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21.
Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
22.
1. 2,4-dinitrophenol, 2,4-dinitrophenetole, 2,4-dinitronaphthol, 4,6-dinitro-o-cresol, and to a lesser extent picric acid, produced an increase in bile flow and a rise in body temperature in the anaesthetized dog. The total biliary bromsulphalein (BSP) excretion in unit time was either slightly reduced, increased or remained at its pre-injection level.2. Picramic acid, the nitrochlorophenols and 2,4-dinitrobenzaldehyde caused a moderate increase in bile flow without an effect on the temperature of the animal.3. The three mononitrophenols, the five remaining isomeric dinitrophenols, isopicramic acid, the aminonitrophenols, phenol, 2,4-dinitroanisole, 2,4-dinitrobenzoic acid, 2,4-dinitrobenzene sulphonic acid, 2,4-dinitroresorcinol and 4-nitracatechol had little effect on bile secretion or body temperature.4. It thus appears that, in order for a compound of this type to have a pronounced effect on bile secretion, it is necessary to have nitro groups in positions 2 and 4 of the benzene ring, and a free or potential hydroxyl group. 相似文献
23.
Blacker D Bertram L Saunders AJ Moscarillo TJ Albert MS Wiener H Perry RT Collins JS Harrell LE Go RC Mahoney A Beaty T Fallin MD Avramopoulos D Chase GA Folstein MF McInnis MG Bassett SS Doheny KJ Pugh EW Tanzi RE;NIMH Genetics Initiative Alzheimer's Disease Study Group 《Human molecular genetics》2003,12(1):23-32
Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD. 相似文献
24.
Variability of skin temperature in the waking monkey 总被引:3,自引:0,他引:3
25.
Immune and pathologic responses in mice infected with Brucella abortus 19, RB51, or 2308. 总被引:2,自引:8,他引:2 下载免费PDF全文
Immune and pathologic responses were measured for 20 weeks after infection of mice with Brucella abortus 19, RB51, or 2308. Live bacteria and bacterial antigens of 19 and RB51 persisted in spleens for 10 and 4 weeks after infection, respectively, whereas 2308 bacteria and bacterial antigens persisted for at least 20 weeks. Small germinal centers and profound lymphoid depletion occurred in spleens of mice during the first 4 weeks of infection with strain 19 or 2308; however, mice infected with strain RB51 had much larger germinal centers but no lymphoid depletion. At 4 weeks, only spleen cells from RB51-infected mice proliferated when incubated with 2308 bacteria. Large germinal centers in the spleen and spleen cell proliferative responses to 2308 did not appear in strain 19-infected mice until 6 weeks or in strain 2308-infected mice until 10 weeks. Similar proliferative responses to 2308 occurred in mice infected with strain 19 or RB51 at 6 weeks and in mice infected with strain 19, RB51, or 2308 at 10 weeks. However, at 20 weeks, spleen cell proliferative responses to 2308 occurred in mice infected with strain 19 or 2308 but not in mice infected with strain RB51. Mice infected with strain RB51 had lower and less persistent antibody titers to 2308 than did mice infected with strain 19 or 2308. Collectively, these results indicate that RB51-infected mice have less persistent immune responses to 2308 than do mice infected with 19 or 2308. The shorter duration of the responses probably resulted because RB51 is considerably less pathogenic and is cleared more rapidly from mice than are 19 and 2308. 相似文献
26.
Jerrold S. Levine Barbara J. Pugh Daqing Hartwell John M. Fitzpatrick Ann Marshak-Rothstein David I. Beller 《European journal of immunology》1993,23(11):2951-2958
Macrophages (M?) from pre-diseased autoimmune-prone MRL mice (both MRL/+ and MRL/1pr) dramatically underproduce the cytokine interleukin-1 (IL-1) in comparison to M? from a number of normal strains. In this study we show that IL-1 dysregulation by MRL M? is fully expressed at birth, and that this defect does not change with time or the development of disease. We also constructed adult irradiation chimeras (consisting of A/J → MRL and MRL → A/J mice), and show that M? isolated from these chimeras display a pattern of IL-1 production indistinguishable from that of the donor strain controls. Moreover, when we constructed a mixed chimera (A/J + MRL → A/J), the A/J and MRL M? coexisting within the same animal retained their individual patterns of IL-1 production when isolated by negative selection. Taken together, these results provide the first substantive evidence for an intrinsic defect (IL-1 dysregulation) in M? from MRL autoimmune-prone mice. 相似文献
27.
28.
The microvascular frontal-subcortical syndrome of aging 总被引:11,自引:0,他引:11
Many features of aging suggest dysfunction in both frontal and subcortical regions. Connections between the two areas form a series of pathways that critically influence various aspects of cognition, motor control, affect, and as recently discovered, normal urinary function. Age-related changes in the structure and integrity of these circuits may be associated with cognitive impairment, mood disorders, loss of balance, falls, and urinary dysfunction. In addition, cardiovascular risk factors in elderly people are associated with the development of cerebral microangiopathic changes in both the periventricular white matter and basal ganglia. These lesions are common, usually unsuspected, and were previously believed to be clinically innocuous. However, increasing evidence supports a role for these lesions as a cause for both dysfunction in frontal-subcortical systems, and many clinical features of aging that account for substantial disability. Because this form of cerebrovascular disease is potentially preventable, interventions that address risk factors for the development of cerebral microangiopathy may go a long way in preventing disability for the next generation of elderly persons. 相似文献
29.
Permeation of human ovarian tissue with cryoprotective agents in preparation for cryopreservation 总被引:18,自引:10,他引:18
Newton H; Fisher J; Arnold JR; Pegg DE; Faddy MJ; Gosden RG 《Human reproduction (Oxford, England)》1998,13(2):376-380
The recent improvements in the treatment of cancer by chemo- and
radiotherapy have led to a significant increase in the survival rates of
patients with malignant disease, but at the expense of distressing side
effects. One major problem, especially for younger patients, is that
aggressive therapy destroys a significant proportion of the follicular
population, which can result in either temporary or permanent infertility.
Freeze-banking pieces of ovarian cortex prior to treatment is one strategy
for preserving fecundity. When the patient is in remission, fertility
could, theoretically, be restored by autografting the thawed tissue at the
orthotopic site or by growing isolated follicles to maturity in vitro.
Recent studies have found good follicular survival in frozen-thawed human
ovarian tissue but to optimize the process an effective cryopreservation
method needs to be developed. An essential part of such a technique is to
permeate the tissue with a cryoprotectant to minimize ice formation and the
extent of this equilibration is an important determinant of post-thaw
cellular survival. In the current study, we have investigated the diffusion
of four cryoprotective agents into human tissue at both 4 degrees C and 37
degrees C. We have also studied the effect of adding different
concentrations of the non penetrating cryoprotective agent, sucrose, to the
freezing media using the release of lactate dehydrogenase as a measure of
its protective effect. At 4 degrees C propylene glycol and glycerol
penetrated the tissue significantly slower than either ethylene glycol or
dimethyl sulphoxide. At the higher temperature of 37 degrees C all four
cryoprotectants penetrated at a faster rate, however concern about enhanced
toxicity prevents the use of these conditions in practice. Thus, the
results suggest that the best method of preparing tissue for freezing is
exposure for 30 min to 1.5 M solutions of ethylene glycol or dimethyl
sulphoxide at 4 degrees C; this achieved a mean tissue concentration that
was almost 80% that of the bathing solution. We also report that the
addition of low concentrations of sucrose to the freezing medium does not
have a significant protective effect against freezing injury.
相似文献
30.
Stein TP; Oram-Smith JC; Leskiw MJ; Wallace HW; Long LC; Leonard JM 《The American journal of physiology》1976,230(5):1321-1325