Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

AIMS/HYPOTHESIS: EGF and gastrin co-administration reverses type 1 diabetes in rodent models. However, the failure of this to translate into a clinical treatment suggests that EGF-mediated tissue repair is a complicated process and warrants further investigation. Thus, we aimed to determine whether EGF receptor (EGFR) feedback inhibition by mitogen-inducible gene 6 protein (MIG6) limits the effectiveness of EGF therapy and promotes type 1 diabetes development. METHODS: We treated Mig6 (also known as Errfi1) haploinsufficient mice (Mig6 (+/-)) and their wild-type littermates (Mig6 (+/+)) with multiple low doses of streptozotocin (STZ), and monitored diabetes development via glucose homeostasis tests and histological analyses. We also investigated MIG6-mediated cytokine-induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells. RESULTS: Whereas STZ-treated Mig6 (+/+) mice became diabetic, STZ-treated Mig6 (+/-) mice remained glucose tolerant. In addition, STZ-treated Mig6 (+/-) mice exhibited preserved circulating insulin levels following a glucose challenge. As insulin sensitivity was similar between Mig6 (+/-) and Mig6 (+/+) mice, the preserved glucose tolerance in STZ-treated Mig6 (+/-) mice probably results from preserved beta cell function. This is supported by elevated Pdx1 and Irs2 mRNA levels in islets isolated from STZ-treated Mig6 (+/-) mice. Conversely, MIG6 overexpression in isolated islets compromises glucose-stimulated insulin secretion. Studies in 832/13 cells suggested that cytokine-induced MIG6 hinders EGFR activation and inhibits DNA damage repair. STZ-treated Mig6 (+/-) mice also have increased beta cell mass recovery. CONCLUSIONS/INTERPRETATION: Reducing Mig6 expression promotes beta cell repair and abates the development of experimental diabetes, suggesting that MIG6 may be a novel therapeutic target for preserving beta cell

Advantages of a Modular Mars Surface Habitat Approach

Early crewed Mars mission concepts developed by the National Aeronautics and Space Administration (NASA) assumed a single, large habitat would house six crew members for a 500-day Mars surface stay. At the end of the first mission, all surface equipment, including the habitat, -would be abandoned and the process would be repeated at a different Martian landing site. This work was documented in a series of NASA publications culminating with the Mars Design Reference Mission 5.0 (NASA-SP-2009-566). The Evolvable Mars Campaign (EMC) explored whether re-using surface equipment at a single landing site could be more affordable than the Apollo-style explore-abandon-repeat mission cadence. Initial EMC assumptions preserved the single, monolithic habitat, the only difference being a new requirement to reuse the surface habitat for multiple expedition crews. A trade study comparing a single large habitat versus smaller, modular habitats leaned towards the monolithic approach as more mass-efficient. More recent work has focused on the operational aspects of building up Mars surface infrastructure over multiple missions, and has identified compelling advantages of the modular approach that should be considered before making a final decision. This paper explores Mars surface mission operational concepts and integrated system analysis, and presents an argument for the modular habitat approach

Applying computational predictions of biorelevant solubility ratio upon self-emulsifying lipid-based formulations dispersion to predict dose number

Computational approaches are increasingly utilised in development of bio-enabling formulations, including self-emulsifying drug delivery systems (SEDDS), facilitating early indicators of success. This study investigated if in silico predictions of drug solubility gain i.e. solubility ratios (SR), after dispersion of a SEDDS in biorelevant media could be predicted from drug properties. Apparent solubility upon dispersion of two SEDDS in FaSSIF was measured for 30 structurally diverse poorly water soluble drugs. Increased drug solubility upon SEDDS dispersion was observed in all cases, with higher SRs observed for cationic and neutral versus anionic drugs at pH 6.5. Molecular descriptors and solid-state properties were used as inputs during partial least squares (PLS) modelling resulting in predictive models for SRMC (r2 = 0.81) and SRLC (r2 = 0.77). Multiple linear regression (MLR) facilitated generation of simplified SR equations with high predictivity (SRMC r2 = 0.74; SRLC r2 = 0.69), requiring only three drug properties; partition coefficient at pH 6.5 (logD6.5), melting point (Tm) and aromatic bonds as fraction of total bonds (FArom_B). Through using the equations to inform drug developability classifications (DCS) for drugs that have already been licensed as lipid based formulations, merits for development with SEDDS was predicted for 2/3 drugs

An Infrared Coronagraphic Survey for Substellar Companions

We have used the F160W filter (1.4-1.8 um) and the coronagraph on the Near-InfraRed Camera and Multi-Object Spectrometer (NICMOS) on the Hubble Space Telescope (HST) to survey 45 single stars with a median age of 0.15 Gyr, an average distance of 30 pc, and an average H-magnitude of 7 mag. For the median age we were capable of detecting a 30 M_Jup companion at separations between 15 and 200 AU. A 5 M_Jup object could have been detected at 30 AU around 36% of our primaries. For several of our targets that were less than 30 Myr old, the lower mass limit was as low as a Jupiter mass, well into the high mass planet region. Results of the entire survey include the proper motion verification of five low-mass stellar companions, two brown dwarfs (HR7329B and TWA5B) and one possible brown dwarf binary (Gl 577B/C).Comment: 11 figures, accepted by A

Over 500 Days in the Life of the Photosphere of the Type Iax Supernova SN 2014dt

Type Iax supernovae (SN Iax) are the largest known class of peculiar white dwarf supernovae, distinct from normal Type Ia supernovae (SN Ia). The unique properties of SN Iax, especially their strong photospheric lines out to extremely late times, allow us to model their optical spectra and derive physical parameters for the long-lasting photosphere. We present an extensive spectral timeseries, including 21 new spectra, of SN Iax 2014dt from +11 to +562 days after maximum light. We are able to reproduce the entire timeseries with a self-consistent, nearly unaltered deflagration explosion model from Fink et al. (2014) using TARDIS, an open-source radiative transfer code (Kerzendorf & Sim 2014; Kerzendorf et al. 2023). We find that the photospheric velocity of SN 2014dt slows its evolution between +64 and +148 days, which closely overlaps the phase when we see SN 2014dt diverge from the normal spectral evolution of SN Ia (+90 to +150 days). The photospheric velocity at these epochs, ~400$-$1000 km s$^{-1}$, may demarcate a boundary within the ejecta below which the physics of SN Iax and normal SN Ia differ. Our results suggest that SN 2014dt is consistent with a weak deflagration explosion model that leaves behind a bound remnant and drives an optically thick, quasi-steady-state wind creating the photospheric lines at late times. The data also suggest that this wind may weaken at epochs past +450 days, perhaps indicating a radioactive power source that has decayed away.Comment: Accepted to ApJ, 22 pages, 8 figures, 3 table

Serology describes a profile of declining malaria transmission in Farafenni, The Gambia

BACKGROUND: Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes. METHODS: Data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011 were compiled. Antibody responses to MSP-119 were measured in samples from all surveys, data were normalized and expressed as seroprevalence and seroconversion rates (SCR) using different mathematical models. RESULTS: Results showed declines in serological metrics with seroprevalence in children aged one to 5 years dropping from 19 % (95 % CI 15-23 %) in 1988 to 1 % (0-2 %) in 2011 (p value for trend in proportions < 0.001) and the SCR dropping from 0.069 year(-1) (0.059-0.080) to 0.022 year(-1) (0.017-0.028; p = 0.004). The serological data were consistent with previously described drops in both parasite prevalence in children aged 1-5 years (62 %, 57-66 %, in 1988 to 2 %, 0-4 %, in 2011; p < 0.001), and all-cause under five mortality rates (37 per 1000 person-years, 34-41, in 1990 to 17, 15-19, in 2006; p = 0.059). CONCLUSIONS: This analysis shows accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses. Demonstrating congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring and evaluation of malaria transmission

Digital Signal Processing

Contains an introduction and reports on twenty research projects.National Science Foundation (Grant ECS 84-07285)U.S. Navy - Office of Naval Research (Contract N00014-81-K-0742)National Science Foundation FellowshipSanders Associates, Inc.U.S. Air Force - Office of Scientific Research (Contract F19628-85-K-0028)Canada, Bell Northern Research ScholarshipCanada, Fonds pour la Formation de Chercheurs et l'Aide a la Recherche Postgraduate FellowshipCanada, Natural Science and Engineering Research Council Postgraduate FellowshipU.S. Navy - Office of Naval Research (Contract N00014-81-K-0472)Fanny and John Hertz Foundation FellowshipCenter for Advanced Television StudiesAmoco Foundation FellowshipU.S. Air Force - Office of Scientific Research (Contract F19628-85-K-0028

Internalization of Modified Lipids by CD36 and SR-A Leads to Hepatic Inflammation and Lysosomal Cholesterol Storage in Kupffer Cells

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio