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911.
Balmus G Zhu M Mukherjee S Lyndaker AM Hume KR Lee J Riccio ML Reeves AP Sutter NB Noden DM Peters RM Weiss RS 《Human molecular genetics》2012,21(15):3408-3420
The human genomic instability syndrome ataxia telangiectasia (A-T), caused by mutations in the gene encoding the DNA damage checkpoint kinase ATM, is characterized by multisystem defects including neurodegeneration, immunodeficiency and increased cancer predisposition. ATM is central to a pathway that responds to double-strand DNA breaks, whereas the related kinase ATR leads a parallel signaling cascade that is activated by replication stress. To dissect the physiological relationship between the ATM and ATR pathways, we generated mice defective for both. Because complete ATR pathway inactivation causes embryonic lethality, we weakened the ATR mechanism to different degrees by impairing HUS1, a member of the 911 complex that is required for efficient ATR signaling. Notably, simultaneous ATM and HUS1 defects caused synthetic lethality. Atm/Hus1 double-mutant embryos showed widespread apoptosis and died mid-gestationally. Despite the underlying DNA damage checkpoint defects, increased DNA damage signaling was observed, as evidenced by H2AX phosphorylation and p53 accumulation. A less severe Hus1 defect together with Atm loss resulted in partial embryonic lethality, with the surviving double-mutant mice showing synergistic increases in genomic instability and specific developmental defects, including dwarfism, craniofacial abnormalities and brachymesophalangy, phenotypes that are observed in several human genomic instability disorders. In addition to identifying tissue-specific consequences of checkpoint dysfunction, these data highlight a robust, cooperative configuration for the mammalian DNA damage response network and further suggest HUS1 and related genes in the ATR pathway as candidate modifiers of disease severity in A-T patients. 相似文献
912.
Cerrato F Sparago A Verde G De Crescenzo A Citro V Cubellis MV Rinaldi MM Boccuto L Neri G Magnani C D'Angelo P Collini P Perotti D Sebastio G Maher ER Riccio A 《Human molecular genetics》2008,17(10):1427-1435
The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome (BWS). These mutations result in the hypermethylation of the remaining IC1 region, loss of IGF2/H19 imprinting and fully penetrant BWS phenotype when maternally transmitted. We now report that 12 additional cases with IC1 hypermethylation have a similar clinical phenotype but showed neither a detectable deletion nor other mutation in the local vicinity. Likewise, no IC1 deletion was detected in 40 sporadic non-syndromic Wilms' tumours. A detailed analysis of the BWS patients showed that the hypermethylation variably affected the IC1 region and was generally mosaic. We observed that all these cases were sporadic and in at least two families affected and unaffected members shared the same maternal IC1 allele but not the abnormal maternal chromosome epigenotype. Furthermore, the chromosome with the imprinting defect derived from either the maternal grandfather or maternal grandmother. Overall, these results indicate that methylation-imprinting defects at the IGF2-H19 locus can result from inherited mutations of the IC and have high recurrence risk or arise independently from the sequence context and generally not transmitted to the progeny. Despite these differences, the epigenetic abnormalities are usually present in the patients in the mosaic form and probably acquired by post-zygotic de novo methylation. Distinguishing between these two groups of cases is important for genetic counselling. 相似文献
913.
丙肝病毒单片段抗体检测分析 总被引:1,自引:0,他引:1
目的 探讨丙型肝炎病毒感染者抗.HCV各区段抗体的反应性及单片段抗体ELISA测定临床应用的可行性和应用价值.方法 留取经2种第三代丙肝病毒总抗体ELISA检测试剂A、B检测结果为阳性的血清36份、可疑血清2份、阴性血清40份,用丙肝单片段抗体检测试剂C对其进行检测,并以CHIRON公司第三代免疫印迹丙肝抗体确认试剂D检测结果作为对照.结果 78份血清中,抗HCV-C、NS3、NS4、NS5四区单片段抗体阳性检出率分别为44.87%、47.44%、30.77%、28.21%;单片段抗体检测试剂C的阳性率为43.59%,与第三代总抗体检测试剂A、B的阳性率(分别为48.72%和46.15%)无显著差异;试剂A、B检出的阳性血清36份中,根据试剂C的核心区、NS3、NS4及NS5区单片段抗体检测结果综合判断确定阳性结果34份,不确定结果2份,阳性符合率为94.44%;2份可疑血清根据单片段抗体检测结果综合判断均为不确定结果;40份阴性血清中,单片段抗体检测检出阴性结果40份,阴性符合率为100%.试剂C对所有78份血清检测结果为阳性34份,不确定4份,阴性40份;而确认试剂D检测结果为阳性34份,不确定3份,阴性41份.结论 NS3区和c区为抗-HCV ELISA检测中的主要血清学标志;单片段检测试剂C与第三代总抗体检测试剂A、B之间的检出率无显著差异,结果符合良好,且与国际上公认的CHIRON第三代免疫印迹丙肝抗体确认试剂检测结果高度一致.单片段抗体检测在临床判断病情、病毒复制情况及预后方面较总抗体检测能提供更多信息. 相似文献
914.
Snow HE Riccio LM Mjaatvedt CH Hoffman S Capehart AA 《The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology》2005,282(2):95-105
Versican, an extracellular matrix proteoglycan, has been implicated in limb development and is expressed in precartilage mesenchymal condensations. However, studies have lacked precise spatial and temporal investigation of versican localization during skeletogenesis and its relationship to patterning of muscle and nerve during mammalian limb development. The transgenic mouse line hdf (heart defect), which bears a lacZ reporter construct disrupting Cspg2 encoding versican, allowed ready detection of hdf transgene expression through histochemical analysis. Hdf transgene expression in whole mount heterozygous embryos and localization of versican relative to cartilage, muscle, and nerve tissues in paraffin-embedded limb sections of wild-type embryos from 10.5-14 days postcoitum were evaluated by lacZ histochemistry, immunohistochemistry, and in situ hybridization. Versican was localized within precartilage condensations and nascent cartilages with expression diminishing during maturation of the cartilage model at later time points. Interestingly, versican remained highly expressed in developing synovial joint interzones, suggesting potential function for versican in joint morphogenesis. Isolated myoblasts, incipient skeletal muscle masses, and neurites were not present in areas of strong versican expression within the developing limb. Versican-expressing tissues may reserve space for the future limb skeleton and developing joints and may aid in patterning of muscle and nerve by deterring muscle migration and innervation into these regions. 相似文献
915.
A. Sanchez‐Mazas B. Vidan‐Jeras J. M. Nunes G. Fischer A.‐M. Little U. Bekmane S. Buhler S. Buus F. H. J. Claas A. Dormoy V. Dubois E. Eglite J. F. Eliaou F. Gonzalez‐Galarza Z. Grubic M. Ivanova B. Lie D. Ligeiro M. L. Lokki B. Martins da Silva J. Martorell D. Mendonça D. Middleton D. Papioannou Voniatis C. Papasteriades F. Poli M. E. Riccio M. Spyropoulou Vlachou G. Sulcebe S. Tonks M. Toungouz Nevessignsky C. Vangenot A.‐M. van Walraven J.‐M. Tiercy 《International journal of immunogenetics》2012,39(6):459-476
HLA‐NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user‐friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1‐4) of the HLA‐NET network at the mid‐term of its activities. WG1 (Population definitions and sampling strategies for population genetics’ analyses) recommends avoiding outdated racial classifications and population names (e.g. ‘Caucasian’) and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. ‘pan‐European’). A standard ‘HLA‐NET POPULATION DATA QUESTIONNAIRE’ has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in ‘HLA‐NET GUIDELINES FOR REPORTING HLA TYPINGS’. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide‐binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the ‘gene[rate]’ computer tools to estimate frequencies, test for Hardy–Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA‐NET guidelines and tools are available through its website http://hla‐net.eu . 相似文献
916.
Body temperature (T(b)) and metabolic rate (O(2) consumption) were measured continuously in naked mole-rats. Circadian rhythms were observed for both parameters. Body temperature increased at the end of the light phase in a 12L:12D cycle in three of four animals. The remaining animal exhibited a freerunning rhythm of T(b). When animals had access to running wheels, the time of elevated T(b) coincided closely with the time of increased running wheel activity. Rhythms of T(b) continued following removal of the wheels, but the duration of increased T(b) was decreased as compared to the duration of T(b) elevation in the presence of wheels. Metabolic rate was increased at the same circadian phase as the increase in T(b) and running wheel activity. These observations extend our earlier findings on circadian rhythms of locomotor activity in naked mole-rats and suggest that the circadian system may have significant physiological functions in this subterranean rodent. 相似文献
917.
Yusuke Abe MD PhD Tsuneo Chinzei MD PhD Takashi Isoyama PhD Toshiya Ono BE Shuichi Mochizuki MD PhD Itsuro Saito PhD Kiyotaka Iwasaki MS Mitsuhiko Ishimaru MD Atsushi Baba MD Akimasa Kouno BL Toshinaga Ozeki MS Takahiro Tohyama BE Kazunori Baba MD PhD Kou Imachi PhD 《Journal of artificial organs》2000,3(2):70-74
In the University of Tokyo, various types of total artificial heart (TAH) have been studied. Based on the experiences of TAH
research, the development of the undulation pump total artifical heart (UPTAH) started in 1994. The undulation pump is a small-size,
continuous-flow, displacement-type blood pump, and the UPTAH is a unique implantable total artificial heart that uses the
undulation pump. To date, three models of UPTAH have been developed. The first model, UPTAH1, was developed to investigate
the possibility of reducing the size of the device so it could be implanted in small adults, such as Japanese patients, in
1994. The second model, UPTAH2, which was the prototype of the animal experimental model, was developed in 1996 to investigate
the possibility of survival with the UPTAH. The third model, UPTAH3, which is the present model, was developed in 1998 to
enable long-term survival in animal experiments and to investigate the pathophysiology of the UPTAH. From July 1996 to October
1999, 22 implantations of UPTAH2 or UPTAH3 were performed in goats. In spite of the limitation of their small chest cavity,
the UPTAH could be implanted into the chest of all goats. Using UPTAH3, survival of 31 days could be obtained. The research
and development of UPTAH are ongoing. 相似文献
918.
Two experiments examined the extent to which retrograde amnesia (RA) is attenuated by prior learning experiences. In Experiment 1, rats initially received either passive avoidance training in a step-through apparatus, exposure to the apparatus, or noncontingent footshock. When training on a second but different passive avoidance task was followed by hypothermia treatment, RA was obtained only in the latter two groups. In Experiment 2, one-way active avoidance training, yoked noncontingent shocks, or apparatus exposure constituted the initial experience. Subsequent step-down passive avoidance training and amnestic treatment resulted in memory loss for the prior apparatus exposure group, but not for either of the preshocked conditions. These experiments demonstrate that certain types of prior aversive experience can substantially modify the magnitude of RA, and, in conjunction with other familiarization studies, emphasize a paradox for interpretations of RA based solely upon CNS disruption. The possibility that hypothermia treatment serves as an important contextual or encoding cue necessary for memory retrieval was considered. It was suggested that prior experience may block RA by enabling rats to differentiate training and treatment conditions. 相似文献
919.
A number of observations indicate that exposure to IL-4 is essential for
the priming of Th2-type effector T cells and that exposure to IL-12 is
essential for the priming of Th1-type effector T cells. However, the
initial source of IL-4 in the early immune response has not been clearly
identified. Dendritic cells (DC) are the most potent antigen- presenting
cells (APC) in priming naive T cells. In this report, we show that DC
exposed to IL-10 may play an important role in the priming of
IL-4-secreting cells in the early immune response. DC isolated from splenic
adherent cell cultures treated with rIL-10 (IL-10-DC) primed naive
ovalbumin (OVA)-TCR transgenic T cells to secrete IL-4 upon re- stimulation
with OVA and splenic APC. By contrast, DC isolated from rIL- 12, rIL-4 or
control treated cultures induced almost exclusively Th1- type effector T
cells. IL-4 secretion was detected in the primary cultures of IL-10-DC plus
naive CD4+ T cells and the priming of IL-4- secreting T cells by IL-10-DC
was dependent on endogenous IL-4 production in the priming culture since
anti-IL-4 neutralizing antibody completely abrogated the priming of
IL-4-secreting cells. Anti-B7-2 but not anti-B7-1 inhibited the ability of
IL-10-DC to prime T cells to secrete IL-4. Furthermore, the ability of
IL-10 DC to prime for IL-4- secreting T cells was closely related to the
down-regulation of CD40 ligand-mediated IL-12 p70 production by DC in the
primary cultures and was markedly reduced by adding exogenous IL-12 to the
priming cultures. Thus, our findings indicate that early immunologic events
that drive Th2 differentiation involve the effects of IL-10 on DC.
相似文献