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111.
Maggy Jennings David B. Morton Emmanuelle Charton Jane Cooper Coenraad Hendriksen Stella Martin Michael C. Pearce Scott Price Keith Redhead Nick Reed Hugh Simmons Stephen Spencer Hilary Willingale 《Biologicals》2010,38(6):684-695
This report aims to facilitate the implementation of the Three Rs (reduction, refinement and replacement) in the testing of vaccines for regulatory and other purposes. The focus is predominantly on identification of reduction and refinement opportunities in batch potency testing but the principles described are widely applicable to other situations that involve experimental infections of animals. The report should also help to interpret the requirements of the European Pharmacopoeia with regard to the use of alternative tests, humane endpoints and other refinements. Two specific worked examples, for batch potency testing of Clostridium chauvoei and canine leptospira, with recommendations for harmonisation of international test requirements for these and other vaccines, are provided as appendices online. 相似文献
112.
Destaing O Planus E Bouvard D Oddou C Badowski C Bossy V Raducanu A Fourcade B Albiges-Rizo C Block MR 《Molecular biology of the cell》2010,21(23):4108-4119
Invadosomes are adhesion structures involved in tissue invasion that are characterized by an intense actin polymerization–depolymerization associated with β1 and β3 integrins and coupled to extracellular matrix (ECM) degradation activity. We induced the formation of invadosomes by expressing the constitutive active form of Src, SrcYF, in different cell types. Use of ECM surfaces micropatterned at the subcellular scale clearly showed that in mesenchymal cells, integrin signaling controls invadosome activity. Using β1−/− or β3−/− cells, it seemed that β1A but not β3 integrins are essential for initiation of invadosome formation. Protein kinase C activity was shown to regulate autoassembly of invadosomes into a ring-like metastructure (rosette), probably by phosphorylation of Ser785 on the β1A tail. Moreover, our study clearly showed that β1A links actin dynamics and ECM degradation in invadosomes. Finally, a new strategy based on fusion of the photosensitizer KillerRed to the β1A cytoplasmic domain allowed specific and immediate loss of function of β1A, resulting in disorganization and disassembly of invadosomes and formation of focal adhesions. 相似文献
113.
Alexandre Hinzpeter Abdel Aissat Elvira Sondo Catherine Costa Nicole Arous Christine Gameiro Natacha Martin Agathe Tarze Laurence Weiss Alix de Becdelièvre Bruno Costes Michel Goossens Luis J. Galietta Emmanuelle Girodon Pascale Fanen 《PLoS genetics》2010,6(10)
Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies. 相似文献
114.
Jean Peccoud Jean-Christophe Simon Carol von Dohlen Armelle Coeur d’acier Manuel Plantegenest Flavie Vanlerberghe-Masutti Emmanuelle Jousselin 《Comptes rendus biologies》2010,333(6-7):474-487
Aphids are intimately linked with their host plants that constitute their only food resource and habitat, and thus impose considerable selective pressure on their evolution. It is therefore commonly assumed that host plants have greatly influenced the diversification of aphids. Here, we review what is known about the role of host plant association on aphid speciation by examining both macroevolutionary and population-level studies. Phylogenetic studies conducted at different taxonomic levels show that, as in many phytophagous insect groups, the radiation of angiosperms has probably favoured the major Tertiary diversification of aphids. These studies also highlight many aphid lineages constrained to sets of related host plants, suggesting strong evolutionary commitment in aphids’ host plant choice, but they fail to document cospeciation events between aphid and host lineages. Instead, phylogenies of several aphid genera reveal that divergence events are often accompanied by host shifts, and suggest, without constituting a formal demonstration, that aphid speciation could be a consequence of adaptation to new hosts. Experimental and field studies below the species level support reproductive isolation between host races as partly due to divergent selection by their host plants. Selected traits are mainly feeding performances and life cycle adaptations to plant phenology. Combined with behavioural preference for favourable host species, these divergent adaptations can induce pre- and post-zygotic barriers between host-specialized aphid populations. However, the hypothesis of host-driven speciation is seldom tested formally and must be weighed against overlooked explanations involving geographic isolation and non-ecological reproductive barriers in the process of speciation. 相似文献
115.
Walter M Lucet IS Patel O Broughton SE Bamert R Williams NK Fantino E Wilks AF Rossjohn J 《Journal of molecular biology》2007,367(3):839-847
c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase. 相似文献
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118.
Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice 总被引:2,自引:0,他引:2
At the neuromuscular junction (NMJ) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can hydrolyze acetylcholine (ACh). Released ACh quanta are known to diffuse rapidly across the narrow synaptic cleft and pairs of ACh molecules cooperate to open endplate channels. During their diffusion through the cleft, or after being released from muscle nicotinic ACh receptors (nAChRs), most ACh molecules are hydrolyzed by AChE highly concentrated at the NMJ. Advances in mouse genomics offered new approaches to assess the role of specific cholinesterases involved in synaptic transmission. AChE knockout mice (AChE-KO) provide a valuable tool for examining the complete abolition of AChE activity and the role of BChE. AChE-KO mice live to adulthood, and exhibit an increased sensitivity to BChE inhibitors, suggesting that BChE activity facilitated their survival and compensated for AChE function. Our results show that BChE is present at the endplate region of wild-type and AChE-KO mature muscles. The decay time constant of focally recorded miniature endplate currents was 1.04 +/- 0.06 ms in wild-type junctions and 5.4 ms +/- 0.3 ms in AChE-KO junctions, and remained unaffected by BChE-specific inhibitors, indicating that BChE is not limiting ACh duration on endplate nAChRs. Inhibition of BChE decreased evoked quantal ACh release in AChE-KO NMJs. This reduction in ACh release can explain the greatest sensitivity of AChE-KO mice to BChE inhibitors. BChE is known to be localized in perisynaptic Schwann cells, and our results strongly suggest that BChE's role at the NMJ is to protect nerve terminals from an excess of ACh. 相似文献
119.
120.
Godefroy E Wang Y Souleimanian NE Scotto L Stevanovic S Chen YT Valmori D Ayyoub M 《Cancer immunology, immunotherapy : CII》2007,56(8):1183-1192
Proteins encoded by genes of the SSX family are specifically expressed in tumors and are therefore relevant targets for cancer immunotherapy. One of the first identified family members, SSX-1, is expressed in a large fraction of synovial sarcomas as a fusion protein together with the product of the SYT gene. In addition, the full-length SSX-1 antigen is frequently expressed in tumors of several other histological types such as sarcoma, melanoma, hepatocellular carcinoma, ovarian cancer and myeloma. To date, however, SSX-1 specific T cell responses have not been investigated and no SSX-1 derived T cell epitopes have been described. Here, we have assessed the presence of CD4(+) T cells directed against the SSX-1 antigen in circulating lymphocytes of cancer-free individuals. After a single in vitro stimulation with a pool of peptides spanning the entire SSX-1 protein we could detect and isolate SSX-1-specific CD4(+) T cells from 5/5 donors analyzed. SSX-1-specific polyclonal populations isolated from these cultures recognized peptides located in three distinct regions of the protein containing clusters of sequences with significant predicted binding to frequently expressed MHC class II alleles. Characterization of specific clonal CD4(+) T cell populations derived from one donor allowed the identification of several naturally processed epitopes recognized in association with HLA-DR. These data document the existence of a significant repertoire of CD4(+) T cells specific for SSX-1 derived sequences in circulating lymphocytes of any individual that can be exploited for the development of both passive and active immunotherapeutic approaches to control disease evolution in cancer patients. 相似文献