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

Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity.

Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity4,5. ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans

Not just for romance: applications of speed dating in social work education

In this article we address how a contemporary adaptation of the \u27speed dating\u27 model was used for educational purposes with two cohorts of social work students. We outline the dimensions of \u27speed dating\u27 as a contemporary social phenomenon, then address how this model relates specifically to groupwork process, and can be used to facilitate social work student learning. The curriculum for two classroom group activities using the \u27speed dating\u27 model are outlined, the first to develop university level study skills, the second for debriefing field placement learning experiences. Finally we examine why the \u27speed dating\u27 metaphor was successful in provoking a playful yet constructively creative space for students to engage in groupwork process.<br /

Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts.

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution

Protective Effects of the Novel Phytonutrient S7 Against Intestinal Tight Junction Disruption: Composition Matters

The prevalence of intestinal inflammatory diseases is increasing, and pharmacologic agents for intervention are currently limited. Preserving epithelial tight junction (TJ) integrity and preventing underlying immune cell activation by intestinal bacteria are key targets for abrogating the perpetual inflammatory cycle that plagues these diseases. Phytonutrients have shown promise for their ability to reduce cellular inflammation, but the extent of their efficacy in an intestinal model of inflammation is not well understood. Here, we hypothesized that S7, a novel phytonutrient derived from extracts rich in curcuminoids and catechins, would reduce immune cell inflammation and preserve TJ integrity in an in vitro co-culture model of intestinal inflammation. We further investigated whether a curcumin-containing formulation (S7-C) or its metabolite, tetrahydrocurcumin (S7-THC) would similarly preserve TJ integrity. An in vitro intestinal co-culture model was established by seeding Caco-2 epithelial cells on semipermeable transwell inserts 21 days prior to the addition of RAW264.7 macrophages in the basolateral chamber. Macrophages were next stimulated with 10 ng/ml lipopolysaccharide (LPS) to induce inflammation, and subsequent TJ disruption in the co-cultured Caco-2 cells was assessed by transepithelial electrical resistance (TEER) using epithelial ohmmeter chopstick electrodes. We found that administration of S7-THC containing 1-5 μM THC produced dose dependent mitigation of LPS-induced decreases in TEER and approached the efficacy of the pharmacologic agent, budesonide. However, S7-C at 5 μM curcumin was unable to preserve TEER, suggesting that the specific combination of phytonutrients is important for preventing inflammation-induced TJ disruption. We also found that, though apical application (Caco-2 only) of budesonide was sufficient for preserving TEER in our model, S7-THC required both apical (Caco-2) and basolateral (RAW264.7) treatment, suggesting that reducing macrophage inflammation is important for limiting epithelial TJ disruption in this context. Interestingly, S7-C was more effective than S7-THC or budesonide at reducing inflammatory basolateral nitric oxide (NO) production as determined by the Griess assay. This suggests that, though S7-C more effectively reduces this aspect of inflammation, another inflammatory mediator is responsible for conveying TJ disruption and is governed differentially by S7-THC. Further support of this comes from our finding that S7-THC, but not S7-C, ameliorated the LPS-induced increase in myosin light chain kinase (MLCK) expression in Caco-2 cells as determined by Western blot. Together, these findings suggest that phytonutrients such as S7-THC have prophylactic potential in the preservation of TJ integrity, and the specific composition of these phytonutrients matters