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1.
Angela M. Tavolieri Daniel T. Murray Isabel Askenasy Joseph M. Pennington Lauren McGarry Christopher B. Stanley M. Elizabeth Stroupe 《Journal of structural biology》2019,205(2):170-179
This is the first X-ray crystal structure of the monomeric form of sulfite reductase (SiR) flavoprotein (SiRFP-60) that shows the relationship between its major domains in an extended position not seen before in any homologous diflavin reductases. Small angle neutron scattering confirms this novel domain orientation also occurs in solution. Activity measurements of SiR and SiRFP variants allow us to propose a novel mechanism for electron transfer from the SiRFP reductase subunit to its oxidase metalloenzyme partner that, together, make up the SiR holoenzyme. Specifically, we propose that SiR performs its 6-electron reduction via intramolecular or intermolecular electron transfer. Our model explains both the significance of the stoichiometric mismatch between reductase and oxidase subunits in the holoenzyme and how SiR can handle such a large volume electron reduction reaction that is at the heart of the sulfur bio-geo cycle. 相似文献
2.
Autoimmune insulitis, the cause of type 1 diabetes, evolves through several discrete stages that culminate in beta-cell death. In the first stage, antigenic epitopes of B-cell-specific peptides are processed by antigen presenting cells in local lymph nodes, and auto-reactive lymphocyte clones are propagated. Subsequently, cell-mediated and direct cytokine-mediated reactions are generated against the beta-cells, and the beta-cells are sensitized to apoptosis. Ironically, the beta-cells themselves contribute some of the cytokines and chemokines that provoke the immune reaction within the islets. Once this vicious cycle of autoimmunity is fully developed, the fate of the beta-cells in the islets is sealed, and clinical diabetes inevitably ensues. Differences in various aspects of these concurrent events appear to underlie the significant discrepancies in experimental data observed in experimental models that simulate autoimmune insulitis. 相似文献
3.
The continuing interest in the biology of stem cells is enhanced by new discoveries surrounding developmental plasticity of both embryonic and adult stem cells. Adoptive transfer of concepts and definitions from the hematopoietic system to other tissue stem cells suggests inclusion of characteristics such as ability to self-renew and differentiate to functionally reconstitute a tissue/organ of origin. How adequate and accurate are these definitions? Within the great unknown of how these cells function, modulate their gene expression patterns and respond to extrinsic signals, it is apparent that there are numerous levels of stemness. We may envision a scale of developmental flexibility. At one end of the scale are positioned the embryonic stem cells, and at the other end are positioned partially-differentiated, differentiation restricted (committed) tissue/organ stem cells. There is evidence that some stem cells in the adult are pluripotent, thus positioned close to the embryonic end of the stem scale. It is uncertain yet to what extent stem cells can move back and forth along the stem scale. 相似文献
4.
Shimon Slavin Aliza Ackerstein Reuven Or Michael Y. Shapira Benjamin Gesundheit Nadir Askenasy Shoshana Morecki 《Cancer immunology, immunotherapy : CII》2010,59(10):1511-1519
The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK)
with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies
and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes;
amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host
disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine
25 mg/m2 or a single dose of cyclophosphamide 1,000 mg/m2, 2 subcutaneous injections of alpha interferon (IFN) 3 × 106 and COX2 inhibitors, followed by administration of IMAK (65 ± 5 CD3+CD56−; 17 ± 5 CD3−CD56+) in conjunction with low dose subcutaneous rIL-2 (6 × 106 IU/m2/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we
present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological
malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on
an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited
grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of
21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude
that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term
disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors,
preferably at a stage of minimal residual disease with the goal in mind to eradicate all malignant cells at an early stage
of the disease. 相似文献
5.
Yolcu ES Ash S Kaminitz A Sagiv Y Askenasy N Yarkoni S 《Immunology and cell biology》2008,86(8):650-658
Activation-induced cell death is a general mechanism of immune homeostasis through negative regulation of clonal expansion of activated immune cells. This mechanism is involved in the maintenance of self- and transplant tolerance through polarization of the immune responses. The Fas/Fas-ligand interaction is a major common executioner of apoptosis in lymphocytes, with a dual role in regulatory T cell (Treg) function: Treg cell homeostasis and Treg cell-mediated suppression. Sensitivity to apoptosis and the patterns of Treg-cell death are of outmost importance in immune homeostasis that affects the equilibrium between cytolytic and suppressor forces in activation and termination of immune activity. Naive innate (naturally occurring) Treg cells present variable sensitivities to apoptosis, related to their turnover rates in tissue under steady state conditions. Following activation, Treg cells are less sensitive to apoptosis than cytotoxic effector subsets. Their susceptibility to apoptosis is influenced by cytokines within the inflammatory environment (primarily interleukin-2), the mode of antigenic stimulation and the proliferation rates. Here, we attempt to resolve some controversies surrounding the sensitivity of Treg cells to apoptosis under various experimental conditions, to delineate the function of cell death in regulation of immunity. 相似文献
6.
Shifra Ash Vered Gigi Nadir Askenasy Ina Fabian Jerry Stein Isaac Yaniv 《Cancer immunology, immunotherapy : CII》2009,58(12):2073-2084
Continuous efforts are dedicated to develop immunotherapeutic approaches to neuroblastoma (NB), a tumor that relapses at high
rates following high-dose conventional cytotoxic therapy and autologous bone marrow cell (BMC) reconstitution. This study
presents a series of transplant experiments aiming to evaluate the efficacy of allogeneic BMC transplantation. Neuro-2a cells
were found to express low levels of class I major histocompatibility complex (MHC) antigens. While radiation and syngeneic
bone marrow transplantation (BMT) reduced tumor growth (P < 0.001), allogeneic BMT further impaired subcutaneous development of Neuro-2a cells (P < 0.001). Allogeneic donor-derived T cells displayed direct cytotoxic activity against Neuro-2a in vitro, a mechanism of
immune-mediated suppression of tumor growth. The proliferation of lymphocytes from congenic mice bearing subcutaneous tumors
was inhibited by tumor lysate, suggesting that a soluble factor suppresses cytotoxic activity of syngeneic lymphocytes. However,
the growth of Neuro-2a cells was impaired when implanted into chimeric mice at various times after syngeneic and allogeneic
BMT. F1 (donor-host) splenocytes were infused attempting to foster immune reconstitution, however they engrafted transiently
and had no effect on tumor growth. Taken together, these data indicate: (1) Neuro-2a cells express MHC antigens and immunogenic
tumor associated antigens. (2) Allogeneic BMT is a significantly better platform to develop graft versus tumor (GVT) immunotherapy
to NB as compared to syngeneic (autologous) immuno-hematopoietic reconstitution. (3) An effective GVT reaction in tumor bearing
mice is primed by MHC disparity and targets tumor associated antigens. 相似文献
7.
The function of creatinekinase (CK) and its effect on phosphorus metabolites was studied inlivers of transgenic mice expressing human ubiquitous mitochondrial CK(CK-Mit) and rat brain CK (CK-B) isoenzymes and their combination.31P NMR spectroscopy and saturation transfer were recordedin livers of anesthetized mice to measure high-energy phosphates andhepatic CK activity. CK reaction velocity was related to total enzyme activity irrespective of the isoenzyme expressed, and it increased with increasing concentrations of creatine (Cr). The fluxesmediated by both isoenzymes in both directions (phosphocreatine or ATP synthesis) were equal. Over a 20-fold increase in CK-Mit activity (28-560 µmol · g wetwt1 · min1), the fraction ofphosphorylated Cr increased 1.6-fold. Hepatic free ADP concentrationscalculated by assuming equilibrium of the CK-catalyzed reaction in vivodecreased from 84 ± 9 to 38 ± 4 nmol/g wet wt. Calculatedfree ADP levels in mice expressing high levels of CK-B (920-1,635µmol · g wet wt1 · min1)were 52 ± 6 nmol/g wet wt. Mice expressing both isoenzymes had calculated free ADP levels of 36 ± 4 nmol/g wet wt. Thesefindings indicate that CK-Mit catalyzes its reaction equally well inboth directions and can lower hepatic apparent free ADP concentrations. 相似文献
8.
Yarkoni S Kaminitz A Sagiv Y Yaniv I Askenasy N 《BioEssays : news and reviews in molecular, cellular and developmental biology》2008,30(9):875-888
A large body of evidence on the activity of regulatory T (Treg) cells was gathered during the last decade, and a similar number of reviews and opinion papers attempted to integrate the experimental findings. The abundant literature clearly delineates an exciting area of research but also underlines some major controversies. A linear cause-result interpretation of experimental maneuvers often ignores the fact that the activity of Treg cells is orchestrated with the effector T (Teff) cells within an intricate network of physiological immune homeostasis. Every modulation of the activity of the effector (cytotoxic) immune system revolves to affect the activity of regulatory (suppressive) cells through elaborate feedback loops of negative and positive regulation. The lack of IL-2 production by innate Treg cells makes this cytokine a prime coupler of the effector and suppressive mechanisms. Here we attempt to integrate evidence that delineates the involvement of IL-2 in primary and secondary feedback loops that regulate the activity of suppressive cells within the elaborate network of physiological immune homeostasis. 相似文献
9.
Stein J Yaniv I Askenasy N 《Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society》2005,43(4):191-195
Durable hematopoietic stem cell engraftment requires efficient homing to and seeding in the recipient bone marrow. Dissection of cellular and molecular mechanisms by retrospective analysis of functional engraftment studies imposes severe limitations on the understanding of the early stages of this process. We have established an experimental approach for in vivo functional imaging of labeled cells at the level of recipient bone marrow in real time. The adhesive interaction of hematopoietic cells with the bone marrow stroma evolves as the most important early event. Adhesion to the marrow, rather than the vascular endothelium, determines the efficiency of both homing and seeding, and is absolutely essential to maintain cell viability in the marrow. Seeding and engraftment may be improved either by bypassing homing or by localized transplant of a large number of cells in a relatively small marrow space. There is functional redundancy in the molecular pathways that mediate the cell-stroma interaction, such that blockage of a single pathway has only minor effect on homing and seeding. We hypothesize that successfully seeding-engrafting cells undergo extensive phenotypic changes as a consequence of interaction with the stroma, without engaging in rapid proliferation. Surprisingly, Fas-ligand appears to promote hematopoietic cell engraftment by immunomodulatory and trophic effects. 相似文献
10.