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Infection-dependent phenotypes in MHC-congenic mice are not due to MHC: can we trust congenic animals?
Erin E McClelland, Kristy Damjanovich, Kyle Gardner, Zack J Groesbeck, Maggie S Ma, Megan Nibley, Kelly S Richardson, Maureen Wilkinson, Linda C Morrison, Paul Bernhardt, Wayne K Potts
BMC Immunology , 2004, DOI: 10.1186/1471-2172-5-14
Abstract: Infected P0 MHC q/q congenic homozygotes lost significantly more weight (p = 0.02) and had significantly higher Salmonella (p < 0.01) and TMEV (p = 0.02) titers than the infected F2 q/q homozygotes. Neither weight nor pathogen load differences were present in sham-infected controls.These data suggest that these strains differ for genes other than those in the MHC congenic region. The most likely explanation is that deleterious recessive mutations affecting response to infection have accumulated in the more than 40 years that this B10.Q-H-2q MHC-congenic strain has been separated from its B10-H-2b parental strain. During typical experiments with congenic strains, the phenotypes of these accumulated mutations will be falsely ascribed to the congenic gene(s). This problem likely affects any strains separated for appreciable time and while usually ignored, can be avoided with the use of F2 segregants.It is assumed that knockout, transgenic or other congenic strains of mice are identical at all loci or genomic regions except the one being studied. There are three principal sources of genetic variation that could cause congenic strains to diverge: 1) residual heterozygosity may remain after the construction of the strains, 2) poor animal husbandry could lead to contamination of the strains, and 3) new mutations could become fixed in the strains. There are documented cases in strains of mice of residual heterozygosity [1], genetic contamination [2] and accumulated mutations [3,4]. The relative importance of these three possible sources of genetic divergence among laboratory strains is unclear.Appreciation of the problem of genetic divergence in strains of inbred mice is not a new one. It has long been expected that independently maintained strains (substrains) might accumulate genetic differences over time [5] and there are now numerous documented cases of phenotypic divergence between substrains. For instance, different substrains of mice respond differently with respect
Inversely Prepolarized Piezoceramic Cantilever  [PDF]
D. P. Sedorook,I. V. Ostrovskii
Physics , 2014,
Abstract: A nonuniform piezoelectric cantilever with enhanced amplitude of vibration at resonances is proposed. The cantilever made of lead zirconate titanate (type of PZT-5H) containing inversely poled piezoelectric domains shows an advantageous increase in vibration amplitude when compared to a single domain device. The amplitude of vibrations is enhanced when the domain boundaries are located at the nodes of vibration displacement. The vibration amplitude of a cantilever with 2 or 3 periodically inverted domains is mostly affected at the 2nd or 3rd resonance frequency, respectively. The amplitudes are calculated using the Finite Element method (FEM).
Generation of a New Congenic Mouse Strain with Enhanced Chymase Expression in Mast Cells  [PDF]
Xi Jin, Wanke Zhao, Kaiyao Shi, Wanting T. Ho, Zhizhuang J. Zhao
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084340
Abstract: Mast cells are effector cells best known for their roles in IgE-associated allergy, but they also play a protective role in defense against pathogens. These cells express high levels of proteases including chymase, tryptase and carboxypeptidase. In the present study, we identified a congenic strain of C57BL/6 mice expressing an extraordinarily high level of chymases Mcp-2 and Mcp-4 in mast cells. The overexpression was associated with variant Mcp-2 and Mcp-4 genes originated from DBA/2 mice that also expressed high levels of the two enzymes. Real time PCR analysis revealed that Mcp-2 and Mcp-4 were selectively overexpressed as tryptases, Cpa3 and several other chymases were kept at normal levels. Reporter gene assays demonstrated that single-nucleotide polymorphisms (SNPs) in the promoter region of Mcp-2 gene may be partly responsible for the increased gene transcription. Our study provides a new model system to study the function of mast cell chymases. The data also suggest that expression of chymases differs considerably in different strains of mice and the increased chymase activity may be responsible for some unique phenotypes observed in DBA/2 mice.
PCSK1和PCSK2单核苷酸多态性与新诊断2型糖尿病的相关性分析  [PDF]
郑晓雅,任伟,龚莉琳,张素华,刘静婧,李素芳,李金超,许丹,毕健琨
解放军医学杂志 , 2014,
Abstract: 目的 探讨重庆地区汉族人前蛋白转化酶枯草溶菌素1(PCSK1)的rs3811951和PCSK2的rs2021785位点单核苷酸多态性(SNPs)与新诊断2型糖尿病(T2DM)之间的相关性。方法 采用病例-对照法,收集新诊T2DM组(n=227例)与对照组(n=152例)的临床资料及血标本,测定血糖、血脂等生化指标,采用质谱技术对rs3811951和rs2021785位点进行SNPs分型。结果 PCSK2的rs2021785位点次要等位基因频率在T2DM组显著低于对照组(20.04%vs26.64%,P=0.0335),次要等位基因A的携带者患T2DM的风险显著降低(OR=0.69,95%CI0.49~0.97,P=0.0335)。PCSK2基因的rs2021785位点AA基因型频率在T2DM组显著低于对照组(6.6%vs10.5%,P<0.05),rs2021785位点基因型分布与T2DM显著相关(共显性模型中OR=0.627,95%CI0.41~0.96,P=0.0308)。PCSK1基因rs3811951位点等位基因频率及基因型分布在T2DM组和对照组差异无统计学意义(P>0.05)。结论 重庆地区汉族人群中PCSK2基因rs2021785位点的多态性与T2DM显著相关,而PCSK1基因rs3811951位点多态性与T2DM无显著相关性。
Brown Norway Chromosome 1 Congenic Reduces Symptoms of Renal Disease in Fatty Zucker Rats  [PDF]
Craig H. Warden, Carolyn Slupsky, Stephen M. Griffey, Ahmed Bettaieb, Esther Min, Anh Le, Janis S. Fisler, Susan Hansen, Fawaz Haj, Judith S. Stern
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087770
Abstract: We previously reported that a congenic rat with Brown Norway (BN) alleles on chromosome 1 reduces renal disease of 15-week old fatty Zucker rats (ZUC). Development of renal disease in fatty BN congenic and fatty ZUC rats from 9 through 28 weeks is now examined. Analysis of urine metabolites by 1H nuclear magnetic resonance (NMR) spectroscopy revealed a significantly increased urinary loss of glucose, myo-inositol, urea, creatine, and valine in ZUC. Food intake was lower in the BN congenic rats at weeks 9–24, but they weighed significantly more at 28 weeks compared with the ZUC group. Fasting glucose was significantly higher in ZUC than congenic and adiponectin levels were significantly lower in ZUC, but there was no significant genotype effect on Insulin levels. Glucose tolerance tests exhibited no significant differences between ZUC and congenic when values were normalized to basal glucose levels. Quantitative PCR on livers revealed evidence for higher gluconeogenesis in congenics than ZUC at 9 weeks. Plasma urea nitrogen and creatinine were more than 2-fold higher in 28-week ZUC. Twelve urine protein markers of glomerular, proximal and distal tubule disease were assayed at three ages. Several proteins that indicate glomerular and proximal tubular disease increased with age in both congenic and ZUC. Epidermal growth factor (EGF) level, a marker whose levels decrease with distal tubule disease, was significantly higher in congenics. Quantitative histology of 28 week old animals revealed the most significant genotype effect was for tubular dilation and intratubular protein. The congenic donor region is protective of kidney disease, and effects on Type 2 diabetes are likely limited to fasting glucose and adiponectin. The loss of urea together with a small increase of food intake in ZUC support the hypothesis that nitrogen balance is altered in ZUC from an early age.
Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC
Zhong-Zhe Lin, Yung-Ming Jeng, Fu-Chang Hu, Hung-Wei Pan, Hsin-Wei Tsao, Po-Lin Lai, Po-Huang Lee, Ann-Lii Cheng, Hey-Chi Hsu
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-461
Abstract: The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and β-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of β-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines.Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with β-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and β-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis.Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment.Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality in Taiwan [1] and many other countries in Asia and Africa [2]. The incidence of HCC is increasing in Europe and the United States [3]. In 2002, HCC became the sixth most common cancer worldwide with 626,000 annual new cases [4]. Despite surgical resection, which provides an opportunity for cure, the majority of patients with HCC have a dismal prognosis [5] because tumor recurrence frequently develops and usually leads to patient's mortality [6]. The development of HCC is closely related to chronic hepatitis B or C, cirrhosis of any etiology, and aflatoxin B1 exposure [2]. However, th
Congenic Mice Confirm That Collagen X Is Required for Proper Hematopoietic Development  [PDF]
Elizabeth Sweeney,Douglas Roberts,Tina Corbo,Olena Jacenko
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009518
Abstract: The link between endochondral skeletal development and hematopoiesis in the marrow was established in the collagen X transgenic (Tg) and null (KO) mice. Disrupted function of collagen X, a major hypertrophic cartilage matrix protein, resulted in skeletal and hematopoietic defects in endochondrally derived tissues. Manifestation of the disease phenotype was variable, ranging from perinatal lethality in a subset of mice, to altered lymphopoiesis and impaired immunity in the surviving mice. To exclude contribution of strain specific modifiers to this variable manifestation of the skeleto-hematopoietic phenotype, C57Bl/6 and DBA/2J collagen X congenic lines were established. Comparable disease manifestations confirmed that the skeleto-hematopoietic alterations are an inherent outcome of disrupted collagen X function. Further, colony forming cell assays, complete blood count analysis, serum antibody ELISA, and organ outgrowth studies established altered lymphopoiesis in all collagen X Tg and KO mice and implicated opportunistic infection as a contributor to the severe disease phenotype. These data support a model where endochondral ossification-specific collagen X contributes to the establishment of a hematopoietic niche at the chondro-osseous junction.
Experimental Meningococcal Sepsis in Congenic Transgenic Mice Expressing Human Transferrin  [PDF]
Marek Szatanik,Eva Hong,Corinne Ruckly,Morgan Ledroit,Dario Giorgini,Katarzyna Jopek,Marie-Anne Nicola,Ala-Eddine Deghmane,Muhamed-Kheir Taha
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022210
Abstract: Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor–associated kinase–3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection.
A locally congenic backcross design in pig: a new regional fine QTL mapping approach miming congenic strains used in mouse
Juliette Riquet, Hélène Gilbert, Bertrand Servin, Marie-Pierre Sanchez, Nathalie Iannuccelli, Yvon Billon, Jean-Pierre Bidanel, Denis Milan
BMC Genetics , 2011, DOI: 10.1186/1471-2156-12-6
Abstract: To overcome the difficulties related to the dominance of the LW QTL allele, a population of dams locally homozygous for the MS haplotype in the QTL region, but with an overall 29/32 LW genetic background, has been set up. Progeny testing results, using these receiver dams, were much more significant than those previously obtained with LW dams, and the SSC1 QTL interval was refined to 8 cM. Considering the results obtained, a powerful experimental design for farm animals is proposed, mimicking locally genetically identical strains used in mouse for QTL fine mapping.We have further characterized the fatness QTL on pig chromosome 1 and refined its map position from a 30 cM interval to a 8 cM interval, using a locally congenic BC design. We have obtained highly significant results and overcome difficulties due to the dominance of the LW allele. This design will be used to produce additional, advanced BC families to further refine this QTL localization.The development of genetic maps in livestock species over the last twenty years has spurred efforts to dissect the molecular basis of the genetic variation of economically important traits (QTL). Numerous chromosomal regions predicted to harbour genes influencing traits of interest in livestock populations have been identified using mapping experiments in outbred populations or in experimental crosses. However, in most cases, mapping resolution has been rather poor due to the limited number of markers, the limited size of experiments and the genetic heterogeneity of the investigated populations. In the majority of livestock populations, genetically homogenous lines do not exist. Nevertheless, recombinant progeny testing (RPT) has successfully been used in pigs for the fine mapping of QTL detected in experimental crosses between domestic European populations and either Wild Boar or Meishan animals [1,2]. It consists in backcrossing individuals carrying a distinguishable recombinant haplotype in the initial confidence interv
Congenic Strain Analysis Reveals Genes That Are Rapidly Evolving Components of a Prezygotic Isolation Mechanism Mediating Incipient Reinforcement  [PDF]
Christina M. Laukaitis, Corina Mauss, Robert C. Karn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035898
Abstract: Two decades ago, we developed a congenic strain of Mus musculus, called b-congenic, by replacing the androgen-binding protein Abpa27a allele in the C3H/HeJ genome with the Abpa27b allele from DBA/2J. We and other researchers used this b-congenic strain and its C3H counterpart, the a-congenic strain, to test the hypothesis that, given the choice between signals from two strains with different a27 alleles on the same genetic background, test subjects would prefer the homosubspecific one. It was our purpose in undertaking this study to characterize the segment transferred from DBA to the C3H background in producing the b-congenic strain on which a role for ABPA27 in behavior has been predicated. We determined the size of the chromosome 7 segment transferred from DBA and the genes it contains that might influence preference. We found that the “functional" DBA segment is about 1% the size of the mouse haploid genome and contains at least 29 genes expressed in salivary glands, however, only three of these encode proteins identified in the mouse salivary proteome. At least two of the three genes Abpa27, Abpbg26 and Abpbg27 encoding the subunits of androgen-binding protein ABP dimers evolved under positive selection and the third one may have also. In the sense that they are subunits of the same two functional entities, the ABP dimers, we propose that their evolutionary histories might not be independent of each other.
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