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Howard S Young - One of the best experts on this subject based on the ideXlab platform.
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mouse prion Protein Polymorphism phe 108 val 189 affects the kinetics of fibril formation and the response to seeding evidence for a two step nucleation polymerization mechanism
Journal of Biological Chemistry, 2013Co-Authors: Leonardo M Cortez, Jitendra Kumar, Ludovic Renault, Howard S Young, Valerie L SimAbstract:Prion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion Protein (PrPC) into an amyloidogenic β-sheet infectious form (PrPSc). The sequence of host PrP is the major determinant of host prion disease susceptibility. In mice, the presence of allele a (Prnpa, encoding the Polymorphism Leu-108/Thr-189) or b (Prnpb, Phe-108/Val-189) is associated with short or long incubation times, respectively, following infection with PrPSc. The molecular bases linking PrP sequence, infection susceptibility, and convertibility of PrPC into PrPSc remain unclear. Here we show that recombinant PrPa and PrPb aggregate and respond to seeding differently in vitro. Our kinetic studies reveal differences during the nucleation phase of the aggregation process, where PrPb exhibits a longer lag phase that cannot be completely eliminated by seeding the reaction with preformed fibrils. Additionally, PrPb is more prone to propagate features of the seeds, as demonstrated by conformational stability and electron microscopy studies of the formed fibrils. We propose a model of polymerization to explain how the Polymorphisms at positions 108 and 189 produce the phenotypes seen in vivo. This model also provides insight into phenomena such as species barrier and prion strain generation, two phenomena also influenced by the primary structure of PrP. Background: Alleles Prnpa and Prnpb of mouse prion Protein (PrP) influence the incubation period of prion disease. Results: PrPa and PrPb, products of these alleles, aggregate differently in vitro. Conclusion: The Polymorphism at 108/189 influences the oligomeric stages of PrP polymerization. Significance: Elucidating the mechanism of PrP aggregation is relevant to understanding prion disease susceptibility, prion strains, and species barriers.
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mouse prion Protein Polymorphism phe 108 val 189 affects the kinetics of fibril formation and the response to seeding evidence for a two step nucleation polymerization mechanism
Journal of Biological Chemistry, 2013Co-Authors: Leonardo M Cortez, Jitendra Kumar, Ludovic Renault, Howard S YoungAbstract:Prion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion Protein (PrPC) into an amyloidogenic β-sheet infectious form (PrPSc). The sequence of host PrP is the major determinant of host prion disease susceptibility. In mice, the presence of allele a (Prnpa, encoding the Polymorphism Leu-108/Thr-189) or b (Prnpb, Phe-108/Val-189) is associated with short or long incubation times, respectively, following infection with PrPSc. The molecular bases linking PrP sequence, infection susceptibility, and convertibility of PrPC into PrPSc remain unclear. Here we show that recombinant PrPa and PrPb aggregate and respond to seeding differently in vitro. Our kinetic studies reveal differences during the nucleation phase of the aggregation process, where PrPb exhibits a longer lag phase that cannot be completely eliminated by seeding the reaction with preformed fibrils. Additionally, PrPb is more prone to propagate features of the seeds, as demonstrated by conformational stability and electron microscopy studies of the formed fibrils. We propose a model of polymerization to explain how the Polymorphisms at positions 108 and 189 produce the phenotypes seen in vivo. This model also provides insight into phenomena such as species barrier and prion strain generation, two phenomena also influenced by the primary structure of PrP.
René J. M. Stet - One of the best experts on this subject based on the ideXlab platform.
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evolution of mhc class ii chain encoding genes in the lake tana barbel species flock barbus intermedius complex
Immunogenetics, 1996Co-Authors: Brian Dixon, Leo A J Nagelkerke, E Egberts, René J. M. StetAbstract:Major histocompatibility complex (MHC) class II Protein Polymorphism is maintained in allelic lineages which evolve in a trans-specific manner, passing from one species to descendant species. Selection pressure on peptide binding residues should be greatest during speciation, when organisms move into new environments and their MHC molecules encounter new pathogens. The isolation of MHC genes from teleost fishes, the most diverse group of vertebrates, has created possibilities for testing this hypothesis. The large barbels of Lake Tana have undergone an adaptive radiation within the last 5 million years, producing 14 morphotypes which inhabit different ecological niches within the lake. We studied the variability in class II beta chain-encoding genes of four of these morphotypes using polymerase chain reaction amplification and DNA sequencing. The sequences obtained were orthologous to four of the known class II genes from the common carp, from which barbels diverged approximately 32 million years ago. When subjected to phylogenetic analysis, the 48 sequences clustered into groups which represent allelic lineages. A comparison of nonsynonymous and synonymous substitutions between the peptide binding region codons and non-peptide binding region codons of these sequences revealed that they are under strong selective pressure.
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evolution of mhc class ii beta chain encoding genes in the lake tana barbel species flock barbus intermedius complex
Immunogenetics, 1996Co-Authors: Brian Dixon, Leo A J Nagelkerke, E Egberts, F A Sibbing, René J. M. StetAbstract:Major histocompatibility complex (MHC) class II Protein Polymorphism is maintained in allelic lineages which evolve in a trans-specific manner, passing from one species to descendant species. Selection pressure on peptide binding residues should be greatest during speciation, when organisms move into new environments and their MHC molecules encounter new pathogens. The isolation of MHC genes from teleost fishes, the most diverse group of vertebrates, has created possibilities for testing this hypothesis. The large barbels of Lake Tana have undergone an adaptive radiation within the last 5 million years, producing 14 morphotypes which inhabit different ecological niches within the lake. We studied the variability in class II beta chain-encoding genes of four of these morphotypes using polymerase chain reaction amplification and DNA sequencing. The sequences obtained were orthologous to four of the known class II genes from the common carp, from which barbels diverged approximately 32 million years ago. When subjected to phylogenetic analysis, the 48 sequences clustered into groups which represent allelic lineages. A comparison of nonsynonymous and synonymous substitutions between the peptide binding region codons and non-peptide binding region codons of these sequences revealed that they are under strong selective pressure.
Brian Dixon - One of the best experts on this subject based on the ideXlab platform.
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evolution of mhc class ii chain encoding genes in the lake tana barbel species flock barbus intermedius complex
Immunogenetics, 1996Co-Authors: Brian Dixon, Leo A J Nagelkerke, E Egberts, René J. M. StetAbstract:Major histocompatibility complex (MHC) class II Protein Polymorphism is maintained in allelic lineages which evolve in a trans-specific manner, passing from one species to descendant species. Selection pressure on peptide binding residues should be greatest during speciation, when organisms move into new environments and their MHC molecules encounter new pathogens. The isolation of MHC genes from teleost fishes, the most diverse group of vertebrates, has created possibilities for testing this hypothesis. The large barbels of Lake Tana have undergone an adaptive radiation within the last 5 million years, producing 14 morphotypes which inhabit different ecological niches within the lake. We studied the variability in class II beta chain-encoding genes of four of these morphotypes using polymerase chain reaction amplification and DNA sequencing. The sequences obtained were orthologous to four of the known class II genes from the common carp, from which barbels diverged approximately 32 million years ago. When subjected to phylogenetic analysis, the 48 sequences clustered into groups which represent allelic lineages. A comparison of nonsynonymous and synonymous substitutions between the peptide binding region codons and non-peptide binding region codons of these sequences revealed that they are under strong selective pressure.
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evolution of mhc class ii beta chain encoding genes in the lake tana barbel species flock barbus intermedius complex
Immunogenetics, 1996Co-Authors: Brian Dixon, Leo A J Nagelkerke, E Egberts, F A Sibbing, René J. M. StetAbstract:Major histocompatibility complex (MHC) class II Protein Polymorphism is maintained in allelic lineages which evolve in a trans-specific manner, passing from one species to descendant species. Selection pressure on peptide binding residues should be greatest during speciation, when organisms move into new environments and their MHC molecules encounter new pathogens. The isolation of MHC genes from teleost fishes, the most diverse group of vertebrates, has created possibilities for testing this hypothesis. The large barbels of Lake Tana have undergone an adaptive radiation within the last 5 million years, producing 14 morphotypes which inhabit different ecological niches within the lake. We studied the variability in class II beta chain-encoding genes of four of these morphotypes using polymerase chain reaction amplification and DNA sequencing. The sequences obtained were orthologous to four of the known class II genes from the common carp, from which barbels diverged approximately 32 million years ago. When subjected to phylogenetic analysis, the 48 sequences clustered into groups which represent allelic lineages. A comparison of nonsynonymous and synonymous substitutions between the peptide binding region codons and non-peptide binding region codons of these sequences revealed that they are under strong selective pressure.
Siv Skeie - One of the best experts on this subject based on the ideXlab platform.
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effects of milk Protein Polymorphism and composition casein micelle size and salt distribution on the milk coagulation properties in norwegian red cattle
International Dairy Journal, 2017Co-Authors: Isaya Appelesy Ketto, Tim Martin Knutsen, Jorun Oyaas, Bjørg Heringstad, Tormod Ådnøy, T G Devold, Siv SkeieAbstract:Effects of milk Protein Polymorphism and composition, casein micelle size and salts distribution on the coagulation properties of milk from 99 Norwegian Red cattle (NRF) were studied. Genetic variants of αS1-casein (CN), β-CN, κ-CN and β-lactoglobulin (LG) affected rennet coagulation properties of milk. Significant effects of κ-CN and the composite genotype αS1-β-κ-CN were observed on acid coagulation properties. Relative concentrations of milk Proteins were significantly affected by individual casein genotypes and the composite genotype of αS1-β-κ-CN while, the relative concentration of β-LG was only affected by β-LG genotypes. The salts distribution in milk and the concentration of milk Proteins affected both rennet and acid coagulation properties. Milk Protein genotypes associated with better rennet coagulation, impaired the acid coagulation properties. However, αS1-β-κ-CN BB-A1A2-BE and BB-A2A2-BB were associated with poor rennet and acid coagulation properties. Breeding programs should focus on decreasing these genotypes in NRF cattle.
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effects of milk Protein Polymorphism and composition casein micelle size and salt distribution on the milk coagulation properties in norwegian red cattle
International Dairy Journal, 2017Co-Authors: Isaya Appelesy Ketto, Tim Martin Knutsen, Jorun Oyaas, Bjørg Heringstad, Tormod Ådnøy, T G Devold, Siv SkeieAbstract:Effects of milk Protein Polymorphism and composition, casein micelle size and salts distribution on the coagulation properties of milk from 99 Norwegian Red cattle (NRF) were studied. Genetic variants of αS1-casein (CN), β-CN, κ-CN and β-lactoglobulin (LG) affected rennet coagulation properties of milk. Significant effects of κ-CN and the composite genotype αS1-β-κ-CN were observed on acid coagulation properties. Relative concentrations of milk Proteins were significantly affected by individual casein genotypes and the composite genotype of αS1-β-κ-CN while, the relative concentration of β-LG was only affected by β-LG genotypes. The salts distribution in milk and the concentration of milk Proteins affected both rennet and acid coagulation properties. Milk Protein genotypes associated with better rennet coagulation, impaired the acid coagulation properties. However, αS1-β-κ-CN BB-A1A2-BE and BB-A2A2-BB were associated with poor rennet and acid coagulation properties. Breeding programs should focus on decreasing these genotypes in NRF cattle.
Hermann E. Wasmuth - One of the best experts on this subject based on the ideXlab platform.
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type i insulin dependent diabetes mellitus and cow milk casein variant consumption
Diabetologia, 1999Co-Authors: R B Elliott, D P Harris, N J Bibby, J.p. Hill, Hermann E. WasmuthAbstract:Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk Protein consumption. Countries which were selected for study had appropriate milk Protein Polymorphism studies, herd breed composition information and low dairy imports from other countries. Total Protein consumption did not correlate with diabetes incidence (r = + 0.402), but consumption of the β-casein A1 variant did (r = + 0.726). Even more pronounced was the relation between β-casein (A1 + B) consumption and diabetes (r = + 0.982). These latter two cow caseins yield a bioactive peptide β-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. β-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all β-casein variants and diabetes incidence. [Diabetologia (1999) 42: 292–296]
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type i insulin dependent diabetes mellitus and cow milk casein variant consumption
Diabetologia, 1999Co-Authors: R B Elliott, D P Harris, N J Bibby, J.p. Hill, Hermann E. WasmuthAbstract:Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk Protein consumption. Countries which were selected for study had appropriate milk Protein Polymorphism studies, herd breed composition information and low dairy imports from other countries. Total Protein consumption did not correlate with diabetes incidence (r = +0.402), but consumption of the beta-casein A1 variant did (r = +0.726). Even more pronounced was the relation between beta-casein (A1+B) consumption and diabetes (r = +0.982). These latter two cow caseins yield a bioactive peptide beta-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. beta-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence.
