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The presence of checkpoint mechanisms which are able to recognize damaged
chromatin and thereafter to prevent exit from metaphase I has been
investigated in giant mouse oocytes produced by fusion of a normal
metaphase I oocyte with an equivalent oocyte with damaged chromatin. The
presence of damaged chromatin did not prevent the onset of anaphase I in
both sets of chromatin in the fused cells. Interestingly, fused or unfused
cells containing only damaged chromatin failed to enter anaphase and
persisted instead in a metaphase-like state. These results demonstrate the
fragility of checkpoint controls in mammalian female germ cells.
相似文献
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Thrombopoietin (Tpo), the ligand for the c-Mpl receptor, is a major regulator of megakaryopoiesis. Treatment of mice with Tpo raises the platelet count fourfold within a few days. Conversely, c-mpl knock-out mice have platelet counts that are 15% that of normal. The subunit structure of the c-Mpl receptor is not fully understood. Some cytokines that stimulate megakaryopoiesis (IL-6, IL-11, leukemia inhibitory factor, and oncostatin M) bind to receptors that use gp130 as a signal transduction subunit. For these reasons, we determined whether gp130 function was required for Tpo-induced signal transduction. Murine marrow cells were cultured in semi-solid media in the presence of Tpo or IL-3, with or without a neutralizing anti-gp130 monoclonal antibody (RX187) or a soluble form of c-Mpl receptor (soluble Mpl) that blocks Tpo bioactivity, and the numbers of colony-forming unit-megakaryocyte (CFU-Meg) colonies were counted on day 5. Murine marrow cells were also cultured in suspension under serum-free conditions for 5 days, and megakaryocyte DNA content was measured by flow cytometry, as an index of nuclear maturation. The addition of RX187 did not block Tpo-induced CFU-Meg colony growth nor CFU-Meg nuclear maturation in suspension culture. However, IL-3-induced CFU-Meg colony growth and megakaryocyte nuclear maturation decreased in the presence of RX187. Soluble Mpl completely ablated Tpo-induced CFU-Meg growth, and partially blocked IL- 3-stimulated CFU-Meg growth. Thus the effects of Tpo on megakaryopoiesis in vitro do not depend on cytokines that signal through gp130. Furthermore, it is unlikely that gp 130 serves as a beta chain for the c-Mpl receptor, as Tpo signalling is unimpaired in the presence of RX187. In contrast, the effects of IL-3 on CFU-Meg growth are mediated in part through Tpo and through gp130-signalling cytokines. 相似文献
5.
Tai X Van Laethem F Pobezinsky L Guinter T Sharrow SO Adams A Granger L Kruhlak M Lindsten T Thompson CB Feigenbaum L Singer A 《Blood》2012,119(22):5155-5163
CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs), but the mechanism by which they do so remains incompletely understood. In the present study, we assessed CTLA-4 protein function in both Tregs and conventional (Tconv) CD4(+) T cells. We report that CTLA-4 proteins are responsible for all 3 characteristic Treg functions of suppression, TCR hyposignaling, and anergy. However, Treg suppression and anergy only required the external domain of CTLA-4, whereas TCR hyposignaling required its internal domain. Surprisingly, TCR hyposignaling was neither required for Treg suppression nor anergy because costimulatory blockade by the external domain of CTLA-4 was sufficient for both functions. We also report that CTLA-4 proteins were localized in Tregs in submembrane vesicles that rapidly recycled to/from the cell surface, whereas CTLA-4 proteins in naive Tconv cells were retained in Golgi vesicles away from the cell membrane and had no effect on Tconv cell function. However, TCR signaling of Tconv cells released CTLA-4 proteins from Golgi retention and caused activated Tconv cells to acquire suppressor function. Therefore, the results of this study demonstrate the importance of intracellular localization for CTLA-4 protein function and reveal that CTLA-4 protein externalization imparts suppressor function to both regulatory and conventional CD4(+) T cells. 相似文献
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NL Vasukutty RG Middleton P Young C Uzoigwe B Barkham S Yusoff THA Minhas 《Annals of the Royal College of Surgeons of England》2014,96(8):597-601
IntroductionDislocation following total hip replacement continues to be a problem for which no completely satisfactory solution has been found. Several methods have been proposed to reduce the incidence of hip dislocations with varying degrees of success, including elevated rim liners, constrained liners and large diameter bearings. We present our experience with the double mobility acetabular component in patients at high risk of instability.MethodsThis was a retrospective review of 65 primary total hip arthroplasties in 55 patients (15 men, 40 women), performed between October 2005 and November 2009. The majority (80%) of patients had at least two and 26% had at least three risk factors for instability. The mean age was 76 years (range: 44–92 years). The patients were followed up for a mean duration of 60 months (range: 36–85 months).ResultsFourteen patients died and one was lost to follow-up, leaving fifty hips for final assessment. Until the final follow-up appointment, no patients had dislocation and none required revision surgery. The mean Oxford hip score improved from 45.0 to 26.5 (p<0.0001). The mean Merle d’Aubigné pain score improved from 1.4 to 4.9 (p<0.0001), the walking score from 2.3 to 3.1 (p<0.07) and the absolute hip function score from 5.4 to 10.8 (p<0.0001). There were no clinical or radiographic signs of loosening.ConclusionsThe double mobility acetabular component was successful at preventing dislocation during early to medium-term follow-up. However, as data are still lacking with regard to polyethylene wear rates at the additional bearing surface, it would be prudent to restrict the use of this implant to selected patients at high risk of instability. 相似文献
7.
Evaluation of atypical human immunodeficiency virus immunoblot reactivity in blood donors 总被引:6,自引:0,他引:6
NL Dock ; HV Lamberson Jr ; TA O''Brien ; DE Tribe ; SS Alexander ; BJ Poiesz 《Transfusion》1988,28(5):412-418
Blood donors reactive by enzyme-linked immunosorbent assay for antibody to the human immunodeficiency virus (HIV) who showed atypical patterns of viral core protein reactivity on Western blot were monitored for several months. Characterization of their antibodies was performed by 1) use of recombinant HIV proteins; 2) determination of cross-reactivity to HTLV-I, HTLV-II, and HTLV-IV: 3) assessment of immune status; and 4) identification of potentially interfering autoantibodies. Nineteen of 20 donors maintained the same HIV antibody reactivity throughout the follow-up period; the other donor became fully antibody-positive. Eighteen of 20 donors' sera showed clear reactivity with HIV recombinant core proteins. Ten of 19 donor samples demonstrated cross-reactivity to HTLV-IV; 3 of these 10 also cross-reacted with HTLV-I. The immune status of all donors was normal, although the medical histories and HLA antibody screens suggested possible autoimmune reactivity in 9 of 18 donors. During follow-up interviews, three donors reported possible risk factors for HIV infection that had not been acknowledged at the time of blood donation. We conclude that exclusion of donors with these atypical serologic test results is warranted while further studies to determine significance are being conducted. 相似文献
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Brown MJ Nijhara R Hallam JA Gignac M Yamada KM Erlandsen SL Delon J Kruhlak M Shaw S 《Blood》2003,102(12):3890-3899
Lymphocyte microvilli mediate initial rolling-adhesion along endothelium but are lost during transmigration from circulation to tissue. However, the mechanism for resorption of lymphocyte microvilli remains unexplored. We show that chemokine stimulation of human peripheral blood T (PBT) cells is sufficient to induce rapid resorption of microvilli. Microvilli in other cells are regulated by ezrin/radixin/moesin (ERM) proteins, which link the plasma membrane to the cortical F-actin cytoskeleton; maintenance of these linkages requires ERM activation, reflected by phosphorylation at a specific carboxy-terminal threonine residue. Carboxyphosphorylated-ERM (cpERM) proteins in resting PBT cells show a punctate peripheral distribution consistent with localization to microvilli. cpERM dephosphorylation begins within seconds of stimulation by chemokines (stromal derived factor 1 alpha [SDF-1 alpha] or secondary lymphoid tissue cytokine), and ERM proteins lose their punctate distribution with kinetics paralleling the loss of microvilli. The cpERM proteins are preferentially associated with the cytoskeleton at rest and this association is lost with chemokine-induced dephosphorylation. Transfection studies show that a dominant-negative ERM construct destroys microvilli, whereas a construct mimicking cpERM facilitates formation of microvilli, retards chemokine-induced loss of microvilli, and markedly impairs chemokine-induced polarization. Thus, chemokine induces rapid dephosphorylation and inactivation of cpERM, which may in turn facilitate 2 aspects of cytoskeletal reorganization involved in lymphocyte recruitment: loss of microvilli and polarization. 相似文献
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