Propulsion simulation for magnetically suspended wind tunnel models

The feasibility of simulating propulsion-induced aerodynamic effects on scaled aircraft models in wind tunnels employing Magnetic Suspension and Balance Systems. The investigation concerned itself with techniques of generating exhaust jets of appropriate characteristics. The objectives were to: (1) define thrust and mass flow requirements of jets; (2) evaluate techniques for generating propulsive gas within volume limitations imposed by magnetically-suspended models; (3) conduct simple diagnostic experiments for techniques involving new concepts; and (4) recommend experiments for demonstration of propulsion simulation techniques. Various techniques of generating exhaust jets of appropriate characteristics were evaluated on scaled aircraft models in wind tunnels with MSBS. Four concepts of remotely-operated propulsion simulators were examined. Three conceptual designs involving innovative adaptation of convenient technologies (compressed gas cylinders, liquid, and solid propellants) were developed. The fourth innovative concept, namely, the laser-assisted thruster, which can potentially simulate both inlet and exhaust flows, was found to require very high power levels for small thrust levels

Targets and genomic constraints of ectopic Dnmt3b expression

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome

Relating jet structure to photometric variability: the Herbig Ae star HD 163296

Herbig Ae/Be stars are intermediate-mass pre-main sequence stars surrounded by circumstellar dust disks. Some are observed to produce jets, whose appearance as a sequence of shock fronts (knots) suggests a past episodic outflow variability. This "jet fossil record" can be used to reconstruct the outflow history. We present the first optical to near-infrared (NIR) VLT/X-shooter spectra of the jet from the Herbig Ae star HD 163296. We determine physical conditions in the knots, as well as their kinematic "launch epochs". Knots are formed simultaneously on either side of the disk, with a regular interval of ~16 yr. The velocity dispersion versus jet velocity and the energy input are comparable in both lobes. However, the mass loss rate, velocity, and shock conditions are asymmetric. We find Mjet/Macc ~ 0.01-0.1, consistent with magneto-centrifugal jet launching models. No evidence for dust is found in the high-velocity jet, suggesting it is launched within the sublimation radius (<0.5 au). The jet inclination measured from proper motions and radial velocities confirms it is perpendicular to the disk. A tentative relation is found between the structure of the jet and the photometric variability of the source. Episodes of NIR brightening were previously detected and attributed to a dusty disk wind. We report for the first time significant optical fadings lasting from a few days up to a year, coinciding with the NIR brightenings. These are likely caused by dust lifted high above the disk plane; this supports the disk wind scenario. The disk wind is launched at a larger radius than the high-velocity atomic jet, although their outflow variability may have a common origin. No significant relation between outflow and accretion variability could be established. Our findings confirm that this source undergoes periodic ejection events, which may be coupled with dust ejections above the disk plane.Comment: 20 pages, 11 figures, accepted for publication in Astronomy & Astrophysic

High-Contrast NIR Polarization Imaging of MWC480

One of the key predictions of modeling from the IR excess of Herbig Ae stars is that for protoplanetary disks, where significant grain growth and settling has occurred, the dust disk has flattened to the point that it can be partially or largely shadowed by the innermost material at or near the dust sublimation radius. When the self-shadowing has already started, the outer disk is expected to be detected in scattered light only in the exceptional cases that the scale height of the dust disk at the sublimation radius is smaller than usual. High-contrast imaging combined with the IR spectral energy distribution allow us to measure the degree of flattening of the disk, as well as to determine the properties of the outer disk. We present polarimetric differential imaging in H band obtained with Subaru/HiCIAO of one such system, MWC 480. The HiCIAO data were obtained at a historic minimum of the NIR excess. The disk is detected in scattered light from 0".2-1"0 (27.4-137 AU). Together with the marginal detection of the disk from 1998 February 24 by HST / NICMOS, our data constrain the opening half angle for the disk to lie between 1.3 <= Theta <=2.2 deg. When compared with similar measures in CO for the gas disk from the literature, the dust disk subtends only approx 30% of the gas disk scale height (H/R approx 0. 03). Such a dust disk is a factor of 5-7 flatter than transitional disks, which have structural signatures that giant planets have formed

Contribution of an Aged Microenvironment to Aging-Associated Myeloproliferative Disease

The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia

Haematopoietic stem cells in perisinusoidal niches are protected from ageing.

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing

Argonaute2 Suppresses Drosophila Fragile X Expression Preventing Neurogenesis and Oogenesis Defects

Fragile X Syndrome is caused by the silencing of the Fragile X Mental Retardation gene (FMR1). Regulating dosage of FMR1 levels is critical for proper development and function of the nervous system and germ line, but the pathways responsible for maintaining normal expression levels are less clearly defined. Loss of Drosophila Fragile X protein (dFMR1) causes several behavioral and developmental defects in the fly, many of which are analogous to those seen in Fragile X patients. Over-expression of dFMR1 also causes specific neuronal and behavioral abnormalities. We have found that Argonaute2 (Ago2), the core component of the small interfering RNA (siRNA) pathway, regulates dfmr1 expression. Previously, the relationship between dFMR1 and Ago2 was defined by their physical interaction and co-regulation of downstream targets. We have found that Ago2 and dFMR1 are also connected through a regulatory relationship. Ago2 mediated repression of dFMR1 prevents axon growth and branching defects of the Drosophila neuromuscular junction (NMJ). Consequently, the neurogenesis defects in larvae mutant for both dfmr1 and Ago2 mirror those in dfmr1 null mutants. The Ago2 null phenotype at the NMJ is rescued in animals carrying an Ago2 genomic rescue construct. However, animals carrying a mutant Ago2 allele that produces Ago2 with significantly reduced endoribonuclease catalytic activity are normal with respect to the NMJ phenotypes examined. dFMR1 regulation by Ago2 is also observed in the germ line causing a multiple oocyte in a single egg chamber mutant phenotype. We have identified Ago2 as a regulator of dfmr1 expression and have clarified an important developmental role for Ago2 in the nervous system and germ line that requires dfmr1 function

The role of epigenetics in renal ageing

An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects

Genetic studies of IgA nephropathy: past, present, and future

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and an important cause of kidney disease in young adults. Highly variable clinical presentation and outcome of IgAN suggest that this diagnosis may encompass multiple subsets of disease that are not distinguishable by currently available clinical tools. Marked differences in disease prevalence between individuals of European, Asian, and African ancestry suggest the existence of susceptibility genes that are present at variable frequencies in these populations. Familial forms of IgAN have also been reported throughout the world but are probably underrecognized because associated urinary abnormalities are often intermittent in affected family members. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently demonstrated. Recent data indicates that these IgA1 glycosylation defects are inherited and constitute a heritable risk factor for IgAN. Because of the complex genetic architecture of IgAN, the efforts to map disease susceptibility genes have been difficult, and no causative mutations have yet been identified. Linkage-based approaches have been hindered by disease heterogeneity and lack of a reliable noninvasive diagnostic test for screening family members at risk of IgAN. Many candidate-gene association studies have been published, but most suffer from small sample size and methodological problems, and none of the results have been convincingly validated. New genomic approaches, including genome-wide association studies currently under way, offer promising tools for elucidating the genetic basis of IgAN