Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon.

UNLABELLED: Previous animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(-) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50) more than 100-fold greater than SPBN(-). In vitro and in vivo mouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR(-/-)) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE: Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-γ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus

Combined 3D analysis of lower-limb morphology and function in children with idiopathic equinovarus clubfoot: A preliminary study

Introduction In children treated for idiopathic equinovarus clubfoot (EVCF), the relation between morphologic defects on clinical examination and standard X-ray on the one hand and functional abnormalities on the other is difficult to objectify. The aim of the present study was to demonstrate the feasibility of combined 3D analysis of the foot and lower limb based on biplanar EOS radiographs and gait analysis. The study hypothesis was that this provides better understanding of abnormalities in form and function. Methods Ten children with unilateral EVCF and “very good” clinical results were included. They underwent gait analysis on the Rizzoli Institute multisegment foot model. Kinematic data were collected for the hip, knee, ankle and foot (hindfoot/midfoot, midfoot/forefoot and hindfoot/forefoot). Biplanar EOS radiographs were taken to determine anatomic landmarks and radiological parameters. Results Complete acquisition time was around 2 hours per patient. No significant differences were found between EVCF and healthy feet except for calcaneal incidence, tibiocalcaneal angle and hindfoot/midfoot and hindfoot/forefoot inversion. Discussion The feasibility of the combined analysis was confirmed. There were no differences in range of motion, moment or power between EVCF and healthy feet in this series of patients with very good results. The functional results are related to radiological results within the normal range. The protocol provided anatomic and kinematic reference data. A larger-scale study could more objectively assess the contribution of EOS radiography using optoelectronic markers. Level of evidence II, low-power prospective study.The authors thank Chaire ParisTech BiomecAM (personalized musculoskeletal modeling) for financial help

Combined gait analysis and radiologic examination in children with X-linked hypophosphatemia

Autre financement : Kyowa Kirin PharmaBackground: X-linked hypophosphataemia causes bone deformities and gait abnormalities that tend to worsen with age in the absence of appropriate treatment. However, doctors do not currently use quantitative tools to characterize these symptoms and their possible interactions. Methods: Radiographs and 3D gait data from 43 non-surgical growing children with X-linked hypophosphataemia were acquired prospectively. Data from age-matched typically developing children were used to form the reference group. Subgroups based on radiological parameters were compared with each other and with the reference population. Linear correlations between radiographic parameters and gait variables were examined. Finding: X-linked hypophosphatemic patients differed from the control group in pelvic tilt, ankle plantarflexion, knee flexion moment and power. High correlations with tibiofemoral angle were found for trunk lean, knee and hip adduction, and knee abduction moment. The Gait Deviation Index was below 80 for 88% of the patients with a high tibiofemoral angle (varus). Compared to other subgroups, varus patients had augmented trunk lean (+3°) and knee adduction (+10°) and decreased hip adduction (-5°) and ankle plantarflexion (-6°). Femoral torsion was associated with alterations in rotation at the knee, and hip. Interpretation: Gait abnormalities induced in X-linked hypophosphataemia have been described in a large cohort of children. Links between gait alterations and lower limb deformities were found, with varus deformities standing out. Since bony deformities appear when X-linked hypophosphatemic children start walking and have been found to alter gait patterns, we suggest that combining radiology with gait analysis may improve the clinical management of X-linked hypophosphataemia

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Modélisation de la propagation d'une mutation lors de l'expansion spatiale d'une population

National audienceno abstrac

Protection Against CNS-Targeted Rabies Virus Infection is Dependent upon Type-1 Immune Mechanisms Induced by Live-Attenuated Rabies Vaccines

Rabies remains a major public health issue worldwide, especially in developing countries where access to medical care can represent a real challenge. While there is still no cure for rabies, it is a vaccine-preventable disease with pre- and post-exposure prophylaxis regimens approved by the World Health Organization (WHO). However, many rabies-exposed individuals have limited access to vaccines and virus-neutralizing antibodies approved for post-exposure prophylaxis. Unfortunately, any delay in the administration of these reagents can have lethal consequences. This highlights the need to develop cost-effective immunological reagents with a greater window of efficacy. Live-attenuated vaccine strains of rabies virus presents a potential treatment in filling this gap. We show here that immunization with live-attenuated vaccines provide long-lasting rabies immunity, superior to the protection induced by inactivated vaccines. In the absence of an immunostimulatory adjuvant, vaccination with multiple doses of inactivated rabies virus induces a type-2 immune response. This type of immunity is highly effective at inducing neutralizing antibody but has limited efficacy in clearing the virus from central nervous system (CNS) tissues. In contrast, a single infection with live-attenuated rabies vaccine safely drives a type-1 immune response, associated with both the production of a neutralizing antibody and the clearance of wild-type rabies virus from CNS tissues. These results indicate that live-attenuated rabies strains have the potential to be more effective in post-exposure prophylaxis than conventional inactivated vaccines

Blood-brain barrier regulation in temporal lobe epilepsy : implication in mechanisms of experimental epileptogenesis.

L'épilepsie du lobe temporal est fréquente et souvent pharmacorésistante. L'épileptogenèse est imputée à la mort neuronale, l'inflammation ou au déséquilibre de la neurotransmission. Récemment, la perméabilité vasculaire a été reconnue comme une cause de crises d'épilepsie. Dans un modèle d'épilepsie chronique, nous avons montré une angiogenèse associant vascularisation, surexpression de VEGF, perte de protéines des jonctions serrées et perméabilité de la BHE. L'observation des immunoglobulines G (IgGs) comme marqueurs de perméabilité vasculaire nous a permis de découvrir que les IgGs s'accumulent dans les neurones. Nous avons alors étudié le rôle de ces protéines dans l'épileptogenèse. Ensuite, afin de corréler la perméabilité de la BHE à l'épileptogenèse, nous avons étudié le kindling, un modèle dans lequel les crises sont induites mais pas spontanées. Nous n'avons observé aucun remaniement vasculaire, si ce n'est une dérégulation transitoire de deux protéines de jonctions serrées. La comparaison de ces deux modèles confirme la contribution de la dérégulation de la BHE dans la genèse des crises et la désigne comme une nouvelle cible thérapeutique.Temporal lobe epilepsy is the most frequent form of pharmacoresistant epilepsies. Epileptogenesis is commonly imputed to neuronal loss, inflammation and an imbalance in neurotransmission. Now, vascular permeability was shown to participate in epileptic seizures generation. In a model of chronic epilepsy, we showed a neo-vascularisation associated with VEGF over expression, loss of tight junction proteins and BBB permeability. The use of immunoglobulins G (IgGs) as markers of permeability vascular allowed us to discover that the IgGs accumulates in neurones. We then studied the role of these proteins in epileptogenesis. Then, to correlate BBB permeability to epileptogenesis, we studied the kindling, a model in which seizures are induced but never spontaneous. We observed no vascular remodeling, except for a transient deregulation of tight junctions proteins. The comparison of these models confirms the contribution of BBB deregulation and points it as new therapeutic target

Analyse prospective et biomécanique de la marche et des déformations osseuses chez les patients atteints de rachitisme hypophosphatémique lié au chromosome X

X-linked hypophosphatemic rickets (XLH) is a rare disease affecting the musculoskeletal system and lower limb function. Most of the symptoms of XLH have a strong impact on the daily life of patients but can be minimized during growth with adapted treatment. To date, only a qualitative assessment of the physical symptoms of XLH is possible. This thesis aims to define a protocol for the quantitative evaluation of XLH and its evolution during growth for the lower limbs. The first part deals with the 3D study of the skeleton. It shows that the femoral shaft is particularly affected. In follow-up we see that the mechanical angles normalize first under the effect of the treatment, the femur and the tibia evolving together. A second part focusing on the quantitative gait analysis shows that the alterations mainly concern the frontal plane and that they are linked to bone deformities. A final part, dealing with muscles, highlights an alteration in composition and muscle atrophy in patients with XLH which may explain the muscle weakness observed. By combining these three examinations, the protocol proposed in this thesis makes it possible both to quantify the alterations of the musculoskeletal system and of gait in children with XLH and to improve our understanding of the existing interactions between these three elements.Le rachitisme hypophosphatémique lié au chromosome X (XLH) est une maladie rare touchant le système musculosquelettique et la fonction des membres inférieurs. La plupart des symptômes du XLH ont un impact fort sur le quotidien des patients mais peuvent être minimisés lors de la croissance sous l’effet d’un traitement adapté. A ce jour, seule une appréciation qualitative des symptômes physiques du XLH est possible. Cette thèse vise à définir un protocole d’évaluation quantitative du XLH et de son évolution durant la croissance pour les membres inférieurs. La première partie porte sur l’étude 3D du squelette. On y montre que la diaphyse fémorale est particulièrement touchée. En suivi on voit que les angles mécaniques se normalisent en premiers sous l’effet du traitement, le fémur et le tibia évoluant au même rythme. Une deuxième partie sur l’analyse quantifiée de la marche montre que les altérations concernent principalement le plan frontal et qu’elles sont liées aux déformations osseuses. Une dernière partie, consacrée aux muscles, met en avant une altération de la composition et une atrophie musculaire chez les patients avec XLH pouvant expliquer la faiblesse musculaire observée. En combinant ces trois examens, le protocole proposé dans cette thèse permet à la fois de quantifier les altérations du système musculosquelettique et de la marche chez des enfants avec XLH et d’améliorer notre compréhension des interactions existantes entre ces trois éléments

Analyse prospective et biomécanique de la marche et des déformations osseuses chez les patients atteints de rachitisme hypophosphatémique lié au chromosome X

X-linked hypophosphatemic rickets (XLH) is a rare disease affecting the musculoskeletal system and lower limb function. Most of the symptoms of XLH have a strong impact on the daily life of patients but can be minimized during growth with adapted treatment. To date, only a qualitative assessment of the physical symptoms of XLH is possible. This thesis aims to define a protocol for the quantitative evaluation of XLH and its evolution during growth for the lower limbs. The first part deals with the 3D study of the skeleton. It shows that the femoral shaft is particularly affected. In follow-up we see that the mechanical angles normalize first under the effect of the treatment, the femur and the tibia evolving together. A second part focusing on the quantitative gait analysis shows that the alterations mainly concern the frontal plane and that they are linked to bone deformities. A final part, dealing with muscles, highlights an alteration in composition and muscle atrophy in patients with XLH which may explain the muscle weakness observed. By combining these three examinations, the protocol proposed in this thesis makes it possible both to quantify the alterations of the musculoskeletal system and of gait in children with XLH and to improve our understanding of the existing interactions between these three elements.Le rachitisme hypophosphatémique lié au chromosome X (XLH) est une maladie rare touchant le système musculosquelettique et la fonction des membres inférieurs. La plupart des symptômes du XLH ont un impact fort sur le quotidien des patients mais peuvent être minimisés lors de la croissance sous l’effet d’un traitement adapté. A ce jour, seule une appréciation qualitative des symptômes physiques du XLH est possible. Cette thèse vise à définir un protocole d’évaluation quantitative du XLH et de son évolution durant la croissance pour les membres inférieurs. La première partie porte sur l’étude 3D du squelette. On y montre que la diaphyse fémorale est particulièrement touchée. En suivi on voit que les angles mécaniques se normalisent en premiers sous l’effet du traitement, le fémur et le tibia évoluant au même rythme. Une deuxième partie sur l’analyse quantifiée de la marche montre que les altérations concernent principalement le plan frontal et qu’elles sont liées aux déformations osseuses. Une dernière partie, consacrée aux muscles, met en avant une altération de la composition et une atrophie musculaire chez les patients avec XLH pouvant expliquer la faiblesse musculaire observée. En combinant ces trois examens, le protocole proposé dans cette thèse permet à la fois de quantifier les altérations du système musculosquelettique et de la marche chez des enfants avec XLH et d’améliorer notre compréhension des interactions existantes entre ces trois éléments