A multi-zone muffle furnace design

A Multi-Zone Muffle-Tube Furnace was designed, built, and tested for the purpose of providing an in-house experience base with tubular furnaces for materials processing in microgravity. As such, it must not only provide the desired temperatures and controlled thermal gradients at several discrete zones along its length but must also be capable of sustaining the rigors of a Space Shuttle launch. The furnace is insulated to minimize radial and axial heat losses. It is contained in a water-cooled enclosure for purposes of dissipating un-wanted residual heat, keeping the outer surfaces of the furnace at a 'touch-safe' temperature, and providing a rugged housing. This report describes the salient features of the furnace, testing procedures and results, and concluding remarks evaluating the overall design

High fidelity simulations of ion trajectories in miniature ion traps using the boundary-element method

In this paper we present numerical modeling results for endcap and linear ion traps, used for experiments at the National Physical Laboratory in the UK and Innsbruck University respectively. The secular frequencies for Strontium-88 and Calcium-40 ions were calculated from ion trajectories, simulated using boundary-element and finite-difference numerical methods. The results were compared against experimental measurements. Both numerical methods showed high accuracy with boundary-element method being more accurate. Such simulations can be useful tools for designing new traps and trap arrays. They can also be used for obtaining precise trapping parameters for desired ion control when no analytical approach is possible as well as for investigating the ion heating rates due to thermal electronic noise.Comment: 6 pages, 5 figures, changes made to the text according to the editor's and referee's comment

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers. Methods: Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline. Results: Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference versus placebo in post-bronchodilator FEV1 slope of change (weeks 4–52) was significant (0.04 L·year−1; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or FeNO levels for most outcomes. Conclusions: Dupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation

The diversity, evolution and ecology of Salmonella in venomous snakes

BACKGROUND: Reptile-associated Salmonella bacteria are a major, but often neglected cause of both gastrointestinal and bloodstream infection in humans globally. The diversity of Salmonella enterica has not yet been determined in venomous snakes, however other ectothermic animals have been reported to carry a broad range of Salmonella bacteria. We investigated the prevalence and diversity of Salmonella in a collection of venomous snakes and non-venomous reptiles. METHODOLOGY/PRINCIPLE FINDINGS: We used a combination of selective enrichment techniques to establish a unique dataset of reptilian isolates to study Salmonella enterica species-level evolution and ecology and used whole-genome sequencing to investigate the relatedness of phylogenetic groups. We observed that 91% of venomous snakes carried Salmonella, and found that a diverse range of serovars (n = 58) were carried by reptiles. The Salmonella serovars belonged to four of the six Salmonella enterica subspecies: diarizonae, enterica, houtanae and salamae. Subspecies enterica isolates were distributed among two distinct phylogenetic clusters, previously described as clade A (52%) and clade B (48%). We identified metabolic differences between S. diarizonae, S. enterica clade A and clade B involving growth on lactose, tartaric acid, dulcitol, myo-inositol and allantoin. SIGNIFICANCE: We present the first whole genome-based comparative study of the Salmonella bacteria that colonise venomous and non-venomous reptiles and shed new light on Salmonella evolution. Venomous snakes examined in this study carried a broad range of Salmonella, including serovars which have been associated with disease in humans such as S. Enteritidis. The findings raise the possibility that venomous snakes could be a reservoir for Salmonella serovars associated with human salmonellosis

Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning

To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy-Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy-Richardson, 52 with a progressive supranuclear palsy-cortical variant (progressive supranuclear palsy-frontal, progressive supranuclear palsy-speech/language, or progressive supranuclear palsy-corticobasal), and 17 with a progressive supranuclear palsy-subcortical variant (progressive supranuclear palsy-parkinsonism or progressive supranuclear palsy-progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a 'subcortical' subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a 'cortical' subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy-subcortical cases and 81% of progressive supranuclear palsy-Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy-cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the 'subcortical' subtype was associated with worse clinical severity scores compared to the 'cortical subtype' (progressive supranuclear palsy rating scale and Unified Parkinson's Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression

ATOCA: an algorithm to treat order contamination. Application to the NIRISS SOSS mode

After a successful launch, the James Webb Space Telescope is preparing to undertake one of its principal missions, the characterization of the atmospheres of exoplanets. The Single Object Slitless Spectroscopy (SOSS) mode of the Near Infrared Imager and Slitless Spectrograph (NIRISS) is the only observing mode that has been specifically designed for this objective. It features a wide simultaneous spectral range (0.6--2.8\,\micron) through two spectral diffraction orders. However, due to mechanical constraints, these two orders overlap slightly over a short range, potentially introducing a ``contamination'' signal in the extracted spectrum. We show that for a typical box extraction, this contaminating signal amounts to 1\% or less over the 1.6--2.8\,\micron\ range (order 1), and up to 1\% over the 0.85--0.95\,\micron\ range (order 2). For observations of exoplanet atmospheres (transits, eclipses or phase curves) where only temporal variations in flux matter, the contamination signal typically biases the results by order of 1\% of the planetary atmosphere spectral features strength. To address this problem, we developed the Algorithm to Treat Order ContAmination (ATOCA). By constructing a linear model of each pixel on the detector, treating the underlying incident spectrum as a free variable, ATOCA is able to perform a simultaneous extraction of both orders. We show that, given appropriate estimates of the spatial trace profiles, the throughputs, the wavelength solutions, as well as the spectral resolution kernels for each order, it is possible to obtain an extracted spectrum accurate to within 10\,ppm over the full spectral range.Comment: Submitted to PASP. 22 pages, 12 figure

Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans

Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. (HEPATOLOGY 2012;56:1108–1116

Near-Infrared Transmission Spectroscopy of HAT-P-18 \,b with NIRISS: Disentangling Planetary and Stellar Features in the Era of JWST

The JWST Early Release Observations (ERO) included a NIRISS/SOSS (0.6-2.8$\,\mu$m) transit of the $\sim\,$850$\,$K Saturn-mass exoplanet HAT-P-18$\,$b. Initial analysis of these data reported detections of water, escaping helium, and haze. However, active K dwarfs like HAT-P-18 possess surface heterogeneities $-$ starspots and faculae $-$ that can complicate the interpretation of transmission spectra, and indeed, a spot-crossing event is present in HAT-P-18$\,$b's NIRISS/SOSS light curves. Here, we present an extensive reanalysis and interpretation of the JWST ERO transmission spectrum of HAT-P-18$\,$b, as well as HST/WFC3 and $\textit{Spitzer}$/IRAC transit observations. We detect H$_2$O (12.5$\,\sigma$), CO$_2$ (7.3$\,\sigma$), a cloud deck (7.4$\,\sigma$), and unocculted starspots (5.8$\,\sigma$), alongside hints of Na (2.7$\,\sigma$). We do not detect the previously reported CH$_4$ ($\log$ CH$_4$ $<$ -6 to 2$\,\sigma$). We obtain excellent agreement between three independent retrieval codes, which find a sub-solar H$_2$O abundance ($\log$ H$_2$O $\approx -4.4 \pm 0.3$). However, the inferred CO$_2$ abundance ($\log$ CO$_2$ $\approx -4.8 \pm 0.4$) is significantly super-solar and requires further investigation into its origin. We also introduce new stellar heterogeneity considerations by fitting for the active regions' surface gravities $-$ a proxy for the effects of magnetic pressure. Finally, we compare our JWST inferences to those from HST/WFC3 and $\textit{Spitzer}$/IRAC. Our results highlight the exceptional promise of simultaneous planetary atmosphere and stellar heterogeneity constraints in the era of JWST and demonstrate that JWST transmission spectra may warrant more complex treatments of the transit light source effect