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Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a 下载免费PDF全文
Amelie Boquoi Sanjeevani Arora Tina Chen Sam Litwin James Koh Greg H. Enders 《Aging cell》2015,14(1):139-147
The cyclin‐dependent kinase (Cdk) inhibitor p16Ink4a (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit‐amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de‐induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16‐mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. 相似文献
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The evolutionary origin of the pinnipeds (seals, sea lions, and walruses)
is still uncertain. Most authors support a hypothesis of a monophyletic
origin of the pinnipeds from a caniform carnivore. A minority view suggests
a diphyletic origin with true seals being related to the mustelids (otters
and ferrets). The phylogenetic relationships of the walrus to other
pinniped and carnivore families are also still particularly problematic.
Here we examined the relative support for mono- and diphyletic hypotheses
using DNA sequence data from the mitochondrial small subunit (12S) rRNA and
cytochrome b genes. We first analyzed a small group of taxa representing
the three pinniped families (Phocidae, Otariidae, and Odobenidae) and
caniform carnivore families thought to be related to them. We inferred
phylogenetic reconstructions from DNA sequence data using standard
parsimony and neighbor-joining algorithms for phylogenetic inference as
well as a new method called spectral analysis (Hendy and Penny) in which
phylogenetic information is displayed independently of any selected tree.
We identified and compensated for potential sources of error known to lead
to selection of incorrect phylogenetic trees. These include sampling error,
unequal evolutionary rates on lineages, unequal nucleotide composition
among lineages, unequal rates of change at different sites, and
inappropriate tree selection criteria. To correct for these errors, we
performed additional transformations of the observed substitution patterns
in the sequence data, applied more stringent structural constraints to the
analyses, and included several additional taxa to help resolve long,
unbranched lineages in the tree. We find that there is strong support for a
monophyletic origin of the pinnipeds from within the caniform carnivores,
close to the bear/raccoon/panda radiation. Evidence for a diphyletic origin
was very weak and can be partially attributed to unequal nucleotide
compositions among the taxa analyzed. Subsequently, there is slightly more
evidence for grouping the walrus with the eared seals versus the true
seals. A more conservative interpretation, however, is that the walrus is
an early, but not the first, independent divergence from the common
pinniped ancestor.
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Stuart A Suttie Alan GK Li Martha Quinn Kenneth GM Park 《World journal of surgical oncology》2007,5(1):1-9
Background
Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens.Methods
Using tissue microarray (TMA) technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar) and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data.Results
No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5), benign breast disease (n = 295) and DCIS (n = 108). However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%). Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers.Conclusion
In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment. 相似文献8.
NaCl-preferring NZB/B1NJ mice and NaCl-avoiding CBA/J mice have similar amiloride inhibition of chorda tympani responses to NaCl 总被引:1,自引:1,他引:0
Integrated chorda tympani nerve responses to NaCl were studied in two mouse
strains, an NaCl-preferring NZB/B1NJ and an NaCl-avoiding CBA/J. The NaCl
responses of both strains had similar magnitude and were suppressed by
amiloride to a similar extent. This suggests that peripheral gustatory
responsiveness to NaCl is not the only mechanism underlying mouse strain
variation in NaCl acceptance.
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Shrinivas Darak Melinda Mills Vinay Kulkarni Sanjeevani Kulkarni Inge Hutter Fanny Janssen 《PloS one》2015,10(4)
Background
HIV infection closely relates to and deeply affects the reproductive career of those infected. However, little is known about the reproductive career trajectories, specifically the interaction of the timing of HIV diagnosis with the timing and sequencing of reproductive events among HIV infected women. This is the first study to describe and typify this interaction.Methods
Retrospective calendar data of ever married HIV infected women aged 15-45 attending a HIV clinic in Pune, Maharashtra, Western India (N=622) on reproductive events such as marriage, cohabitation with the partner, use of contraception, pregnancy, childbirth and HIV diagnosis were analyzed using sequence analysis and multinomial logistic regression.Results
Optimal matching revealed three distinct trajectories: 1) HIV diagnosis concurrent with childbearing (40.7%), 2) HIV diagnosis after childbearing (32.1%), and 3) HIV diagnosis after husband’s death (27.2%). Multinomial logistic regression (trajectory 1 = baseline) showed that women who got married before the age of 21 years and who had no or primary level education had a significantly higher risk of knowing their HIV status either after childbearing or close to their husband’s death. The risk of HIV diagnosis after husband’s death was also higher among rural women and those who were diagnosed before 2005.Conclusions
Three distinct patterns of interaction of timing of HIV diagnosis with timing and sequencing of events in the reproductive career were observed that have clear implications for (i) understanding of the individual life planning process in the context of HIV, (ii) formulation of assumptions for estimating HIV infected women in need of PMTCT services, and (iii) provision of care services. 相似文献10.
Ekanayake DK Horadagoda NU Sanjeevani GK Arulkanthan A Gunatilake KA Dittus WP 《American journal of primatology》2003,61(1):13-28
Hematological studies were conducted in three wild groups of toque macaques (Macaca sinica) inhabiting the Polonnaruwa Sanctuary in northeastern Sri Lanka. The macaques were temporarily trapped and anesthetized, and femoral blood was drawn from 35 males and 37 females (age range: 0.33-24.5 yr). Statistically significant (P<0.05) differences were observed by sex for total plasma proteins (PP), and by age for red blood cell (RBC) counts, hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular Hb (MCH), mean corpuscular Hb concentration (MCHC), PP, erythrocyte sedimentation rate (ESR), differential and absolute neutrophil counts, differential lymphocyte counts, and absolute eosinophil counts. In general, the results were similar to those reported for other species of colony-bred and free-ranging macaques. However, there also were differences. First, in contrast to earlier studies of nonhuman primates, we examined the hematology of infants. Compared to other age classes, infants (<1 yr old) had lower RBC, Hb, MCHC, and ESR values, and a higher MCV. These findings were similar to those obtained in human infants. Second, we observed variations in hematology among social groups in relation to their ecology. Two groups (IH3 and M3) had ready access to water throughout the dry season (the period of sampling), whereas the third group (J) did not. The Hb, RBC, and PP values obtained in groups IH3 and M3 were similar to those reported in other macaque species. However, these parameters in group J were significantly (P<0.01) higher, which suggests that this group (representing about 26% of the sample) had been dehydrated during the dry season. Finally, two indices indicative of injury and infection--the ESR and leukocyte counts--were higher in the wild toque macaques than has been reported for other species of macaques held in captivity, and about 15% of the toque macaques sampled had extreme outlier values for these parameters; however, none were visibly ill or died. These results suggest that wild toque macaques are subject to a wide array of physical and biological insults that are unique to natural populations. 相似文献