Space shuttle: Effect of configuration changes on the directional characteristics of a GD/C booster Mach no. 1.2 - 4.96

Force tests on a 0.0035-scale model of the General Dynamics/Convair aerospace space shuttle B-15B-1 booster were conducted in the MSFC trisonic wind tunnel. The configuration has a low delta wing, all-movable delta-planform canard controls, and a single vertical tail. The test was devoted to investigating the effects of various configuration variables upon lateral-directional characteristics. These variables included wing dihedral, rudder flare, and body flap deflection. Yaw runs were made at angles of attack of 6, 10, 15, 25, 30, and 35 degrees. The Mach number range for this test was 1.20 to 4.96

Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcription

Analysis of lung cancer response to chemotherapeutic agents showed the accumulation of a Taxol-induced protein that reacted with an anti-phospho-MEK1/2 antibody. Mass spectroscopy identified the protein as nucleophosmin/B23 (NPM), a multifunctional protein with diverse roles: ribosome biosynthesis, p53 regulation, nuclear-cytoplasmic shuttling, and centrosome duplication. Our work demonstrates that following cellular exposure to mitosis-arresting agents NPM is phosphorylated and its chromatographic property is altered, suggesting changes in function during mitosis. To determine the functional relevance of NPM, its expression in tumor cells was reduced by siRNA. Cells with reduced NPM were treated with Taxol followed by microarray profiling accompanied by gene/protein pathway analyses. These studies demonstrate several expected and unexpected consequences of NPM depletion. The predominant downstream effectors of NPM are genes involved in cell proliferation, cancer, and the cell cycle. In congruence with its role in cancer, NPM is over-expressed in primary malignant lung cancer tissues. We also demonstrate a role for NPM in the expression of genes encoding SET (TAF1β) and the histone methylase SET8. Additionally, we show that NPM is required for a previously unobserved G2/M upregulation of TAF1A, which encodes the rDNA transcription factor TAFI48. These results demonstrate multi-faceted functions of NPM that can affect cancer cells

Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis

With enhanced concerns of terrorist attacks, dual exposure to radiation and thermal combined injury (RCI) has become a real threat with devastating immunosuppression. NLRP12, a member of the NOD-like receptor family, is expressed in myeloid and bone marrow cells and has been implicated as a checkpoint regulator of inflammatory cytokines as well as an inflammasome activator. We show that NLRP12 has a profound impact on hematopoietic recovery during RCI by serving as a checkpoint of TNF signaling and preventing hematopoietic apoptosis. Using a mouse model of RCI, increased NLRP12 expression was detected in target tissues. Nlrp12−/− mice exhibited significantly greater mortality, inability to fight bacterial infection, heightened levels of pro-inflammatory cytokines, overt granulocyte/monocyte progenitor cell apoptosis and failure to reconstitute peripheral myeloid populations. Anti-TNF antibody administration improved peripheral immune recovery. These data suggest that NLRP12 is essential for survival after RCI by regulating myelopoiesis and immune reconstitution

NLRP3 (NALP3, Cryopyrin) Facilitates In Vivo Caspase-1 Activation, Necrosis, and HMGB1 Release via Inflammasome-Dependent and -Independent Pathways

Bacterial infection elicits a range of beneficial as well as detrimental host inflammatory responses. Key among these responses are macrophage/monocyte necrosis, release of the pro-inflammatory factor high-mobility group box 1 protein (HMGB1), and induction of the cytokine IL-1. While the control of IL-1β has been well-studied, processes that control macrophage cell death and HMGB-1 release in animals are poorly understood. This study utilizes Klebsiella pneumonia as a model organism since it elicits all three responses in vivo. The regulation of these responses is studied in the context of the inflammasome components, NLRP3 and ASC, which are important for caspase-1 activation and IL-1β release. Using a pulmonary infection model that reflects human infection, we show that K. pneumonia-induced mouse macrophage necrosis, HMGB-1 and IL-1β release are dependent on NLRP3 and ASC. K. pneumoniae infection of mice lacking Nlrp3 results in decreased lung inflammation and reduced survival relative to control indicating the overall protective role of this gene. Macrophage/monocyte necrosis and HMGB1 release are controlled independently of caspase-1 suggesting that the former two responses are separable from inflammasome-associated functions. These results provide critical in vivo validation that the physiologic role of NLRP3 and ASC is not limited to inflammasome formation

Analysis of NLRP3 in the Development of Allergic Airway Disease in Mice

The contribution of NLRP3, a member of the nucleotide-binding domain leucine-rich repeat containing (NLR) family, in the development of allergic airway disease is currently controversial. Here, we used multiple allergic asthma models to examine the physiologic role of NLRP3. We found no significant differences in airway eosinophilia, histopathology, mucus production and airway hyperreactivity between wild type and Nlrp3-/- mice in either acute (alum-dependent) or chronic (alum-independent) OVA models. In addition to the OVA model, we also did not detect a role for NLRP3 in the development of allergic airway disease induced by either acute or chronic house dust mite (HDM) antigen exposure. While we did not observe significant phenotypic differences in any of the models tested, we did observe a significant reduction of IL-13 and IL-33 in Nlrp3-/- mice compared to wild type controls in the chronic OVA model without added alum. In all of the allergic airway disease models, the levels of the NLRP3 inflammasome associated cytokines IL-1β and IL-18 in the lung were below the level of detection. In sum, this report surveyed four different allergic asthma models and found a modest and selected role for NLRP3 in the alum-free OVA model. However this difference did not greatly alter the clinical outcome of the disease. This suggests that the role of NLRP3 in allergic asthma has to be re-evaluated

MyD88 provides a protective role in long-term radiation-induced lung injury

The role of innate immune regulators is investigated in injury sustained from irradiation as in the clinic for cancer treatment or from a nuclear incident. The protective benefits of flagellin signaling through Toll-like receptors (TLR) in an irradiation setting warrant study of a key intracellular adaptor of TLR signaling, namely Myeloid differentiation primary response factor 88 (MyD88). The role of MyD88 in regulating innate immunity and Nuclear factor kappa-B (NF-κB)-activated responses targets this critical factor for influencing injury and recovery as well as maintaining immune homeostasis