We present a new maximum-light optical spectrum of the extremely low luminosity and exceptionally low-energy Type Ia supernova (SN Ia) 2008ha, obtained one week before the earliest published ...spectrum. Previous observations of SN 2008ha were unable to distinguish between a massive star and white dwarf (WD) origin for the SN. The new maximum-light spectrum, obtained one week before the earliest previously published spectrum, unambiguously shows features corresponding to intermediate mass elements, including silicon, sulfur, and carbon. Although strong silicon features are seen in some core-collapse SNe, sulfur features, which are a signature of carbon/oxygen burning, have always been observed to be weak in such events. It is therefore likely that SN 2008ha was the result of a thermonuclear explosion of a carbon-oxygen WD. Carbon features at maximum light show that unburned material is present to significant depths in the SN ejecta, strengthening the case that SN 2008ha was a failed deflagration. We also present late-time imaging and spectroscopy that are consistent with this scenario.
Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in obesity, and the intracellular accumulation of the sphingolipid ceramide has been implicated in ...these processes. Here, we explored the role of circulating ceramide on the pathogenesis of insulin resistance. Ceramide transported in LDL is elevated in the plasma of obese patients with type 2 diabetes and correlated with insulin resistance but not with the degree of obesity. Treating cultured myotubes with LDL containing ceramide promoted ceramide accrual in cells and was accompanied by reduced insulin-stimulated glucose uptake, Akt phosphorylation, and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a proinflammatory response in cultured macrophages via toll-like receptor-dependent and -independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin-stimulated glucose uptake, and this was due to impaired insulin action specifically in skeletal muscle. These newly identified roles of LDL-ceramide suggest that strategies aimed at reducing hepatic ceramide production or reducing ceramide packaging into lipoproteins may improve skeletal muscle insulin action.
To evaluate the clinical usefulness of a quantitative deep learning-derived vascular severity score for retinopathy of prematurity (ROP) by assessing its correlation with clinical ROP diagnosis and ...by measuring clinician agreement in applying a novel scale.
Analysis of existing database of posterior pole fundus images and corresponding ophthalmoscopic examinations using 2 methods of assigning a quantitative scale to vascular severity.
Images were from clinical examinations of patients in the Imaging and Informatics in ROP Consortium. Four ophthalmologists and 1 study coordinator evaluated vascular severity on a scale from 1 to 9.
A quantitative vascular severity score (1-9) was applied to each image using a deep learning algorithm. A database of 499 images was developed for assessment of interobserver agreement.
Distribution of deep learning-derived vascular severity scores with the clinical assessment of zone (I, II, or III), stage (0, 1, 2, or 3), and extent (<3 clock hours, 3-6 clock hours, and >6 clock hours) of stage 3 evaluated using multivariate linear regression and weighted κ values and Pearson correlation coefficients for interobserver agreement on a 1-to-9 vascular severity scale.
For deep learning analysis, a total of 6344 clinical examinations were analyzed. A higher deep learning-derived vascular severity score was associated with more posterior disease, higher disease stage, and higher extent of stage 3 disease (P < 0.001 for all). For a given ROP stage, the vascular severity score was higher in zone I than zones II or III (P < 0.001). Multivariate regression found zone, stage, and extent all were associated independently with the severity score (P < 0.001 for all). For interobserver agreement, the mean ± standard deviation weighted κ value was 0.67 ± 0.06, and the Pearson correlation coefficient ± standard deviation was 0.88 ± 0.04 on the use of a 1-to-9 vascular severity scale.
A vascular severity scale for ROP seems feasible for clinical adoption; corresponds with zone, stage, extent of stage 3, and plus disease; and facilitates the use of objective technology such as deep learning to improve the consistency of ROP diagnosis.
ABSTRACT
The Type Ia supernovae (SNe Ia) 2011by, hosted in NGC 3972, and 2011fe, hosted in M101, are optical ‘twins,’ having almost identical optical light-curve shapes, colours, and ...near-maximum-brightness spectra. However, SN 2011fe had significantly more ultraviolet (UV; 1600 < λ < 2500 Å) flux than SN 2011by before and at peak luminosity. Several theoretical models predict that SNe Ia with higher progenitor metallicity should (1) have additional UV opacity and thus lower UV flux; (2) have an essentially unchanged optical spectral-energy distribution; (3) have a similar optical light-curve shape; and (4) because of the excess neutrons, produce more stable Fe-group elements at the expense of radioactive 56Ni and thus have a lower peak luminosity. Following these predictions, Foley and Kirshner suggested that the difference in UV flux between SNe 2011by and 2011fe was the result of their progenitors having significantly different metallicities. They also measured a large, but insignificant, difference between the peak absolute magnitudes of the SNe (ΔMV, peak = 0.60 ± 0.36 mag), with SN 2011fe being more luminous. We present a new Cepheid-based distance to NGC 3972, substantially improving the precision of the distance measurement for SN 2011by. With these new data, we determine that the SNe have significantly different peak luminosities (ΔMV, peak = 0.335 ± 0.069 mag). Consequently, SN 2011fe produced 38 per cent more 56Ni than SN 2011by, consistent with predictions for progenitor metallicity differences for these SNe, although alternative models may also explain this difference. We discuss how progenitor metallicity differences can contribute to the intrinsic scatter for light-curve-shape-corrected SN luminosities, the use of ‘twin’ SNe for measuring distances, and implications for using SNe Ia for constraining cosmological parameters.
Abstract
Estimating the amount of foreground extinction due to the Milky Way dust along the line of sight is often a first step in determining the luminosity of an object. The amount of Galactic dust ...inferred by infrared emission maps can be contaminated by infrared light from nearby galaxies. By comparing extinction values at and around the location of nearby galaxies, we compile a list of 95 galaxies that likely contaminate the maps with an excess or improperly subtracted galaxian infrared emission, and tabulate our recommended values for the MW contribution. In addition to M82, which inspired this work, six more sources have an excess visual extinction
A
V
of at least 0.05 mag greater than our annular values; including M83, NGC 1313, NGC 6822, NGC 918, UGC 11501, and UGC 11797. M33 is shown to be oversubtracted. NGC 88 and the outskirts of NGC 4258 are located in gaps in the Infrared Astronomical Satellite imaging. The recommended dust map values for the LMC, SMC, and M31 may also not be correctly returned by some software packages. Accurate reddening estimates are important for measuring stellar and supernova luminosities in these nearby galaxies.
Chlorhexidine is widely used as an antiseptic or disinfectant in both hospital and community settings. A number of bacterial species display resistance to this membrane-active biocide. We examined ...the transcriptomic response of a representative nosocomial human pathogen, Acinetobacter baumannii , to chlorhexidine to identify the primary chlorhexidine resistance elements. The most highly up-regulated genes encoded components of a major multidrug efflux system, AdeAB. The next most highly overexpressed gene under chlorhexidine stress was annotated as encoding a hypothetical protein, named here as AceI. Orthologs of the aceI gene are conserved within the genomes of a broad range of proteobacterial species. Expression of aceI or its orthologs from several other γ- or β-proteobacterial species in Escherichia coli resulted in significant increases in resistance to chlorhexidine. Additionally, disruption of the aceI ortholog in Acinetobacter baylyi rendered it more susceptible to chlorhexidine. The AceI protein was localized to the membrane after overexpression in E. coli . This protein was purified, and binding assays demonstrated direct and specific interactions between AceI and chlorhexidine. Transport assays using ¹⁴C-chlorhexidine determined that AceI was able to mediate the energy-dependent efflux of chlorhexidine. An E15Q AceI mutant with a mutation in a conserved acidic residue, although unable to mediate chlorhexidine resistance and transport, was still able to bind chlorhexidine. Taken together, these data are consistent with AceI being an active chlorhexidine efflux protein and the founding member of a family of bacterial drug efflux transporters.
Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient, and patients invariably develop ...sorafenib resistance (SR). Recently, TYRO3, a member of the TYRO3‐AXL‐MER family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC; however, its role in SR is unknown. In this study, we generated two functionally distinct sorafenib‐resistant human Huh‐7 HCC cell lines in order to identify new mechanisms to abrogate acquired SR as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA (miR), miR‐7‐5p (miR‐7), in both in vitro and in vivo preclinical models of human HCC and identified miR‐7 as a potent tumor suppressor of human HCC. We identified TYRO3 as a new functional target of miR‐7, which regulates proliferation, migration, and invasion of Huh‐7 cells through the phosphoinositide 3‐kinase/protein kinase B pathway and is markedly elevated with acquisition of SR. Furthermore, miR‐7 effectively silenced TYRO3 expression in both sorafenib‐sensitive and sorafenib‐resistant Huh‐7 cells, inhibiting TYRO3/growth arrest specific 6‐mediated cancer cell migration and invasion. Conclusion: We identified a mechanism for acquiring SR in HCC that is through the aberrant expression of the TYRO3/phosphoinositide 3‐kinase/protein kinase B signal transduction pathway, and that can be overcome by miR‐7 overexpression. Taken together, these data suggest a potential role for miR‐7 as an RNA‐based therapeutic to treat refractory and drug‐resistant HCC. (Hepatology 2018;67:216‐231)
microRNAs (miRNAs) are short non-coding RNAs that fine-tune gene expression. The aberrant expression of miRNAs is associated with many diseases and they have both therapeutic and biomarker potential. ...However, our understanding of their usefulness is dependent on the tools we have to study them. Previous studies have identified the need to optimise and standardise RNA extraction methods in order to avoid biased results. Herein, we extracted RNA from murine lung, liver and brain tissues using five commercially available total RNA extraction methods. These included either: phenol: chloroform extraction followed by alcohol precipitation (TRIzol), phenol:chloroform followed by solid-phase extraction (column-based; miRVana and miRNeasy) and solid-phase separation with/without affinity resin (Norgen total and Isolate II). We then evaluated each extraction method for the quality and quantity of RNA recovered, and the expression of miRNAs and target genes.
We identified differences between each of the RNA extraction methods in the quantity and quality of RNA samples, and in the analysis of miRNA and target gene expression. For the purposes of consistency in quantity, quality and high recovery of miRNAs from tissues, we identified that Phenol:chloroform phase separation combined with silica column-based solid extraction method was preferable (miRVana microRNA isolation). We also identified a method that is not appropriate for miRNA analysis from tissue samples (Bioline Isolate II). For target gene expression any of the kits could be used to analyse mRNA, but if interested in analysing mRNA and miRNA from the same RNA samples some methods should be avoided.
Different methods used to isolate miRNAs will yield different results and therefore a robust RNA isolation method is required for reproducibility. Researchers should optimise these methods for their specific application and keep in mind that "total RNA" extraction methods do not isolate all types of RNA equally.
Childhood blindness from retinopathy of prematurity (ROP) is increasing as a result of improvements in neonatal care worldwide. We evaluate the effectiveness of artificial intelligence (AI)-based ...screening in an Indian ROP telemedicine program and whether differences in ROP severity between neonatal care units (NCUs) identified by using AI are related to differences in oxygen-titrating capability.
External validation study of an existing AI-based quantitative severity scale for ROP on a data set of images from the Retinopathy of Prematurity Eradication Save Our Sight ROP telemedicine program in India. All images were assigned an ROP severity score (1-9) by using the Imaging and Informatics in Retinopathy of Prematurity Deep Learning system. We calculated the area under the receiver operating characteristic curve and sensitivity and specificity for treatment-requiring retinopathy of prematurity. Using multivariable linear regression, we evaluated the mean and median ROP severity in each NCU as a function of mean birth weight, gestational age, and the presence of oxygen blenders and pulse oxygenation monitors.
The area under the receiver operating characteristic curve for detection of treatment-requiring retinopathy of prematurity was 0.98, with 100% sensitivity and 78% specificity. We found higher median (interquartile range) ROP severity in NCUs without oxygen blenders and pulse oxygenation monitors, most apparent in bigger infants (>1500 g and 31 weeks' gestation: 2.7 2.5-3.0 vs 3.1 2.4-3.8;
= .007, with adjustment for birth weight and gestational age).
Integration of AI into ROP screening programs may lead to improved access to care for secondary prevention of ROP and may facilitate assessment of disease epidemiology and NCU resources.
Context: Longitudinal studies of risk factors for hypothyroidism are required to inform debate regarding the TSH reference range. There are limited longitudinal data on the predictive value of ...thyroid antibodies measured by automated immunoassay (as opposed to semiquantitative methods).
Methods: We measured TSH, free T4, thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs) using the Immulite platform on sera from 1184 participants in the 1981 and 1994 Busselton Health Surveys. Outcome measures at follow-up were hypothyroidism, defined as TSH greater than 4.0 mU/liter or on thyroxine treatment; and overt hypothyroidism, defined as TSH above 10.0 mU/liter or on thyroxine treatment. Receiver-operator characteristic analysis was used to determine optimal cutoffs for baseline TSH, TPOAbs, and TgAbs as predictors of hypothyroidism.
Results: At 13 yr follow-up, 110 subjects (84 women) had hypothyroidism, of whom 42 (38 women) had overt hypothyroidism. Optimal cutoffs for predicting hypothyroidism were baseline TSH above 2.5 mU/liter, TPOAbs above 29 kIU/liter, and TgAbs above 22 kIU/liter, compared with reference range upper limits of 4.0 mU/liter, 35 kIU/liter, and 55 kIU/liter, respectively. In women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up (with 95% confidence intervals) was 12.0% (3.0–21.0%) when baseline TSH was 2.5 mU/liter or less, 55.2% (37.1–73.3%) for TSH between 2.5 and 4.0 mU/liter, and 85.7% (74.1–97.3%) for TSH above 4.0 mU/liter.
Conclusions: The use of TSH cutoffs of 2.5 and 4.0 mU/liter, combined with thyroid antibodies, provides a clinically useful estimate of the long-term risk of hypothyroidism.
The long-term risk of hypothyroidism can be estimated using risk stratification based on TSH cut-offs of 2.5 and 4.0 mU/liter, thyroid antibodies, and gender.
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