A study of unmanned mission opportunities to comets and asteroids

Several unmanned multiple-target mission opportunities to comets and asteroids were studied. The targets investigated include Grigg-Skjellerup, Giacobini-Zinner, Tuttle-Giacobini-Kresak, Borrelly, Halley, Schaumasse, Geographos, Eros, Icarus, and Toro, and the trajectories consist of purely ballistic flight, except that powered swingbys and deep space burns are employed when necessary. Optimum solar electric rendezvous trajectories to the comets Giacobini-Zinner/85, Borrelly/87, and Temple (2)/83 and /88 employing the 8.67 kw Sert III spacecraft modified for interplanetary flight were also investigated. The problem of optimizing electric propulsion heliocentric trajectories, including the effects of geocentric launch asymptote declination on launch vehicle performance capability, was formulated, and a solution developed using variational calculus techniques. Improvements were made to the HILTOP trajectory optimization computer program. An error analysis of high-thrust maneuvers involving spin-stabilized spacecraft was developed and applied to a synchronous meteorological satellite mission

Non-LTE Monte Carlo Radiative Transfer: II. Non-Isothermal Solutions for Viscous Keplerian Disks

We discuss the basic hydrodynamics that determines the density structure of the disks around hot stars. Observational evidence supports the idea that these disks are Keplerian (rotationally supported) gaseous disks. A popular scenario in the literature, which naturally leads to the formation of Keplerian disks, is the viscous decretion model. According to this scenario, the disks are hydrostatically supported in the vertical direction, while the radial structure is governed by the viscous transport. This suggests that the temperature is one primary factor that governs the disk density structure. In a previous study we demonstrated, using 3-D NLTE Monte Carlo simulations, that viscous keplerian disks can be highly non-isothermal. In this paper we build upon our previous work and solve the full problem of the steady-state non-isothermal viscous diffusion and vertical hydrostatic equilibrium. We find that the self-consistent solution departs significantly from the analytic isothermal density, with potentially large effects on the emergent spectrum. This implies that non-isothermal disk models must be used for a detailed modeling of Be star disks.Comment: 22 pages, 9 figures, Ap

2-D Radiative Transfer in Protostellar Envelopes: I. Effects of Geometry on Class I Sources

We present 2-D radiation transfer models of Class I Protostars and show the effect of including more realistic geometries on the resulting spectral energy distributions and images. We begin with a rotationally flattened infalling envelope as our comparison model, and add a flared disk and bipolar cavity. The disk affects the spectral energy distribution most strongly at edge-on inclinations, causing a broad dip at about 10 um (independent of the silicate feature) due to high extinction and low scattering albedo in this wavelength region. The bipolar cavities allow more direct stellar+disk radiation to emerge into polar directions, and more scattering radiation to emerge into all directions. The wavelength-integrated flux, often interpreted as luminosity, varies with viewing angle, with pole-on viewing angles seeing 2-4 times as much flux as edge-on, depending on geometry. Thus, observational estimates of luminosity should take into account the inclination of a source. The envelopes with cavities are significantly bluer in near-IR and mid-IR color-color plots than those without cavities. Using 1-D models to interpret Class I sources with bipolar cavities would lead to an underestimate of envelope mass and an overestimate of the implied evolutionary state. We compute images at near-, mid-, and far-IR wavelengths. We find that the mid-IR colors and images are sensitive to scattering albedo, and that the flared disk shadows the midplane on large size scales at all wavelengths plotted. Finally, our models produce polarization spectra which can be used to diagnose dust properties, such as albedo variations due to grain growth. Our results of polarization across the 3.1 um ice feature agree well with observations for ice mantles covering 5% of the radius of the grains.Comment: Accepted for publication in ApJ, 37 pages, 13 figures (several figures reduced in quality; find original version at http://gemelli.colorado.edu/~bwhitney/preprints.html

Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance

In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11ß to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.Tam Nguyen, Jonas Bjorkman, Barbara C. Paton and Denis I. Cran

Achernar: Rapid Polarization Variability as Evidence of Photospheric and Circumstellar Activity

We present the results of a high accuracy ($\sigma \approx 0.005$) polarization monitoring of the Be Star Achernar that was carried out between July 7th and November 5th, 2006. Our results indicate that, after a near quiescent phase from 1998 to 2002, Achernar is presently in an active phase and has built a circumstellar disk. We detect variations both in the polarization level and position angle in timescales as short as one hour and as long as several weeks. Detailed modeling of the observed polarization strongly suggests that the short-term variations originate from discrete mass ejection events which produce transient inhomogeneities in the inner disk. Long-term variations, on the other hand, can be explained by the formation of an inner ring following one or several mass ejection events.Comment: 16 pages, 5 figures, Accepted to Ap

In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa

Background: Artemether-lumefantrine (AL) is a major and highly effective artemisinin-based combination therapy that is becoming increasingly important as a new first-line therapy against Plasmodium falciparum malaria. However, recrudescences occurring after AL treatment have been reported. Identification of drug-specific parasite determinants that contribute to treatment failures will provide important tools for the detection and surveillance of AL resistance. Methods: The findings from a 42-day follow-up efficacy trial in Tanzania that compared AL with sulfadoxinepyrimethamine (SP) were analyzed to identify candidate markers for lumefantrine tolerance/resistance in the chloroquine resistance transporter gene (pfcrt) and multidrug resistance gene 1 (pfmdr1). The findings were corroborated in vitro with genetically modified isogenic P. falciparum parasite lines. Results: Treatment with AL selected for the chloroquine-susceptible pfcrt K76 allele (P \u3c .0001) and, to a lesser extent, the pfmdr1 N86 (P = .048) allele among recurrent infections. These genotypes were not selected during SP treatment. No pfmdr1 gene amplifications were observed. Isogenic pfcrt-modified parasite lines demonstrated a 2-fold increase in susceptibility to lumefantrine, which was directly attributable to the K76T mutation. Conclusions: Our findings suggest that the pfcrt K76T mutation is a drug-specific contributor to enhanced P. falciparum susceptibility to lumefantrine in vivo and in vitro, and they highlight the benefit of using AL in areas affected by chloroquine-resistant P. falciparum malaria. © 2009 by the Infectious Diseases Society of America. All rights reserved

pfmdr1 amplification is related to increased Plasmodium falciparum In Vitro sensitivity to the Bisquinoline Piperaquine

The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC50 and P = 0.002 for IC90) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.Swedish Development Cooperation Agency-Department for Research Cooperation [SWE 2005-0017, SWE 2005-4596, SWE-2007-174, SWE-2005-4027]; Fundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Ciencia e Ensino Superior, Portugal-MCES [SFRH/BPD/76614/2011]; Wellcome Trust of Great Britaininfo:eu-repo/semantics/publishedVersio

HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design

Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens

Plasmodium falciparum Drug Resistance Genes pfmdr1 and pfcrt In Vivo Co-Expression During Artemether-Lumefantrine Therapy

Background: Artemisinin-based combination therapies (ACTs) are the global mainstay treatment of uncomplicated Plasmodium falciparum infections. PfMDR1 and PfCRT are two transmembrane transporters, associated with sensitivity to several antimalarials, found in the parasite food vacuole. Herein, we explore if their relatedness extends to overlapping patterns of gene transcriptional activity before and during ACT administration.Methods: In a clinical trial performed in Tanzania, we explored the pfmdr1 and pfcrt transcription levels from 48 patients with uncomplicated P. falciparum malaria infections who underwent treatment with artemether-lumefantrine (AL). Samples analyzed were collected before treatment initiation and during the first 24 h of treatment. The frequency of PfMDR1 N86Y and PfCRT K76T was determined through PCR-RFLP or direct amplicon sequencing. Gene expression was analyzed by real-time quantitative PCR.Results: A wide range of pre-treatment expression levels was observed for both genes, approximately 10-fold for pfcrt and 50-fold for pfmdr1. In addition, a significant positive correlation demonstrates pfmdr1 and pfcrt co-expression. After AL treatment initiation, pfmdr1 and pfcrt maintained the positive co-expression correlation, with mild downregulation throughout the 24 h post-treatment. Additionally, a trend was observed for PfMDR1 N86 alleles and higher expression before treatment initiation.Conclusion: pfmdr1 and pfcrt showed significant co-expression patterns in vivo, which were generally maintained during ACT treatment. This observation points to relevant related roles in the normal parasite physiology, which seem essential to be maintained when the parasite is exposed to drug stress. In addition, keeping the simultaneous expression of both transporters might be advantageous for responding to the drug action