Dynamic stability and handling qualities tests on a highly augmented, statically unstable airplane

Initial envelope clearance and subsequent flight testing of a new, fully augmented airplane with an extremely high degree of static instability can place unusual demands on the flight test approach. Previous flight test experience with these kinds of airplanes is very limited or nonexistent. The safe and efficient flight testing may be further complicated by a multiplicity of control effectors that may be present on this class of airplanes. This paper describes some novel flight test and analysis techniques in the flight dynamics and handling qualities area. These techniques were utilized during the initial flight envelope clearance of the X-29A aircraft and were largely responsible for the completion of the flight controls clearance program without any incidents or significant delays

Stability and Control Analysis of the F-15B Quiet SpikeTM Aircraft

The primary purpose of the Quiet Spike(TradeMark) flight research program was to analyze the aerodynamic, structural, and mechanical proof-of-concept of a large multi-stage telescoping nose spike installed on the National Aeronautics and Space Administration Dryden Flight Research Center (Edwards, California) F-15B airplane. This report describes the preflight stability and control analysis performed to assess the effect of the spike on the stability, controllability, and handling qualities of the airplane; and to develop an envelope expansion approach to maintain safety of flight. The overall flight test objective was to collect flight data to validate the spike structural dynamics and loads model up to Mach 1.8. Other objectives included validating the mechanical feasibility of a morphing fuselage at operational conditions and determining the near-field shock wave characterization. The two main issues relevant to the stability and control objectives were the effects of the spike-influenced aerodynamics on the F-15B airplane flight dynamics, and the air data and angle-of-attack sensors. The analysis covered the sensitivity of the stability margins, and the handling qualities due to aerodynamic variation and the maneuvering limitations of the F-15B Quiet Spike configuration. The results of the analysis and the implications for the flight test program are also presented

Flight Test of the F/A-18 Active Aeroelastic Wing Airplane

Successful flight-testing of the Active Aeroelastic Wing airplane was completed in March 2005. This program, which started in 1996, was a joint activity sponsored by NASA, Air Force Research Laboratory, and industry contractors. The test program contained two flight test phases conducted in early 2003 and early 2005. During the first phase of flight test, aerodynamic models and load models of the wing control surfaces and wing structure were developed. Design teams built new research control laws for the Active Aeroelastic Wing airplane using these flight-validated models; and throughout the final phase of flight test, these new control laws were demonstrated. The control laws were designed to optimize strategies for moving the wing control surfaces to maximize roll rates in the transonic and supersonic flight regimes. Control surface hinge moments and wing loads were constrained to remain within hydraulic and load limits. This paper describes briefly the flight control system architecture as well as the design approach used by Active Aeroelastic Wing project engineers to develop flight control system gains. Additionally, this paper presents flight test techniques and comparison between flight test results and predictions

Development and Testing of Control Laws for the Active Aeroelastic Wing Program

The Active Aeroelastic Wing research program was a joint program between the U.S. Air Force Research Laboratory and NASA established to investigate the characteristics of an aeroelastic wing and the technique of using wing twist for roll control. The flight test program employed the use of an F/A-18 aircraft modified by reducing the wing torsional stiffness and adding a custom research flight control system. The research flight control system was optimized to maximize roll rate using only wing surfaces to twist the wing while simultaneously maintaining design load limits, stability margins, and handling qualities. NASA Dryden Flight Research Center developed control laws using the software design tool called CONDUIT, which employs a multi-objective function optimization to tune selected control system design parameters. Modifications were made to the Active Aeroelastic Wing implementation in this new software design tool to incorporate the NASA Dryden Flight Research Center nonlinear F/A-18 simulation for time history analysis. This paper describes the design process, including how the control law requirements were incorporated into constraints for the optimization of this specific software design tool. Predicted performance is also compared to results from flight

PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.This work was supported by the Center Prevention and Research Institute of Texas (CPRIT) (RP160451 and R120501) and the NIH (DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, and P30 CA016672). The Welch Foundation (G-0040), MD Anderson’s MoonShot Program, the Baylor Research Advocates for Student Scientists, and the BCM MSTP program also provided support. K.T. is supported by a Khalifa Physician Scientist Award, the Physician Scientist Program at MD Anderson, and a Leukemia SPORE Career Enhancement Award. G.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015), the Kay Kendall Leukaemia Fund, Bloodwise, and core funding from the Sanger Institute (WT098051). We also thank the Samuel Waxman Cancer Research Foundation

An approach to analyse the specific impact of rapamycin on mRNA-ribosome association

<p>Abstract</p> <p>Background</p> <p>Recent work, using both cell culture model systems and tumour derived cell lines, suggests that the differential recruitment into polysomes of mRNA populations may be sufficient to initiate and maintain tumour formation. Consequently, a major effort is underway to use high density microarray profiles to establish molecular fingerprints for cells exposed to defined drug regimes. The aim of these pharmacogenomic approaches is to provide new information on how drugs can impact on the translational read-out within a defined cellular background.</p> <p>Methods</p> <p>We describe an approach that permits the analysis of de-novo mRNA-ribosome association in-vivo during short drug exposures. It combines hypertonic shock, polysome fractionation and high-throughput analysis to provide a molecular phenotype of translationally responsive transcripts. Compared to previous translational profiling studies, the procedure offers increased specificity due to the elimination of the drugs secondary effects (e.g. on the transcriptional read-out). For this pilot "proof-of-principle" assay we selected the drug rapamycin because of its extensively studied impact on translation initiation.</p> <p>Results</p> <p>High throughput analysis on both the light and heavy polysomal fractions has identified mRNAs whose re-recruitment onto free ribosomes responded to short exposure to the drug rapamycin. The results of the microarray have been confirmed using real-time RT-PCR. The selective down-regulation of TOP transcripts is also consistent with previous translational profiling studies using this drug.</p> <p>Conclusion</p> <p>The technical advance outlined in this manuscript offers the possibility of new insights into mRNA features that impact on translation initiation and provides a molecular fingerprint for transcript-ribosome association in any cell type and in the presence of a range of drugs of interest. Such molecular phenotypes defined pre-clinically may ultimately impact on the evaluation of a particular drug in a living cell.</p

The translational response of the human mdm2 gene in HEK293T cells exposed to rapamycin: a role for the 5′-UTRs

Polysomal messenger RNA (mRNA) populations change rapidly in response to alterations in the physiological status of the cell. For this reason, translational regulation, mediated principally at the level of initiation, plays a key role in the maintenance of cellular homeostasis. In an earlier translational profiling study, we followed the impact of rapamycin on polysome re-seeding. Despite the overall negative effect on transcript recruitment, we nonetheless observed that some mRNAs were significantly less affected. Consequently, their relative polysomal occupancy increased in the rapamycin-treated cells. The behaviour of one of these genes, mdm2, has been further analysed. Despite the absence of internal ribosome entry site activity we demonstrate, using a dual reporter assay, that both the reported mdm2 5′-UTRs confer resistance to rapamycin relative to the 5′-UTR of β-actin. This relative resistance is responsive to the downstream targets mTORC1 but did not respond to changes in the La protein, a reported factor acting positively on MDM2 translational expression. Furthermore, extended exposure to rapamycin in the presence of serum increased the steady-state level of the endogenous MDM2 protein. However, this response was effectively reversed when serum levels were reduced. Taken globally, these studies suggest that experimental conditions can dramatically modulate the expressional output during rapamycin exposure

Relative Undernourishment and Food Insecurity Associations with Plasmodium falciparum Among Batwa Pygmies in Uganda: Evidence from a Cross-Sectional Survey

Although malnutrition and malaria co-occur among individuals and populations globally, effects of nutritional status on risk for parasitemia and clinical illness remain poorly understood. We investigated associations between Plasmodium falciparum infection, nutrition, and food security in a cross-sectional survey of 365 Batwa pygmies in Kanungu District, Uganda in January of 2013. We identified 4.1% parasite prevalence among individuals over 5 years old. Severe food insecurity was associated with increased risk for positive rapid immunochromatographic test outcome (adjusted relative risk [ARR] = 13.09; 95% confidence interval [95% CI] = 2.23–76.79). High age/sex-adjusted mid-upper arm circumference was associated with decreased risk for positive test among individuals who were not severely food-insecure (ARR = 0.37; 95% CI = 0.19–0.69). Within Batwa pygmy communities, where malnutrition and food insecurity are common, individuals who are particularly undernourished or severely food-insecure may have elevated risk for P. falciparum parasitemia. This finding may motivate integrated control of malaria and malnutrition in low-transmission settings

Oncogenic EGFR Signaling Activates an mTORC2-NF- B Pathway That Promotes Chemotherapy Resistance

Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival, and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in GBM pathogenesis, including through activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in cancer