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101.
Claude Sadis Sophie Detienne Beno?t Vokaer Louis-Marie Charbonnier Philippe Lema?tre Chloé Spilleboudt Sandrine Delbauve Carole Kubjak Véronique Flamand Kenneth A. Field Michel Goldman Fleur S. Benghiat Alain Le Moine 《PloS one》2013,8(11)
Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant. 相似文献
102.
Although the pivotal implication of the host-encoded Prion protein, PrP, in the neuropathology of transmissible spongiform encephalopathy is known for decades, its biological role remains mostly elusive. Genetic inactivation is one way to assess such issue but, so far, PrP-knockout mice did not help much. However, recent reports involving (1) further studies of these mice during embryogenesis, (2) knockdown experiments in Zebrafish and (3) knockdown of Shadoo, a protein with PrP-like functional domains, in PrP-knockout mice, all suggested a role of the Prion protein family in early embryogenesis. This view is challenged by the recent report that PrP/Shadoo knockout mice are healthy and fertile. Although puzzling, these apparently contradictory data may on the contrary help at deciphering the Prion protein family role through focusing scientific attention outside the central nervous system and by helping the identification of other loci involved in the genetic robustness associated with PrP. 相似文献
103.
Xiao-Hong Li William de Castro-Borges Sophie Parker-Manuel Gillian M. Vance Ricardo DeMarco Leandro X. Neves Gareth J. O. Evans R. Alan Wilson 《PLoS neglected tropical diseases》2013,7(7)
Background
Although the ultrastructure of the schistosome esophageal gland was described >35 years ago, its role in the processing of ingested blood has never been established. The current study was prompted by our identification of MEG-4.1 expression in the gland and the observation of erythrocyte uncoating in the posterior esophagus.Methodology/Principal Findings
The salient feature of the posterior esophagus, characterized by confocal and electron microscopy, is the enormous increase in membrane surface area provided by the plate-like extensions and basal invaginations of the lining syncytium, with unique crystalloid vesicles releasing their contents between the plates. The feeding process was shown by video microscopy to be divided into two phases, blood first accumulating in the anterior lumen before passing as a bolus to the posterior. There it streamed around a plug of material revealed by confocal microscopy as tethered leucocytes. These were present in far larger numbers than predicted from the volume of the lumen, and in varying states of damage and destruction. Intact erythrocytes were detected in the anterior esophagus but not observed thereafter, implying that their lysis occurred rapidly as they enter the posterior. Two further genes, MEGs 4.2 and 14, were shown to be expressed exclusively in the esophageal gland. Bioinformatics predicted that MEGs 4.1 and 4.2 possessed a common hydrophobic region with a shared motif, while antibodies to SjMEG-4.1 showed it was bound to leucocytes in the esophageal lumen. It was also predicted that MEGs 4.1 and 14 were heavily O-glycosylated and this was confirmed for the former by 2D-electrophoresis and Western blotting.Conclusions/Significance
The esophageal gland and its products play a central role in the processing of ingested blood. The binding of host antibodies in the esophageal lumen shows that some constituents are antibody targets and could provide a new source of vaccine candidates. 相似文献104.
Fabien Dépis Eric Hatterer Romain Ballet Bruno Daubeuf Laura Cons Sophie Glatt Walter Reith Marie Kosco-Vilbois Yann Dean 《MABS-AUSTIN》2013,5(4):555-564
Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration. 相似文献
105.
How do humans perceive the passage of time and the duration of events without a dedicated sensory system for timing? Previous studies have demonstrated that when a stimulus changes over time, its duration is subjectively dilated, indicating that duration judgments are based on the number of changes within an interval. In this study, we tested predictions derived from three different accounts describing the relation between a changing stimulus and its subjective duration as either based on (1) the objective rate of changes of the stimulus, (2) the perceived saliency of the changes, or (3) the neural energy expended in processing the stimulus. We used visual stimuli flickering at different frequencies (4–166 Hz) to study how the number of changes affects subjective duration. To this end, we assessed the subjective duration of these stimuli and measured participants'' behavioral flicker fusion threshold (the highest frequency perceived as flicker), as well as their threshold for a frequency-specific neural response to the flicker using EEG. We found that only consciously perceived flicker dilated perceived duration, such that a 2 s long stimulus flickering at 4 Hz was perceived as lasting as long as a 2.7 s steady stimulus. This effect was most pronounced at the slowest flicker frequencies, at which participants reported the most consistent flicker perception. Flicker frequencies higher than the flicker fusion threshold did not affect perceived duration at all, even if they evoked a significant frequency-specific neural response. In sum, our findings indicate that time perception in the peri-second range is driven by the subjective saliency of the stimulus'' temporal features rather than the objective rate of stimulus changes or the neural response to the changes. 相似文献
106.
Rapeephan R. Maude Md Amir Hossain Mahtab Uddin Hassan Sophie Osbourne Katherine Langan Abu Sayeed Mohammed Rezaul Karim Rasheda Samad Shyamanga Borooah Bal Dhillon Nicholas P. J. Day Arjen M. Dondorp Richard J. Maude 《PloS one》2013,8(12)
Introduction
Measurement of optic nerve sheath diameter (ONSD) by ultrasound is increasingly used as a marker to detect raised intracranial pressure (ICP). ONSD varies with age and there is no clear consensus between studies for an upper limit of normal. Knowledge of normal ONSD in a healthy population is essential to interpret this measurement.Methods
In a prospective observational study, ONSD was measured using a 15 MHz ultrasound probe in healthy volunteers in Chittagong, Bangladesh. The aims were to determine the normal range of ONSD in healthy Bangladeshi adults and children, compare measurements in males and females, horizontal and vertical beam orientations and left and right eyes in the same individual and to determine whether ONSD varies with head circumference independent of age.Results
136 subjects were enrolled, 12.5% of whom were age 16 or under. Median ONSD was 4.41 mm with 95% of subjects in the range 4.25–4.75 mm. ONSD was bimodally distributed. There was no relationship between ONSD and age (≥4 years), gender, head circumference, and no difference in left vs right eye or horizontal vs vertical beam.Conclusions
Ultrasonographic ONSD in Bangladeshi healthy volunteers has a narrow bimodal distribution independent of age (≥4 years), gender and head circumference. ONSD >4.75 mm in this population should be considered abnormal. 相似文献107.
Jerome Hottin Edy Wijaya Laurent Hay Sophie Maricot Mohamed Bouazaoui Jean-Pierre Vilcot 《Plasmonics (Norwell, Mass.)》2013,8(2):619-624
A large majority of surface plasmon resonance (SPR) sensors reported in the literature are designed to operate in the visible electromagnetic spectrum. However, the near-infrared, particularly at the telecommunications wavelength of 1550 nm, is also especially attractive for SPR sensing applications. In fact, SPR sensors operating in this region benefit from narrower resonance and deeper field penetration. In this paper, we report a theoretical and experimental study of an SPR sensor operating at a fixed wavelength of 1550 nm. The influence of the choice of metals and the interrogation methods on the sensitivity of the resulting SPR sensor is investigated. Two types of sensor chips (simple gold (Au) and bimetallic silver/Au structure) and three interrogation methods (monitoring of the position of the reflectivity minimum, the position of the centroid, and the intensity evolution of the reflectivity) are examined. We show that a refractive index resolution of 2.7?×?10?6 refractive index unit can be easily obtained, and with further optimization of the measurement system, the ultimate limit of detection is expected to be even lowered. Therefore, the approach discussed here already shows a promising potential for highly sensitive SPR sensors. 相似文献
108.
François Binet Gaëlle Mawambo Nicholas Sitaras Nicolas Tetreault Eric Lapalme Sandra Favret Agustin Cerani Dominique Leboeuf Sophie Tremblay Flavio Rezende Aimee M. Juan Andreas Stahl Jean-Sebastien Joyal Éric Milot Randal J. Kaufman Martin Guimond Timothy E. Kennedy Przemyslaw Sapieha 《Cell metabolism》2013,17(3):353-371
Highlights? Canonical ER stress pathways are activated in central neurons during hypoxia/ischemia ? The ER stress endoribonuclease IRE1α degrades the neurovascular guidance cue netrin-1 ? Neuronal-derived netrin-1 activates a reparative proangiogenic program in microglial cells ? Neuronal ER stress prevents reparative angiogenesis in the ischemic neural retina 相似文献
109.
Anne Lopes Sophie Sacquin-Mora Viktoriya Dimitrova Elodie Laine Yann Ponty Alessandra Carbone 《PLoS computational biology》2013,9(12)
Large-scale analyses of protein-protein interactions based on coarse-grain molecular docking simulations and binding site predictions resulting from evolutionary sequence analysis, are possible and realizable on hundreds of proteins with variate structures and interfaces. We demonstrated this on the 168 proteins of the Mintseris Benchmark 2.0. On the one hand, we evaluated the quality of the interaction signal and the contribution of docking information compared to evolutionary information showing that the combination of the two improves partner identification. On the other hand, since protein interactions usually occur in crowded environments with several competing partners, we realized a thorough analysis of the interactions of proteins with true partners but also with non-partners to evaluate whether proteins in the environment, competing with the true partner, affect its identification. We found three populations of proteins: strongly competing, never competing, and interacting with different levels of strength. Populations and levels of strength are numerically characterized and provide a signature for the behavior of a protein in the crowded environment. We showed that partner identification, to some extent, does not depend on the competing partners present in the environment, that certain biochemical classes of proteins are intrinsically easier to analyze than others, and that small proteins are not more promiscuous than large ones. Our approach brings to light that the knowledge of the binding site can be used to reduce the high computational cost of docking simulations with no consequence in the quality of the results, demonstrating the possibility to apply coarse-grain docking to datasets made of thousands of proteins. Comparison with all available large-scale analyses aimed to partner predictions is realized. We release the complete decoys set issued by coarse-grain docking simulations of both true and false interacting partners, and their evolutionary sequence analysis leading to binding site predictions. Download site: http://www.lgm.upmc.fr/CCDMintseris/ 相似文献
110.
Sophie Garnier Vinh Truong Jessy Brocheton Tanja Zeller Maxime Rovital Philipp S. Wild Andreas Ziegler The Cardiogenics Consortium Thomas Munzel Laurence Tiret Stefan Blankenberg Panos Deloukas Jeannette Erdmann Christian Hengstenberg Nilesh J. Samani Heribert Schunkert Willem H. Ouwehand Alison H. Goodall Fran?ois Cambien David-Alexandre Trégou?t 《PLoS genetics》2013,9(1)