skinfold chambers (Visudyne® 800 µg/kg, fluence rate 300 mW/cm2 , light dose of 200 J/cm2). Leukocyte interaction with endothelial cells was inhibited by antibodies functionally blocking adhesion molecules ("MABS-PDT" group, n = 5); control animals had PDT but no antibody injection (group "PDT", n = 7). By intravital microscopy, we monitored leukocyte rolling and sticking in real-time before, 90 and 180 minutes after PDT. The extravasation of FITC-D from striated muscle vessels into the interstitial space was determined in vivo during 45 minutes to assess treatment-induced alterations of vascular permeability. RESULTS: PDT significantly increased the recruitment of leukocytes and enhanced the leakage of FITC-D. Neutralization of adhesion molecules before PDT suppressed the rolling of leukocytes along the venular endothelium and significantly reduced the extravasation of FITC-D as compared to control animals (156 ± 27 vs. 11 ± 2 (mean ± SEM, number of WBC/30 seconds mm vessel circumference; P < 0.05) at 90 minutes after PDT and 194 ± 21 vs. 14 ± 4 at 180 minutes after PDT). In contrast, leukocyte sticking was not downregulated by the antibody treatment. CONCLUSION: Leukocyte recruitment plays an essential role in the permeability-enhancing effect of PDT.

Nouveaux traitements de l'hépatite C: aspects pharmacologiques et potentiel d'interaction [New hepatitis C treatments: pharmacological considerations and potential for drug interactions].

Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed.

DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB.

Detection of viral nucleic acids is central to antiviral immunity. Recently, DAI/ZBP1 (DNA-dependent activator of IRFs/Z-DNA binding protein 1) was identified as a cytoplasmic DNA sensor and shown to activate the interferon regulatory factor (IRF) and nuclear factor-kappa B (NF-kappaB) transcription factors, leading to type-I interferon production. DAI-induced IRF activation depends on TANK-binding kinase 1 (TBK1), whereas signalling pathways and molecular components involved in NF-kappaB activation remain elusive. Here, we report the identification of two receptor-interacting protein (RIP) homotypic interaction motifs (RHIMs) in the DAI protein sequence, and show that these domains relay DAI-induced NF-kappaB signals through the recruitment of the RHIM-containing kinases RIP1 and RIP3. We show that knockdown of not only RIP1, but also RIP3 affects DAI-induced NF-kappaB activation. Importantly, RIP recruitment to DAI is inhibited by the RHIM-containing murine cytomegalovirus (MCMV) protein M45. These findings delineate the DAI signalling pathway to NF-kappaB and suggest a possible new immune modulation strategy of the MCMV.

Interaction between neuropeptide Y (NPY) and brain-derived neurotrophic factor in NPY-mediated neuroprotection against excitotoxicity : a role for microglia

The neuroprotective effect of neuropeptide Y (NPY) receptor activation was investigated in organotypic mouse hippocampal slice cultures exposed to the glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Exposure of 2-week-old slice cultures, derived from 7-day-old C57BL/6 mice, to 8 microm AMPA, for 24 h, induced degeneration of CA1 and CA3 pyramidal cells, as measured by cellular uptake of propidium iodide (PI). A significant neuroprotection, with a reduction of PI uptake in CA1 and CA3 pyramidal cell layers, was observed after incubation with a Y(2) receptor agonist [NPY(13-36), 300 nm]. This effect was sensitive to the presence of the selective Y(2) receptor antagonist (BIIE0246, 1 microm), but was not affected by addition of TrkB-Fc or by a neutralizing antibody against brain-derived neurotrophic factor (BDNF). Moreover, addition of a Y(1) receptor antagonist (BIBP3226, 1 microm) or a NPY-neutralizing antibody helped to disclose a neuroprotective role of endogenous NPY in CA1 region. Cultures exposed to 8 microm AMPA for 24 h, displayed, as measured by an enzyme-linked immunosorbent assay, a significant increase in BDNF. In such cultures there was an up-regulation of neuronal TrkB immunoreactivity, as well as the presence of BDNF-immunoreactive microglial cells at sites of injury. Thus, an increase of AMPA-receptor mediated neurodegeneration, in the mouse hippocampus, was prevented by neuroprotective pathways activated by NPY receptors (Y(1) and Y(2)), which can be affected by BDNF released by microglia and neurons.

Interaction analysis and psychology: A dialogical perspective

Interaction analysis is not a prerogative of any discipline in social sciences. It has its own history within each disciplinary field and is related to specific research objects. From the standpoint of psychology, this article first draws upon a distinction between factorial and dialogical conceptions of interaction. It then briefly presents the basis of a dialogical approach in psychology and focuses upon four basic assumptions. Each of them is examined on a theoretical and on a methodological level with a leading question: to what extent is it possible to develop analytical tools that are fully coherent with dialogical assumptions? The conclusion stresses the difficulty of developing methodological tools that are fully consistent with dialogical assumptions and argues that there is an unavoidable tension between accounting for the complexity of an interaction and using methodological tools which necessarily "monologise" this complexity.

Transition to parenthood: The role of social interaction and endogenous networks

Empirical studies indicate that the transition to parenthood is influenced by an individual's peer group. To study the mechanisms creating interdepen- dencies across individuals' transition to parenthood and its timing we apply an agent-based simulation model. We build a one-sex model and provide agents with three different characteristics regarding age, intended education and parity. Agents endogenously form their network based on social closeness. Network members then may influence the agents' transition to higher parity levels. Our numerical simulations indicate that accounting for social inter- actions can explain the shift of first-birth probabilities in Austria over the period 1984 to 2004. Moreover, we apply our model to forecast age-specific fertility rates up to 2016.

A Picture of Performance Goals in the Social Plenum: The Interpersonal Antecedents and Consequences of Performance Goals

Bien que les activités où la compétence est un enjeu (p. ex. : problème académique) prennent souvent place dans des contextes interpersonnels (p. ex. : classe), hiérarchiques (p. ex. : enseignant-e/élèves), et spécifiques en termes de normes et de valeurs (p. ex. : culture), l'étude des buts de performance-le désir de se montrer compétent-e relativement à autrui-a le plus souvent été conduite au seul niveau intrapersonnel. S'appuyant sur le modèle transactionnel du stress et du coping, le modèle circumplexe des comportements interpersonnels, ainsi que sur la théorie de l'élaboration du conflit, la première partie de cette thèse révèle les conséquences interpersonnelles des buts de performance sur la régulation d'un comportement spécifique, à savoir le conflit sociocognitif (c.-à-d., une situation de confrontation avec un intéractant en désaccord) : les buts de performance-approche-le désir d'être meilleur-e qu'autrui-prédisent une régulation du conflit fortement agentique (dominante), soit la validation de son point de vue au détriment de celui de l'intéractant (que nous désignons régulation compétitive) ; alors que les buts de performance-évitement-le désir de ne pas être moins bon-ne qu'autrui-prédisent une régulation du conflit faiblement agentique (soumise), soit l'invalidation de son point de vue au bénéfice de celui de l'intéractant (que nous désignons régulation protective). De plus, les effets susmentionnés augmentent à mesure que l'intéractant est présenté comme supérieurement (vs. similairement) compétent. S'appuyant sur la littérature sur les structures de buts de groupe, et celle sur la socialisation des valeurs, la seconde partie de cette thèse révèle les antécédents interpersonnels des buts de performance, et plus spécifiquement le rôle du superviseur dans la socialisation des buts de performance : les buts de performance-approche d'un superviseur sont positivement associés avec l'émergence au cours du temps des buts de performance-approche de ses subordonnés (particulièrement lorsqu'ils se perçoivent comme compétents) et celle de leurs buts de performance-évitement (particulièrement lorsqu'ils se perçoivent comme incompétents). En outre, ce phénomène consistant en un processus de socialisation, les effets susmentionnés augmentent lorsque l'identification à l'endogroupe des subordonnées augmente, et lorsque l'adhésion aux valeurs culturelles occidentales dominantes (c.-à-d., rehaussement de soi) du superviseur augmente. Dans leur ensemble, ces résultats soulignent la nécessité d'étudier les buts dans leur plenum social, autrement dit, en adoptant une perspective interpersonnelle (c.-à-d., étudier les effets des buts entre les individus), positionnelle (c.-à-d., entre des individus de différentes positions sociales), et idéologique (c.- à-d., entre des individus se conformant à des normes spécifiques et adhérant à des valeurs spécifiques). -- Although competence-relevant activities (e.g., solving an academic problem) are often embedded in interpersonal (e.g., classroom), hierarchical (e.g., teacher/pupils), and norm-/value-specific (e.g., culture) settings, the study of performance goals-the desire to demonstrate competence relative to others-has mostly been conducted at the intrapersonal level alone. Drawing on the transactional model of stress and coping, the circumplex model of interpersonal behaviors, as well as on the conflict elaboration theory, the first part of this thesis reveals the interpersonal consequences of performance goals on the regulation of a specific behavior, namely socio-cognitive conflict (i.e., a situation of confrontation with a disagreeing interactant): Performance-approach goals-the desire to outperform others- predicted a highly agentic (dominant) conflict regulation, that is, the validation of one's point of view at the expense of that of the interactant (which we labeled competitive regulation); whereas performance-avoidance goals-the desire not to be outperformed by others- predicted a poorly agentic (submissive) conflict regulation, that is, the invalidation of one's point of view to the benefit of that of the interactant (which we labeled protective regulation). Furthermore, both the aforementioned effects were found to increase when the interactant was presented as being superiorly (vs. equally) in competence. Drawing on the literature on group goal structure, as well as on research on socialization of supervisors-based values, the second part of this thesis reveals the interpersonal antecedents of performance-based goals endorsement, focusing-more specifically-on the role of group-supervisors in performance goals socialization: Supervisor's performance-approach goals were positively associated with the emergence over time of subordinates' performance-approach (especially when perceiving themselves as competent) and -avoidance goals (especially when perceiving themselves as incompetent). Furthermore, providing evidence that this phenomenon essentially reflects a socialization process, both the aforementioned effects were found to increase as subordinates' in-group identification increased, and as supervisors' adherence to dominant Western values (i.e., self-enhancement values) increased. Taken together, these results advocate the need to study performance goals in their social plenum, that is, adopting an interpersonal (i.e., studying the effects of goals between individuals), positional (i.e., between individuals from different social positions), and ideological (i.e., between individuals following specific norms and endorsing specific values) perspective.

Functional interaction between the estrogen receptor and CTF1: analysis of the vitellogenin gene B1 promoter in yeast.

Eukaryotic gene expression depends on a complex interplay between the transcriptional apparatus and chromatin structure. We report here a yeast model system for investigating the functional interaction between the human estrogen receptor (hER) and CTF1, a member of the CTF/NFI transcription factor family. We show that a CTF1-fusion protein and the hER transactivate a synthetic promoter in yeast in a synergistic manner. This interaction requires the proline-rich transactivation domain of CTF1. When the natural estrogen-dependent vitellogenin B1 promoter is tested in yeast, CTF1 and CTF1-fusion proteins are unable to activate transcription, and no synergy is observed between hER, which activates the B1 promoter, and these factors. Chromatin structure analysis on this promoter reveals positioned nucleosomes at -430 to -270 (+/-20 bp) and at -270 to - 100 (+/-20 bp) relative to the start site of transcription. The positions of the nucleosomes remain unchanged upon hormone-dependent transcriptional activation of the promoter, and the more proximal nucleosome appears to mask the CTF/NFI site located at - 101 to -114. We conclude that a functional interaction of hER with the estrogen response element located upstream of a basal promoter occurs in yeast despite the nucleosomal organization of this promoter, whereas the interaction of CTF1 with its target site is apparently precluded by a nucleosome.

Positive impact of inhibitory Ly49 receptor-MHC class I interaction on NK cell development.

NK cells can kill MHC-different or MHC-deficient but not syngeneic MHC-expressing target cells. This MHC class I-specific tolerance is acquired during NK cell development. MHC recognition by murine NK cells largely depends on clonally distributed Ly49 family receptors, which inhibit NK cell function upon ligand engagement. We investigated whether these receptors play a role for the development of NK cells and provide evidence that the expression of a Ly49 receptor transgene on developing NK cells endowed these cells with a significant developmental advantage over NK cells lacking such a receptor, but only if the relevant MHC ligand was present in the environment. The data suggest that the transgenic Ly49 receptor accelerates and/or rescues the development of NK cells which would otherwise fail to acquire sufficient numbers of self-MHC-specific receptors. Interestingly, the positive effect on NK cell development is most prominent when the MHC ligand is simultaneously present on both hemopoietic and nonhemopoietic cells. These findings correlate with functional data showing that MHC class I ligand on all cells is required to generate functionally mature NK cells capable of reacting to cells lacking the respective MHC ligand. We conclude that the engagement of inhibitory MHC receptors during NK cell development provides signals that are important for further NK cell differentiation and/or maturation.

Splenium of corpus callosum: patterns of interhemispheric interaction in children and adults.

The splenium of the corpus callosum connects the posterior cortices with fibers varying in size from thin late-myelinating axons in the anterior part, predominantly connecting parietal and temporal areas, to thick early-myelinating fibers in the posterior part, linking primary and secondary visual areas. In the adult human brain, the function of the splenium in a given area is defined by the specialization of the area and implemented via excitation and/or suppression of the contralateral homotopic and heterotopic areas at the same or different level of visual hierarchy. These mechanisms are facilitated by interhemispheric synchronization of oscillatory activity, also supported by the splenium. In postnatal ontogenesis, structural MRI reveals a protracted formation of the splenium during the first two decades of human life. In doing so, the slow myelination of the splenium correlates with the formation of interhemispheric excitatory influences in the extrastriate areas and the EEG synchronization, while the gradual increase of inhibitory effects in the striate cortex is linked to the local inhibitory circuitry. Reshaping interactions between interhemispherically distributed networks under various perceptual contexts allows sparsification of responses to superfluous information from the visual environment, leading to a reduction of metabolic and structural redundancy in a child's brain.