Absence of autoantigen Ku in mature human neutrophils and human promyelocytic leukemia line (HL-60) cells and lymphocytes undergoing apoptosis

The Ku autoantigen is a heterodimer of 70- and 80-kD proteins recognized by autoantibodies from patients with systemic lupus erythematosus and related diseases that is the DNA-binding component of a DNA-dependent protein kinase. The catalytic activity of DNA-dependent protein kinase is carried by a 350-kD subunit (p350). In light of the recently described role of Ku in repairing double-strand DNA breaks, we investigated the regulation of Ku and p350 levels in neutrophils, a terminally differentiated cell type destined to undergo apoptosis. Since the appearance of double-strand DNA breaks is characteristic of apoptosis, we were interested in the possibility that Ku might oppose programmed cell death. Analysis of peripheral blood cells by flow cytometry using anti-Ku and anti-p350 monoclonal antibodies revealed that neutrophils were unstained, whereas resting (G0) lymphocytes were positive. The absence of Ku in mature neutrophils was confirmed by Western blotting and enzyme-linked immunosorbent assay for Ku antigen. In contrast, the human promyelocytic leukemia line, HL-60, which undergoes differentiation toward neutrophils after dimethylsulfoxide treatment, was positive for Ku and p350. In view of the short lifespan of neutrophils and the prolonged half-life of Ku and p350 (> 5 d), these data suggested that Ku was actively degraded during myeloid differentiation. Analysis of HL-60 cells by flow cytometry revealed that Ku staining was bimodal. Cells in G1/G0, S, or G2/M were all stained positively, whereas cells with a subdiploid DNA content characteristic of apoptosis were Ku negative. Similar results were obtained with phytohemagglutin-stimulated human lymphocytes. These data suggest that the Ku antigen is actively degraded in both myeloid cells destined to undergo apoptosis and apoptotic lymphocytes, raising the possibility that degradation of Ku may help to prevent the inappropriate repair of fragmented nuclear DNA during apoptosis

Delayed Apoptotic Cell Clearance and Lupus-like Autoimmunity in Mice Lacking the c-mer Membrane Tyrosine Kinase

Mice lacking the membrane tyrosine kinase c-mer have been shown to have altered macro-phage cytokine production and defective phagocytosis of apoptotic cells despite normal phagocytosis of other particles. We show here that c-mer–deficient mice have impaired clearance of infused apoptotic cells and that they develop progressive lupus-like autoimmunity, with antibodies to chromatin, DNA, and IgG. The autoimmunity appears to be driven by endogenous antigens, with little polyclonal B cell activation. These mice should be an excellent model for studying the role of apoptotic debris as an immunogenic stimulus for systemic autoimmunity

La Montología Global 4D: Hacia las Ciencias Convergentes y Transdisciplinarias de Montaña a través del Tiempo y el Espacio

With mountain studies we use integrative approaches for geoliteracy about productive socioecological landscapes, and motivate further transdisciplinary research in montology. We conceived this white paper as a confluence of individual expertise and collective reasoning towards forming synergistic research clusters dealing with convergent mountain science, to advance montology to a new level, whereby innovative thinking about sustainability science and regenerative development incorporates alternative propositions for maintenance, improvement, or regeneration of living conditions of mountainscapes. We seek to use this contemporary framing of sustainability and ecological restoration as the impetus to better understand nature-culture relations, framed on lived-in mountains that operate in four dimensions (length, width, depth, and time) oriented at maximizing the cross-cutting of themes around mountains as productive socioecological systems, in a new academic institutionalized convergent unit. We conclude with a call for consilient, sustainable, regenerative development in the world’s mountains.La utilización de los estudios de montaña requiere de narrativas integradoras para la geoalfabetización sobre paisajes socioecológicos productivos y motiva más investigaciones transdisciplinares en el campo de la montología. Concebimos este artículo como la confluencia de la experiencia individual y el razonamiento colectivo hacia la formación de grupos de investigación sinérgicos que se ocupan de la ciencia de montaña convergente, para hacer avanzar la montología a un nuevo nivel, mediante el cual el pensamiento innovador sobre la ciencia de la sustentabilidad y el desarrollo regenerativo incorpora propuestas alternativas para el mantenimiento, la mejora, o regeneración de las condiciones de vida de los paisajes de montaña. Buscamos utilizar este marco contemporáneo de sustentabilidad y restauración ecológica como el ímpetu para comprender mejor las relaciones de la naturaleza y la cultura, desde una perspectiva transdisciplinar, en montañas habitadas que operan en cuatro dimensiones (largo, ancho, alto y tiempo). El artículo está orientado a potenciar la transversalidad de temáticas en torno a las montañas como sistemas socioecológicos productivos, en una nueva disciplina académica institucionalizada y convergente. Concluimos con un llamado a un desarrollo regenerativo, sustentable y consiliente en las montañas del mundo

A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.ClinicalTrials.gov NCT00626015

Nitzschia pungens Grunow f. multiseries Hasle: growth phases and toxicity of clonal cultures isolated from Galveston, Texas

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