Mars Orbiter Study. Volume 2: Mission Design, Science Instrument Accommodation, Spacecraft Design

Spacecraft system and subsystem designs were developed at the conceptual level to perform either of two Mars Orbiter Missions, a Climatology Mission and an Aeronomy Mission. The objectives of these missions are to obtain and return data to increase knowledge of Mars

Relating geologic units and mobility system kinematics contributing to Curiosity wheel damage at Gale Crater, Mars

Curiosity landed on plains to the north of Mount Sharp in August 2012. By June 2016 the rover had traversed 12.9 km to the southwest, encountering extensive strata that were deposited in a fluvial-deltaic-lacustrine system. Initial drives across sharp sandstone outcrops initiated an unacceptably high rate of punctures and cracks in the thin aluminum wheel skin structures. Initial damage was found to be related to the drive control mode of the six wheel drive actuators and the kinematics of the rocker-bogie suspension. Wheels leading a suspension pivot were forced onto sharp, immobile surfaces by the other wheels as they maintained their commanded angular velocities. Wheel damage mechanisms such as geometry-induced stress concentration cracking and low-cycle fatigue were then exacerbated. A geomorphic map was generated to assist in planning traverses that would minimize further wheel damage. A steady increase in punctures and cracks between landing and June 2016 was due in part because of drives across the sharp sandstone outcrops that could not be avoided. Wheel lifetime estimates show that with careful path planning the wheels will be operational for an additional ten kilometers or more, allowing the rover to reach key strata exposed on the slopes of Mount Sharp

A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes

New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways

Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice

Catechol-O-methyltransferase (COMT) is an ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity (Andersen & Skorpen, 2009) and risk for developing psychiatric disorders (Harrison & Tunbridge, 2008). A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation (Nackley et al., 2006). However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have assessed Comt1 gene expression levels in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed among the strains, and this differential expression is cis-regulated. A B2 Short Interspersed Element (SINE) was inserted in the 3′UTR of Comt1 in 14 strains generating a common haplotype that correlates with gene expression. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element demonstrate that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3′ UTR B2 SINE element, regulates Comt1 expression and some mouse behaviors

Genome Wide Analysis of Inbred Mouse Lines Identifies a Locus Containing Ppar-γ as Contributing to Enhanced Malaria Survival

The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-γ in malaria infection