The Development of a SLS Composite Material

The development of a commercial SLS nylon-based composite material (LNC 7000) is described. Nylon composite candidate systems with different volume fractions of a number of glass fiber and glass bead reinforcements were screened. It was found that fully dense SLS parts with excellent mechanical properties could be made from a number of reinforced nylon materials. An optimized material containing 29 volume percent 35 Ilm diameter glass beads was selected based on the processing behavior and mechanical properties of the candidate systems. The performance of this optimized material is described. In addition, complementary aspects of the composite nylon and unreinforced nylon materials (LN 4010 and LNF 5000) are discussed.Mechanical Engineerin

Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids

Mutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequencing to investigate the role of TMPRSS3. Defective Tmprss3 leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells demonstrate reduced numbers of BK channels and lower expressions of genes encoding calcium ion-binding proteins, suggesting a disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to ER of cells in inner ear organoids. Our in vitro model recapitulated salient features of genetically associated inner ear abnormalities and will serve as a powerful tool for studying inner ear disorders

Adolescent bullying and sleep difficulties

This study evaluated whether adolescents who report having been bullied, being bullies, or report both being a bully and being bullied experience more sleep difficulties than children uninvolved in bullying. The study drew upon cognitive theories of insomnia, investigating whether the extent to which young people report worrying about bullying can moderate associations between victimization and sleep difficulties. Participants were 5420 adolescents who completed a self-report questionnaire. Pure Victims (OR = 1.72: 95% CI [1.07 – 2.75]), Pure Bullies (OR = 1.80: 95% CI [1.16 – 2.81]), and Bully-Victims (OR = 2.90: 95% CI [1.17 – 4.92]) were all more likely to experience sleep difficulties when compared to uninvolved young people. The extent to which young people reported worrying about being bullied did not moderate the links between victimization and sleep difficulties. In this way, bullying is clearly related to sleep difficulties among adolescents but the conceptual reach of the cognitive model of insomnia in this domain is questioned

Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo

We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration

ALMA 1.3 Millimeter Map of the HD 95086 System

Planets and minor bodies such as asteroids, Kuiper-belt objects and comets are integral components of a planetary system. Interactions among them leave clues about the formation process of a planetary system. The signature of such interactions is most prominent through observations of its debris disk at millimeter wavelengths where emission is dominated by the population of large grains that stay close to their parent bodies. Here we present ALMA 1.3 mm observations of HD 95086, a young early-type star that hosts a directly imaged giant planet b and a massive debris disk with both asteroid- and Kuiper-belt analogs. The location of the Kuiper-belt analog is resolved for the first time. The system can be depicted as a broad ($\Delta R/R \sim$0.84), inclined (30\arcdeg$\pm$3\arcdeg) ring with millimeter emission peaked at 200$\pm$6 au from the star. The 1.3 mm disk emission is consistent with a broad disk with sharp boundaries from 106$\pm$6 to 320$\pm$20 au with a surface density distribution described by a power law with an index of --0.5$\pm$0.2. Our deep ALMA map also reveals a bright source located near the edge of the ring, whose brightness at 1.3 mm and potential spectral energy distribution are consistent with it being a luminous star-forming galaxy at high redshift. We set constraints on the orbital properties of planet b assuming co-planarity with the observed disk.Comment: accepted for publication in A

A Fresh Look at Road Salt: Aquatic Toxicity and Water-Quality Impacts on Local, Regional, and National Scales

A new perspective on the severity of aquatic toxicity impact of road salt was gained by a focused research effort directed at winter runoff periods. Dramatic impacts were observed on local, regional, and national scales. Locally, samples from 7 of 13 Milwaukee, Wisconsin area streams exhibited toxicity in Ceriodaphnia dubia and Pimephales promelas bioassays during road-salt runoff. Another Milwaukee stream was sampled from 1996 to 2008 with 72% of 37 samples exhibiting toxicity in chronic bioassays and 43% in acute bioassays. The maximum chloride concentration was 7730 mg/L. Regionally, in southeast Wisconsin, continuous specific conductance was monitored as a chloride surrogate in 11 watersheds with urban land use from 6.0 to 100%. Elevated specific conductance was observed between November and April at all sites, with continuing effects between May and October at sites with the highest specific conductance. Specific conductance was measured as high as 30 800 μS/cm (Cl = 11 200 mg/L). Chloride concentrations exceeded U.S. Environmental Protection Agency (USEPA) acute (860 mg/L) and chronic (230 mg/L) water-quality criteria at 55 and 100% of monitored sites, respectively. Nationally, U.S. Geological Survey historical data were examined for 13 northern and 4 southern metropolitan areas. Chloride concentrations exceeded USEPA water-quality criteria at 55% (chronic) and 25% (acute) of the 168 monitoring locations in northern metropolitan areas from November to April. Only 16% (chronic) and 1% (acute) of sites exceeded criteria from May to October. At southern sites, very few samples exceeded chronic water-quality criteria, and no samples exceeded acute criteria

Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma.

13C MRI of hyperpolarized [1-13C]pyruvate metabolism has been used in oncology to detect disease, investigate disease progression, and monitor response to treatment with a view to guiding treatment in individual patients. This technique has translated to the clinic with initial studies in prostate cancer. Here, we use the technique to investigate its potential uses in patients with glioblastoma (GB). We assessed the metabolism of hyperpolarized [1-13C]pyruvate in an orthotopically implanted cell line model (U87) of GB and in patient-derived tumors, where these were produced by orthotopic implantation of cells derived from different patients. Lactate labeling was higher in the U87 tumor when compared with patient-derived tumors, which displayed intertumoral heterogeneity, reflecting the intra- and intertumoral heterogeneity in the patients' tumors from which they were derived. Labeling in some patient-derived tumors could be observed before their appearance in morphologic images, whereas in other tumors it was not significantly greater than the surrounding brain. Increased lactate labeling in tumors correlated with c-Myc-driven expression of hexokinase 2, lactate dehydrogenase A, and the monocarboxylate transporters and was accompanied by increased radioresistance. Because c-Myc expression correlates with glioma grade, this study demonstrates that imaging with hyperpolarized [1-13C]pyruvate could be used clinically with patients with GB to determine disease prognosis, to detect early responses to drugs that modulate c-Myc expression, and to select tumors, and regions of tumors for increased radiotherapy dose.Significance: Metabolic imaging with hyperpolarized [1-13C]pyruvate detects low levels of c-Myc-driven glycolysis in patient-derived glioblastoma models, which, when translated to the clinic, could be used to detect occult disease, determine disease prognosis, and target radiotherapy. Cancer Res; 78(18); 5408-18. ©2018 AACR.The work was supported by a Cancer Research UK Programme grant (17242) and by the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465) awarded to K. M. Brindle. F. Kreis was supported by a Marie Curie ITN studentship (EUROPOL) and R. Mair by Addenbrooke's Charitable Trust and a CRUK Cambridge Centre Fellowship