AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model

Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood–brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the AppNL-G-F Alzheimer’s mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets

Characterization of the Rabbit Neonatal Fc Receptor (FcRn) and Analyzing the Immunophenotype of the Transgenic Rabbits That Overexpresses FcRn

The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, takes an active role in phagocytosis, and delivers antigen for presentation. We have previously shown that overexpression of FcRn in transgenic mice significantly improves the humoral immune response. Because rabbits are an important source of polyclonal and monoclonal antibodies, adaptation of our FcRn overexpression technology in this species would bring significant advantages. We cloned the full length cDNA of the rabbit FcRn alpha-chain and found that it is similar to its orthologous analyzed so far. The rabbit FcRn - IgG contact residues are highly conserved, and based on this we predicted pH dependent interaction, which we confirmed by analyzing the pH dependent binding of FcRn to rabbit IgG using yolk sac lysates of rabbit fetuses by Western blot. Using immunohistochemistry, we detected strong FcRn staining in the endodermal cells of the rabbit yolk sac membrane, while the placental trophoblast cells and amnion showed no FcRn staining. Then, using BAC transgenesis we generated transgenic rabbits carrying and overexpressing a 110 kb rabbit genomic fragment encoding the FcRn. These transgenic rabbits – having one extra copy of the FcRn when hemizygous and two extra copies when homozygous - showed improved IgG protection and an augmented humoral immune response when immunized with a variety of different antigens. Our results in these transgenic rabbits demonstrate an increased immune response, similar to what we described in mice, indicating that FcRn overexpression brings significant advantages for the production of polyclonal and monoclonal antibodies

Lectures on holographic methods for condensed matter physics

These notes are loosely based on lectures given at the CERN Winter School on Supergravity, Strings and Gauge theories, February 2009 and at the IPM String School in Tehran, April 2009. I have focused on a few concrete topics and also on addressing questions that have arisen repeatedly. Background condensed matter physics material is included as motivation and easy reference for the high energy physics community. The discussion of holographic techniques progresses from equilibrium, to transport and to superconductivity.Comment: 1+85 pages. 15 figures. v2: typos fixed and references added. v3: another typo fixe

Gene expression variability across cells and species shapes innate immunity.

As the first line of defence against pathogens, cells mount an innate immune response, which varies widely from cell to cell. The response must be potent but carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here we characterize the innate immune response's transcriptional divergence between species and variability in expression among cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we map the architecture of the innate immune response. Transcriptionally diverging genes, including those that encode cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes that are involved in the regulation of this response, such as those that encode transcription factors and kinases, are conserved between species and display low cell-to-cell variability in expression. We suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective but balanced response

Tissue CA-19.9 content in colorectal adenomas and its value in the assesment of dysplasia Detección de CA-19.9 citosólico en adenomas colorrectales: Utilidad en el diagnóstico de la displasia

Background: occasionally, the risk of malignant transformation may be difficult to establish in adenomatous polyps due to the fact that they contain areas with variable grades of dysplasia. A measurement of tissue tumor markers may be useful to recognize these adenomas. Objectives: the aims of this study were: to establish firstly the relationship between carbohydrate antigen 19.9 (CA-19.9) content in the colorectal mucosa and the characteristics of polyps, and secondly, the diagnostic value of the former's measurement. Patients and methods: tissue CA-19.9 concentration was measured in 155 colorectal samples obtained from 145 patients (21 normal mucosa; 113 adenomatous polyps; 21 adenocarcinoma). Cytosol CA-19.9 content was determined by enzyme-linked immunoadsorbant assay, and the measurement of this protein was achieved by quantitative assay. Tissue samples were also processed for histological examination. Results: we demonstrated that CA-19.9 levels in adenomatous polyps and adenocarcinomas were significantly higher than in the normal mucosa. These levels varied significantly according to polyp size, histological type, and grade of dysplasia. CA-19.9 contents were higher in polyps with a high risk of malignant transformation than in those with a low risk of severe dysplasia. The cut-off value 214 U/mg of protein properly differentiated both types of risk. The area under the receiver operating characteristic (ROC) curves showed that cytosol CA-19.9 levels allow classifying polyps according to their histological features. Conclusions: we concluded that the measurement of CA-19.9 content in adenomatous polyps may be useful to classify these tumors and confirm the feasibility to separate adenomas into two groups: low and high risk of malignant change.Introducción: en ocasiones, el riesgo de transformación maligna de los pólipos adenomatosos es difícil de identificar por existir zonas con distintos grados de displasia simultáneamente. La determinación tisular de los marcadores tumorales puede ser útil para clasificar estos adenomas. Objetivos: conocer la relación existente entre las tasas de antígeno carbohidratado 19.9 citosólico (CA-19.9) del tejido colónico y las características morfológicas de los pólipos, para posteriormente valorar la utilidad diagnóstica de esta medición. Pacientes y métodos: se estudiaron histológicamente 155 muestras de colon (21 muestras de mucosa normal, 113 pólipos adenomatosos y 21 adenocarcinomas) en las que además se determinó la concentración tisular de CA-19.9 mediante enzimoinmunoanálisis. Resultados: los niveles de CA-19.9 citosólico en los pólipos adenomatosos y los adenocarcinomas fueron significativamente más altos que los encontrados en la mucosa normal. En los adenomas, estos niveles variaban significativamente con el tamaño, el tipo histológico y el grado de displasia. El contenido de CA-19.9 tisular en los pólipos con alto grado de displasia fue mayor que en los de bajo riesgo de displasia. La tasa de 214 U/mg de proteína diferenció adecuadamente ambos tipos de pólipos. Al estimar las áreas bajo las curvas de eficacia diagnóstica se demostró que los niveles citosólicos de CA-19.9 permiten clasificar los pólipos adenomatosos de acuerdo con sus características histológicas. Conclusiones: la determinación tisular de CA-19.9 puede ser útil en la evaluación de los pólipos adenomatosos y confirma la posibilidad de clasificar los adenomas en dos grupos: bajo y alto grado de transformación maligna

Recherches sur l'amelioration des methodes de conservation des souches de champignons

SIGLECNRS AR 11908 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Etude in vitro des interactions entre champignons imparfaits, bacteries et basidiomycetes lignivores tous issus du platane (plaies de taille et carpophores)

Available at INIST (FR), Document Supply Service, under shelf-number : RP 185 (2852) / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc