A Flight Investigation to Determine the Lateral Oscillatory Damping Acceptable for an Airplane in the Landing Approach

An F-86E airplane, in which servo actuation of the ailerons and rudder provides artificial variation of the important lateral and directional aerodynamic stability parameters, has been flown by test pilots of the NASA, U.S. Air Force, and one aircraft manufacturer to determine satisfactory and acceptable levels of lateral oscillatory damping in the landing approach. In addition to normal operational use, particular consideration was given to the emergency condition of failure of stability-augmentation equipment. In this study, the pilots' opinions of the airplane dynamic stability and control characteristics in smooth and simulated rough air have been recorded according to a numerical rating scale. The results are presented in the form of boundaries in terms of cycles to damp to half amplitude, 1/C(sub 1/2), or time to damp to half amplitude, 1/T(1/2) and bank-to-sideslip ratio, and are discussed in relation to existing flying-qualities criteria. Though the present results, which were obtained at 170 knots indicated airspeed and 10,000-feet altitude, indicated that increased damping is required with increased bank-to-sideslip ratio (as found in previous work), consideration of the dampers-failed condition indicated a great reduction in the minimum acceptable damping. At moderate values of bank-to-sideslip ratio, effects of lateral-oscillation period on pilot-opinion variation with damping appeared to be taken into account by use of the parameter 1/T(sub 1/2)

Chikungunya virus infection results in higher and persistent viral replication in aged Rhesus macaques due to defects in anti-viral immunity

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne Alphavirus that causes a clinical disease involving fever, myalgia, nausea and rash. The distinguishing feature of CHIKV infection is the severe debilitating poly-arthralgia that may persist for several months after viral clearance. Since its re-emergence in 2004, CHIKV has spread from the Indian Ocean region to new locations including metropolitan Europe, Japan, and even the United States. The risk of importing CHIKV to new areas of the world is increasing due to high levels of viremia in infected individuals as well as the recent adaptation of the virus to the mosquito species Aedes albopictus. CHIKV re-emergence is also associated with new clinical complications including severe morbidity and, for the first time, mortality. In this study, we characterized disease progression and host immune responses in adult and aged Rhesus macaques infected with either the recent CHIKV outbreak strain La Reunion (LR) or the West African strain 37997. Our results indicate that following intravenous infection and regardless of the virus used, Rhesus macaques become viremic between days 1-5 post infection. While adult animals are able to control viral infection, aged animals show persistent virus in the spleen. Virus-specific T cell responses in the aged animals were reduced compared to adult animals and the B cell responses were also delayed and reduced in aged animals. Interestingly, regardless of age, T cell and antibody responses were more robust in animals infected with LR compared to 37997 CHIKV strain. Taken together these data suggest that the reduced immune responses in the aged animals promotes long-term virus persistence in CHIKV-LR infected Rhesus monkeys

The Effect of Lateral-Directional Control Coupling on Pilot Control of an Airplane as Determined in Flight and in a Fixed-Base Flight Simulator

A flight and fixed-base simulator study was made of the effects of aileron-induced yaw on pilot opinion of aircraft lateral-directional controllability characteristics. A wide range of adverse and favorable aileron-induced yaw was investigated in flight at several levels of Dutch-roll damping. The flight results indicated that the optimum values of aileron- induced yaw differed only slightly from zero for Dutch-roll damping from satisfactory to marginally controllable levels. It was also shown that each range of values of aileron-induced yawing moment considered satisfactory, acceptable, or controllable increased with an increase in the Dutch- roll damping. The increase was most marked for marginally controllable configurations exhibiting favorable aileron-induced yaw. Comparison of fixed-base flight simulator results with flight results showed agreement, indicating that absence of kinesthetic motion cues did not markedly affect the pilots' evaluation of the type of control problem considered in this study. The results of the flight study were recast in terms of several parameters which were considered to have an important effect on pilot opinion of lateral-directional handling qualities, including the effects of control coupling. Results of brief tests with a three-axis side-arm controller indicated that for control coupling problems associated with highly favorable yaw and cross-control techniques, use of the three-axis controller resulted in a deterioration of control relative to results obtained with the conventional center stick and rudder pedals

Structure-based discovery of novel US28 small molecule ligands with different modes of action

The human cytomegalovirus-encoded G protein-coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 Å crystal structure, potent and US28-specific tool compounds are still scarce. Here, we used structural information from a refined US28:VUF2274 complex for virtual screening of &gt; 12 million commercially available small molecule compounds. Using a combined receptor- and ligand-based approach, we tested 98 of the top 0.1% ranked compounds, revealing novel chemotypes as compared to the ~1.45 million known ligands in the ChEMBL database. Two compounds were confirmed as agonist and inverse agonist, respectively, in both IP accumulation and Ca(2+) mobilization assays. The screening setup presented in this work is computationally inexpensive and therefore particularly useful in an academic setting as it enables simultaneous testing in binding as well as in different functional assays and/or species without actual chemical synthesis. This article is protected by copyright. All rights reserved.</p

KSHV infection of endothelial cells manipulates CXCR7-mediated signaling: implications for Kaposi’s Sarcoma progression and intervention

CXCR7 was recently characterized as an alternative receptor for the chemokine CXCL12/SDF-1, previously thought to bind and signal exclusively through CXCR4.We recently identified CXCR7 as a key cellular factor in the endothelial cell (EC) dysfunction associated with KSHV infection. CXCL12 signaling is critically associated with tumor growth, angiogenesis and metastasis in several diverse tumors and is one of the most studied chemokine/chemokine receptor interactions in cancer systems. The tumorigenic activity of the CXCL12 signaling axis offers an attractive target for therapeutic intervention in multiple cancers including Kaposi’s Sarcoma (KS). However, most of the research to date was based on the assumption that CXCR4 was the sole CXCL12 receptor, and thus focused on the development of CXCR4-targeted treatments

HCMV pUS28 initiates pro-migratory signaling via activation of Pyk2 kinase

Background: Human Cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease and chronic allograft rejection. Recently, the virus has been associated with glioblastoma and other tumors. We have previously shown that the HCMV-encoded chemokine receptor pUS28 mediates smooth muscle cell (SMC) and macrophage motility and this activity has been implicated in the acceleration of vascular disease. pUS28 induced SMC migration involves the activation of the protein tyrosine kinases (PTKs) Src and Focal adhesion kinase as well as the small GTPase RhoA. The PTK Pyk2 has been shown to play a role in cellular migration and formation of cancer, especially glioblastoma. The role of Pyk2 in pUS28 signaling and migration are unknown. Methods: In the current study, we examined the involvement of the PTK Pyk2 in pUS28-induced cellular motility. We utilized in vitro migration of SMC to determine the requirements for Pyk2 in pUS28 pro-migratory signaling. We performed biochemical analysis of Pyk2 signaling in response to pUS28 activation to determine the mechanisms involved in pUS28 migration. We performed mass spectrometric analysis of Pyk2 complexes to identify novel Pyk2 binding partners. Results: Expression of a mutant form of Pyk2 lacking the autophosphorylation site (Tyr-402) blocks pUS28-mediated SMC migration in response to CCL5, while the kinase-inactive Pyk2 mutant failed to elicit the same negative effect on migration. pUS28 stimulation with CCL5 results in ligand-dependent and calcium-dependent phosphorylation of Pyk2 Tyr-402 and induced the formation of an active Pyk2 kinase complex containing several novel Pyk2 binding proteins. Expression of the autophosphorylation null mutant Pyk2 F402Y did not abrogate the formation of an active Pyk2 kinase complex, but instead prevented pUS28-mediated activation of RhoA. Additionally, pUS28 activated RhoA via Pyk2 in the U373 glioblastoma cells. Interestingly, the Pyk2 kinase complex in U373 contained several proteins known to participate in glioma tumorigenesis. Conclusions: These findings represent the first demonstration that pUS28 signals through Pyk2 and that this PTK participates in pUS28-mediated cellular motility via activation of RhoA. Furthermore, these results provide a potential mechanistic link between HCMV-pUS28 and glioblastoma cell activation

Differential Ligand Binding to a Human Cytomegalovirus Chemokine Receptor Determines Cell Type–Specific Motility

While most chemokine receptors fail to cross the chemokine class boundary with respect to the ligands that they bind, the human cytomegalovirus (HCMV)-encoded chemokine receptor US28 binds multiple CC-chemokines and the CX3C-chemokine Fractalkine. US28 binding to CC-chemokines is both necessary and sufficient to induce vascular smooth muscle cell (SMC) migration in response to HCMV infection. However, the function of Fractalkine binding to US28 is unknown. In this report, we demonstrate that Fractalkine binding to US28 not only induces migration of macrophages but also acts to inhibit RANTES-mediated SMC migration. Similarly, RANTES inhibits Fractalkine-mediated US28 migration in macrophages. While US28 binding of both RANTES and Fractalkine activate FAK and ERK-1/2, RANTES signals through Gα12 and Fractalkine through Gαq. These findings represent the first example of differential chemotactic signaling via a multiple chemokine family binding receptor that results in migration of two different cell types. Additionally, the demonstration that US28-mediated chemotaxis is both ligand-specific and cell type–specific has important implications in the role of US28 in HCMV pathogenesis