An integrated Rotorcraft Avionics/Controls Architecture to support advanced controls and low-altitude guidance flight research

Salient design features of a new NASA/Army research rotorcraft--the Rotorcraft-Aircrew Systems Concepts Airborne Laboratory (RASCAL) are described. Using a UH-60A Black Hawk helicopter as a baseline vehicle, the RASCAL will be a flying laboratory capable of supporting the research requirements of major NASA and Army guidance, control, and display research programs. The paper describes the research facility requirements of these programs together with other critical constraints on the design of the research system. Research program schedules demand a phased development approach, wherein specific research capability milestones are met and flight research projects are flown throughout the complete development cycle of the RASCAL. This development approach is summarized, and selected features of the research system are described. The research system includes a real-time obstacle detection and avoidance system which will generate low-altitude guidance commands to the pilot on a wide field-of-view, color helmet-mounted display and a full-authority, programmable, fault-tolerant/fail-safe, fly-by-wire flight control system

Briefly Bound to Activate: Transient Binding of a Second Catalytic Magnesium Activates the Structure and Dynamics of CDK2 Kinase for Catalysis

SummaryWe have determined high-resolution crystal structures of a CDK2/Cyclin A transition state complex bound to ADP, substrate peptide, and MgF3−. Compared to previous structures of active CDK2, the catalytic subunit of the kinase adopts a more closed conformation around the active site and now allows observation of a second Mg2+ ion in the active site. Coupled with a strong [Mg2+] effect on in vitro kinase activity, the structures suggest that the transient binding of the second Mg2+ ion is necessary to achieve maximum rate enhancement of the chemical reaction, and Mg2+ concentration could represent an important regulator of CDK2 activity in vivo. Molecular dynamics simulations illustrate how the simultaneous binding of substrate peptide, ATP, and two Mg2+ ions is able to induce a more rigid and closed organization of the active site that functions to orient the phosphates, stabilize the buildup of negative charge, and shield the subsequently activated γ-phosphate from solvent

Preliminary design features of the RASCAL: A NASA /Army rotorcraft in-flight simulator

Salient design features of a new NASA/Army research rotorcraft - the Rotorcraft-Aircrew Systems Concepts Airborne Laboratory (RASCAL) - are described. Using a UH-60A Black Hawk helicopter as a baseline vehicle, the RASCAL will be a flying laboratory capable of supporting the research requirements of major NASA and Army guidance, control, and display research programs. The paper describes the research facility requirements of these programs together with other critical constraints on the design of the research system, including safety-of-flight. Research program schedules demand a phased development approach, wherein specific research capability milestones are met and flight research projects are flown throughout the complete development cycle of the RASCAL. This development approach is summarized, and selected features of the research system are described. The research system includes a full-authority, programmable, fault-tolerant/fail-safe, fly-by-wire flight control system and a real-time obstacle detection and avoidance system which will generate low-altitude guidance commands to the pilot on a wide field-of-view, color helmet-mounted display

Diastolic dysfunction and left atrial volume A population-based study

ObjectivesWe examined the association between diastolic function and left atrial volume indexed to body surface area (LAVi) in a population-based study.BackgroundAtrial enlargement has been suggested as a marker of the severity and duration of diastolic dysfunction (DD). However, the association between DD and atrial enlargement and their individual prognostic implications in the population is poorly defined.MethodsA cross-sectional sample of Olmsted County, Minnesota, residents ≥45 years of age (n = 2,042) underwent comprehensive Doppler echocardiography and medical record review.ResultsThe LAVi increased with worsening DD: 23 ± 6 ml/m2(normal), 25 ± 8 ml/m2(grade I DD), 31 ± 8 ml/m2(grade II DD), 48 ± 12 ml/m2(grades III to IV DD). In bivariate analyses, age, left ventricular mass index, and DD grade were positively associated, whereas female gender and ejection fraction (EF) were inversely associated with LAVi (p < 0.001 for all). When controlling for age, gender, cardiovascular (CV) disease, EF, and left ventricular mass, grade II DD was associated with a 24%, and grade III to IV DD was associated with a 62% larger LA volume (p < 0.0001 for both). The area under the receiver-operator characteristic curve for LAVi to detect grade I, grade II, or grade III to IV DD was 0.57, 0.81, and 0.98, respectively. Both DD and LAVi were predictive of all-cause mortality, but when controlling for DD, LAVi was not an independent predictor of mortality.ConclusionsThese data suggest that DD contributes to LA remodeling. Indeed, DD is a stronger predictor of mortality; presumably it better reflects the impact of CV disease within the general population

Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection: 2008 Recommendations of an International AIDS Society-USA Panel

Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly importan

Rapidly Decaying Supernova 2010X: A Candidate ".Ia" Explosion

We present the discovery, photometric and spectroscopic follow-up observations of SN 2010X (PTF 10bhp). This supernova decays exponentially with tau_d=5 days, and rivals the current recordholder in speed, SN 2002bj. SN 2010X peaks at M_r=-17mag and has mean velocities of 10,000 km/s. Our light curve modeling suggests a radioactivity powered event and an ejecta mass of 0.16 Msun. If powered by Nickel, we show that the Nickel mass must be very small (0.02 Msun) and that the supernova quickly becomes optically thin to gamma-rays. Our spectral modeling suggests that SN 2010X and SN 2002bj have similar chemical compositions and that one of Aluminum or Helium is present. If Aluminum is present, we speculate that this may be an accretion induced collapse of an O-Ne-Mg white dwarf. If Helium is present, all observables of SN 2010X are consistent with being a thermonuclear Helium shell detonation on a white dwarf, a ".Ia" explosion. With the 1-day dynamic-cadence experiment on the Palomar Transient Factory, we expect to annually discover a few such events.Comment: 6 pages, 5 figures; Minor Changes; Note correction in Fig 4 caption; published by ApJ

Generation of bivalent chromatin domains during cell fate decisions

<p>Abstract</p> <p>Background</p> <p>In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3) lineage control genes while 'poising' (H3K4me3) them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined.</p> <p>Results</p> <p>Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3.</p> <p>Conclusions</p> <p>While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different.</p

Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England

For women with preeclampsia, BMI &gt;30 kg/m2, infection, or those having cesarean delivery, VTE risk remained elevated for 6 weeks postpartum.For women with postpartum hemorrhage or preterm birth, the relative rate of VTE was only increased for the first 3 weeks postpartum.Impact on the timing of first postpartum venous thromboembolism (VTE) for women with specific risk factors is of crucial importance when planning the duration of thromboprophylaxis regimen. We observed this using a large linked primary and secondary care database containing 222 334 pregnancies resulting in live and stillbirth births between 1997 and 2010. We assessed the impact of risk factors on the timing of postpartum VTE in term of absolute rates (ARs) and incidence rate ratios (IRRs) using a Poisson regression model. Women with preeclampsia/eclampsia and postpartum acute systemic infection had the highest risk of VTE during the first 3 weeks postpartum (ARs ≥2263/100 000 person-years; IRR ≥2.5) and at 4-6 weeks postpartum (AR ≥1360; IRR ≥3.5). Women with body mass index (BMI) &gt;30 kg/m2 or those having cesarean delivery also had elevated rates up to 6 weeks (AR ≥1425 at 1-3 weeks and ≥722 at 4-6 weeks). Women with postpartum hemorrhage or preterm birth, had significantly increased VTE rates only in the first 3 weeks (AR ≥1736; IRR ≥2). Our findings suggest that the duration of the increased VTE risk after childbirth varies based on the type of risk factors and can extend up to the first 3 to 6 weeks postpartum

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

MERTK tyrosine kinase is ectopically expressed in 30–50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia

Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3'-untranslated region (with less frequency observed for coding sequence and 5'-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability.This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers