Virginia Air and Space Center

ABSTRACTInfantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a β-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis.Graphical abstract

Abstract On the dayside of August 25–26, 2018 (main phase, MP of the storm), we unveiled the storm time effects on the latitudinal distribution of ionospheric total electron content (TEC). We used 17 and 19 Global Positioning System receivers in American and Asian‐Australian sectors, respectively. Also, we employed a pair of magnetometers in each sector to unveil storm time effects on vertical E × B upward directed inferred drift velocity in the F region ionosphere. Also used is NASA Thermosphere Ionosphere Mesosphere Energetics and Dynamics satellite airglow instrument to investigate storm time changes in neutral composition, O/N2 ratio. In this investigation, we corrected the latitudinal offset found in the works of Younas et al. (2020, https://doi.org/10.1029/2020JA027981). Interestingly, we observed that a double‐humped increase (DHI) seen at a middle latitude station (MGUE, ∼22°S) after the MP on the dayside in American sector (Younas et al., 2020, https://doi.org/10.1029/2020JA027981) did straddle ∼23.58°N and ∼22°S. On August 25, 2018, storm commencement was evident in Sym‐H (∼−8 nT) around 18:00 UT. It later became intensified (∼−174 nT) on August 26 around 08:00 UT. During storm's MP (after the MP), fountain effect operation was significantly enhanced (inhibited) in Asian‐Australian (American) sector. Middle latitude TEC during MP got reduced in American sector (13:00 LT–15:40 LT) compared to those seen in Asian‐Australian sector (13:00 LT–15:40 LT). The northern equatorial peak (∼25 TECU) seen at IHYO (14:00 LT) after MP in the American sector is higher when compared with that (∼21 TECU) seen at PPPC (11:40 LT) during MP in Asian‐Australian sector.

Fracture mechanics analyses of subsurface defects within the joggle regions of the Space Shuttle wing-leading-edge RCC panels are performed. A 2D plane strain idealized joggle finite element model is developed to study the fracture behavior of the panels for three distinct loading conditions - lift-off and ascent, on-orbit, and entry. For lift-off and ascent, an estimated bounding aerodynamic pressure load is used for the analyses, while for on-orbit and entry, thermo-mechanical analyses are performed using the extreme cold and hot temperatures experienced by the panels. In addition, a best estimate for the material stress-free temperature is used in the thermo-mechanical analyses. In the finite element models, the substrate and coating are modeled separately as two distinct materials. Subsurface defects are introduced at the coating-substrate interface and within the substrate. The objective of the fracture mechanics analyses is to evaluate the defect driving forces, which are characterized by the strain energy release rates, and determine if defects can become unstable for each of the loading conditions.

The virtual agency concept is now used within the United States Government as an alliance approach to manage large research and development (R&D) processes across departments. This paper examines the history of the virtual agency concept and its important characteristics. The paper identifies the potential benefits and associated risks involved in managing R&D within a virtual agency. Three cases are examined where the virtual agency concept has been applied to R&D programs: the High Performance Computing and Communications initiative, the Next Generation Internet, and the Partnership for a New Generation of Vehicles. The case studies indicate that the R&D process is attempting to balance formal process controls with the agility to adapt rapidly to new research opportunities. Virtual agencies can be used to improve organizational efficiency, improve knowledge transfer, increase interoperability through standards, provide better alignment of agency missions with national policy, and introduce increased flexibility into the R&D process. At the same time, the virtual agency concept has major risks including inefficiencies due to organizational complexity, the danger of collective myopia, the problem of adopting standards too early, the difficulty of reaching objectives in a loose organizational structure, and the problem of properly balancing the tension between agency mission objectives and national policy agendas.