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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
5.
Macaluso GM Graven-Nielsen T Svensson P 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2001,136(1):114-119
A heteronymous H reflex in the temporalis muscle can be elicited by selective stimulation of the masseteric nerve. The present study aimed at defining the optimal amplitude of the H reflex to detect inhibitory changes induced by stimulation of the perioral afferents and at providing new information on the control of masticatory muscles. Sixteen healthy volunteers participated in the experiment. A conditioning stimulus (CS) to the perioral skin was applied at various delays before an ipsilateral selective masseteric nerve stimulation (test stimulus: TS) while the subject was clenching the teeth at 25% of the maximal voluntary contraction. Two intensities of CS and TS were employed, high and low. The peak-to-peak amplitude of the H reflex (TS) and the root-mean-square value of the preceding electromyography were measured and the data analyzed by three-way analysis of variance and Tukey's posthoc tests. For both intensities used the heteronymous H reflex in the temporalis muscle was significantly decreased by prior activation of perioral afferents for delays from 5 to 60 ms. With a delay of 5 and 35 ms the preceding EMG level was not changed, while it was reduced at 20 and 60 ms delay. The intensities used to elicit the heteronymous H reflex of the temporalis muscle were appropriate to detect a reduction in motoneuron excitability. The reduction in the H reflex without a change in the preceding EMG at 5 and 35 ms delays could be due to presynaptic inhibition of the masseteric afferents exerted by the ipsilateral perioral afferents. 相似文献
6.
Rickettsia-macrophage interactions: host cell responses to Rickettsia akari and Rickettsia typhi
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Radulovic S Price PW Beier MS Gaywee J Macaluso JA Azad A 《Infection and immunity》2002,70(5):2576-2582
The existence of intracellular rickettsiae requires entry, survival, and replication in the eukaryotic host cells and exit to initiate new infection. While endothelial cells are the preferred target cells for most pathogenic rickettsiae, infection of monocytes/macrophages may also contribute to the establishment of rickettsial infection and resulting pathogenesis. We initiated studies to characterize macrophage-Rickettsia akari and -Rickettsia typhi interactions and to determine how rickettsiae survive within phagocytic cells. Flow cytometry, microscopic analysis, and LDH release demonstrated that R. akari and R. typhi caused negligible cytotoxicity in mouse peritoneal macrophages as well as in macrophage-like cell line, P388D1. Host cells responded to rickettsial infection with increased secretion of proinflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-6. Furthermore, macrophage infection with R. akari and R. typhi resulted in differential synthesis and expression of IL-beta and IL-6, which may correlate with the existence of biological differences among these two closely related bacteria. In contrast, levels of gamma interferon (IFN-gamma), IL-10, and IL-12 in supernatants of infected P388D1 cells and mouse peritoneal macrophages did not change significantly during the course of infection and remained below the enzyme-linked immunosorbent assay cytokine detection limits. In addition, differential expression of cytokines was observed between R. akari- and R. typhi-infected macrophages, which may correlate with the biological differences among these closely related bacteria. 相似文献
7.
In this study the extraction and the immunochemical features of a lipopolysaccharide-like (LPSL) macromolecule of T. denticola strains 35405, 35404, 33521 and 11 were investigated. The yield of LPSL molecule ranged between 0.5-0.9% of the cell dry weight, it possessed Limulus amebocyte lysate clotting activity, and it contained glucosamine, phosphate, heptose, glucose, small amounts of KDO, myristic and beta hydroxy myristic acid. Sera obtained from healthy individuals (ADA type I) periodontitis, from 3-8 month old infants, or the mouse monoclonal antibody, diluted 1:2, against T. pallidum did not react with the LPSL antigens of T. denticola strains 35405, 35404, 33521, and 11. Sera from patients with ADA type III-IV periodontitis were reactive with two 8-14 kDa bands even at serum dilutions of 1:2000. Sera from patients with ADA type II periodontitis showed good antibody response to the 8-14 kDa band at a dilution of 1:50, but were weekly reactive, or nonreactive at serum dilutions of 1:200. This study indicates that extraction of a lipopolysaccharide-like macromolecule is feasible from the assay spirochetes, and this macromolecule may be used as an antigen for the diagnosis of ADA types II-IV periodontitis. 相似文献
8.
In a child with some features of Turner's syndrome, gonosomal mosaicism with an isodicentric nonfluorescent (idic)Y chromosome was detected (mos 45,X/47,X,idic(Y)(q11),idic(Y)(11)/46,X,idic(Y)(q11)). Histopathological examination showed streak gonads with some evidence of ovarian stroma and no sign of gonadoblastoma. Polymerase chain reaction (PCR) analysis in blood lymphocytes and gonadal tissues using primers of seven loci along the Y chromosome, including the sex determined region (SRY), azoospermia factor region (AZF) and the deleted in azoospermia ( DAZ ) gene was positive for all loci tested, confirming the isodicentric character of the Y chromosome and indicating the presence of the AZF region. It is remarkable that the existence of spermatogenesis controlling genes does not play an important role in gonadal development and differentiation in a phenotypic female with some Turner stigmata. The data presented here are briefly discussed with previously-described patients. 相似文献
9.
Membrane knobs are required for the microcirculatory obstruction induced by Plasmodium falciparum-infected erythrocytes. 总被引:15,自引:2,他引:13
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C Raventos-Suarez D K Kaul F Macaluso R L Nagel 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(11):3829-3833
We have studied the pathophysiology of the vascular obstruction induced by Plasmodium falciparum-parasitized erythrocytes with the use of an ex vivo microcirculatory preparation perfused with red cells infected with knobless and knobby clones of the FCR-3 strain. We find that parasitized erythrocyte membrane knobs are indispensable for the generation of the circulatory obstruction. Uninfected erythrocytes incubated in culture and erythrocytes infected with early or late forms of the knobless clones or the early forms of the knobby clone all failed to obstruct the microcirculation, although exhibiting various effects on bulk viscosity and peripheral resistance during flow. In contrast, late forms of the knobby clone produced significantly higher peripheral resistance during flow and significant obstruction as detected by changes in time of pressure flow recovery as well as by direct videorecorded microscopic observation. Optical and electron microscopy showed that the adherence of parasitized cells to the endothelium was limited to the venules and involved the knobs in junctions. In addition, we were able to follow the sequence of events during obstruction: initial red-cell adherence to the venular endothelium (sometimes only transitory) followed by progressive recruitment at the venule surface, finally leading to total obstruction that involved parasitized and nonparasitized erythrocytes. Sometimes, retrograde aggregation would extend the obstruction to the capillaries or even precapillary arterioles. These results show that knobs are necessary and sufficient to produce vascular obstruction and that other factors (spleen, immunological, etc.) can only have a modulating role. These results also exclude the possibility that the exclusive adherence to venules is the consequence of "plasma factors" found in the malaric patients. 相似文献
10.
Grad Roland Leger Daniel Kaczorowski Janusz Schuster Tibor Adler Samara Aman Marya Archibald Douglas Beaulieu Marie-Claude Chmelicek John Cornelissen Evelyn Delleman Bethany Hadj-Mimoune Sonia Horvey Samantha Macaluso Steven Mintsioulis Stephen Murdoch Stuart Ng Brian Papineau Alain Rangwala Sohil Rousseau Mathieu Rudkin Teresa Schabort Inge Schultz Karen Snow Pamela Wong Eric Wu Pearson Brailovsky Carlos 《Advances in health sciences education : theory and practice》2021,26(3):771-783
Advances in Health Sciences Education - Spaced education is a learning strategy to improve knowledge acquisition and retention. To date, no robust evidence exists to support the utility of spaced... 相似文献