Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
443
result(s) for
"Butler, Victoria"
Sort by:
Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response
The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.
Journal Article
Measuring the Temperature of Extremely Hot Shock-heated Gas in the Major Merger MACS J0717.5+3745 with Relativistic Corrections to the Sunyaev–Zel’dovich Effect
The conversion of gravitational potential to kinetic energy results in an intracluster medium (ICM) gas with a characteristic temperature near 10 keV in the most massive galaxy clusters. X-ray observations, primarily from Chandra and XMM-Newton, have revealed a wealth of information about the thermodynamics of this gas. However, two regimes remain difficult to study with current instruments: superheated gas well above 10 keV generated by shocks from major mergers, and distant systems strongly impacted by cosmological dimming. Relativistic corrections to the Sunyaev–Zel’dovich effect (rSZe) produce a fractional spectral distortion in the cosmic microwave background at submillimeter and millimeter wavelengths that could offer a complementary probe of both high-temperature and high-redshift ICM gas. Here we describe multiband measurements of the rSZe, including observations from the Fourier Transform Spectrometer on the Herschel-SPIRE instrument, that constrain the ICM thermodynamics of the major merger MACS J0717.5+3745. Within the seven observed lines of sight, we find an average temperature of TrSZe =15.1−3.3+3.8 keV, which is consistent with the values obtained from X-ray measurements of the same regions, with TChandra =18.0−1.1+1.1 keV and TXMM =13.9−0.9+0.9 keV. This work demonstrates that the rSZe signal can be detected with moderate spectral resolution submillimeter data, while also establishing the utility of such measurements for probing superheated regions of the ICM.
Journal Article
PCAT-DE: Reconstructing Pointlike and Diffuse Signals in Astronomical Images Using Spatial and Spectral Information
Observational data from astronomical imaging surveys contain information about a variety of source populations and environments, and their complexity will increase substantially as telescopes become more sensitive. Even for existing observations, measuring the correlations between pointlike and diffuse emission can be crucial to correctly inferring the properties of any individual component. For this task, information is typically lost, because of conservative data cuts, aggressive filtering, or incomplete treatment of contaminated data. We present the code PCAT-DE, an extension of probabilistic cataloging, designed to simultaneously model pointlike and diffuse signals. This work incorporates both explicit spatial templates and a set of nonparametric Fourier component templates into a forward model of astronomical images, reducing the number of processing steps applied to the observed data. Using synthetic Herschel-SPIRE multiband observations, we demonstrate that point-source and diffuse emission can be reliably separated and measured. We present two applications of this model. For the first, we perform point-source detection/photometry in the presence of galactic cirrus and demonstrate that cosmic infrared background galaxy counts can be recovered in cases of significant contamination. In the second, we show that the spatially extended thermal Sunyaev–Zel’dovich effect signal can be reliably measured even when it is subdominant to the pointlike emission from individual galaxies.
Journal Article
Measurement of the Relativistic Sunyaev–Zeldovich Correction in RX J1347.5-1145
We present a measurement of the relativistic corrections to the thermal Sunyaev–Zel’dovich (SZ) effect spectrum, the rSZ effect, toward the massive galaxy cluster RX J1347.5-1145 by combining submillimeter images from Herschel-SPIRE with millimeter wavelength Bolocam maps. Our analysis simultaneously models the SZ effect signal, the population of cosmic infrared background galaxies, and the galactic cirrus dust emission in a manner that fully accounts for their spatial and frequency-dependent correlations. Gravitational lensing of background galaxies by RX J1347.5-1145 is included in our methodology based on a mass model derived from the Hubble Space Telescope observations. Utilizing a set of realistic mock observations, we employ a forward modeling approach that accounts for the non-Gaussian covariances between the observed astrophysical components to determine the posterior distribution of SZ effect brightness values consistent with the observed data. We determine a maximum a posteriori (MAP) value of the average Comptonization parameter of the intracluster medium (ICM) within R 2500 to be 〈y〉2500 = 1.56 × 10−4, with corresponding 68% credible interval [1.42, 1.63] × 10−4, and a MAP ICM electron temperature of 〈T sz〉2500 = 22.4 keV with 68% credible interval spanning [10.4, 33.0] keV. This is in good agreement with the pressure-weighted temperature obtained from Chandra X-ray observations, 〈T x,pw〉2500 = 17.4 ± 2.3 keV. We aim to apply this methodology to comparable existing data for a sample of 39 galaxy clusters, with an estimated uncertainty on the ensemble mean 〈T sz〉2500 at the ≃ 1 keV level, sufficiently precise to probe ICM physics and to inform X-ray temperature calibration.
Journal Article
Virtual finger boosts three-dimensional imaging and microsurgery as well as terabyte volume image visualization and analysis
Three-dimensional (3D) bioimaging, visualization and data analysis are in strong need of powerful 3D exploration techniques. We develop virtual finger (VF) to generate 3D curves, points and regions-of-interest in the 3D space of a volumetric image with a single finger operation, such as a computer mouse stroke, or click or zoom from the 2D-projection plane of an image as visualized with a computer. VF provides efficient methods for acquisition, visualization and analysis of 3D images for roundworm, fruitfly, dragonfly, mouse, rat and human. Specifically, VF enables instant 3D optical zoom-in imaging, 3D free-form optical microsurgery, and 3D visualization and annotation of terabytes of whole-brain image volumes. VF also leads to orders of magnitude better efficiency of automated 3D reconstruction of neurons and similar biostructures over our previous systems. We use VF to generate from images of 1,107
Drosophila
GAL4 lines a projectome of a
Drosophila
brain.
Large three-dimensional images are commonly generated through biological experimentation. Here the authors report software tools for exploration of three-dimensional images along with applications to assist in imaging, microsurgery, visualization and annotation of large image data sets.
Journal Article
TIME Commissioning Observations. I. Mapping Dust and Molecular Gas in the Sgr A Molecular Cloud Complex at the Galactic Center
We present the processing of an observation of Sagittarius A (Sgr A) with the Tomographic Ionized-carbon Mapping Experiment (TIME), part of the 2021–2022 commissioning run, to verify TIME’s hyperspectral imaging capabilities for future line-intensity mapping. Using an observation of Jupiter to calibrate detector gains and pointing offsets, we process the Sgr A observation in a purpose-built pipeline that removes correlated noise through common-mode subtraction with correlation-weighted scaling, and uses map-domain principal component analysis to identify further systematic errors. The resulting frequency-resolved maps recover strong 12CO(2–1) and 13CO(2–1) emission, and a continuum component whose spectral index discriminates free–free emission in the circumnuclear disk versus thermal dust emission in the 20 and 50 km s−1 molecular clouds. Broadband continuum flux comparisons with the Bolocam Galactic Plane Survey show agreement to within ∼5% in high signal-to-noise ratio molecular clouds in the Sgr A region. From the CO line detections, we estimate a molecular hydrogen mass of between 5.4 × 105M⊙ and 5.7 × 105M⊙, consistent with prior studies. These results demonstrate TIME’s ability to recover both continuum and spectral-line signals in complex Galactic fields, validating its readiness for upcoming extragalactic CO and [C ii] surveys.
Journal Article
A Comparative Analysis of Patient Demographics and Referral Trends Pre‐ and Post‐Intervention of the TIA Pathway: A Retrospective Observational Study
Background and Aims Timely diagnosis of Transient Ischaemic Attack (TIA) is critical for stroke prevention. This study evaluated referral patterns, demographic predictors, and diagnostic outcomes before and after a service improvement intervention at North Tees and Hartlepool NHS Foundation Trust. Methods A retrospective observational study was conducted using 2,167 patient records from 2021 to 2024. Demographic and referral data were analysed using IBM SPSS Statistics v27. Chi‐square analyses were used to assess associations between TIA diagnosis and age group, gender, local authority, and referral source (two‐sided, p < 0.05). A multivariable logistic regression was performed to identify independent predictors, with odds ratios (ORs) and 95% confidence intervals (CIs) used to assess the strength and precision of associations. Results The TIA diagnosis rate was 37.8%. Older adults (≥ 65 years) accounted for 72.3% of TIA cases. Digital referrals (Email and WebICE) increased significantly post‐intervention, replacing GP and consultant routes. Consultant referrals, though rare, had the highest diagnostic yield (53.8%). Chi‐square analysis showed significant associations between TIA diagnosis and age group, gender, local authority, and referral source (p < 0.05). In regression analysis (N = 1959), increasing age and consultant referrals were associated with higher odds of diagnosis. Middle deprivation was associated with slightly lower odds (OR = 0.77, p = 0.05). Gender was not a statistically significant predictor (p = 0.16). Conclusion TIA diagnosis is strongly associated with age and referral source. Service changes improved referral standardisation, with digital pathways becoming the dominant mode of referral. Clinical judgment appears to play an important role, as reflected in the higher diagnostic yield of consultant referrals. These findings highlight the importance of considering key demographic and system‐level factors in stroke prevention pathways.
Journal Article
Evaluation of area based socioeconomic inequalities and neonatal mortality rates in France: national population based study
ObjectiveTo investigate the magnitude and evolution of inequalities in neonatal mortality rates by using area based socioeconomic indices in France.DesignNational population based study.SettingFor 2015-20, data from the French National Health Data System (Système National des Données de Santé, SNDS). For 2001-08, neonatal death certificates and aggregate vital statistics data by municipality of residence.ParticipantsLive births with a gestational age ≥22 completed weeks to a mother residing in metropolitan France, 2015-20 (4 293 403 live births and 10 869 neonatal deaths), compared with a 2001-08 study (6 202 918 live births and 14 851 neonatal deaths).Main outcome measuresDifferences in neonatal mortality rate (death before day 28 of life) according to the socioeconomic characteristics of the mother's municipality of residence. Comparison with data from a 2001-08 study to assess changes in socioeconomic inequalities and their contribution to the increase in neonatal mortality rate.ResultsThe neonatal mortality rate was 2.53 per 1000 live births in 2015-20. Five indicators, previously associated with perinatal mortality, were combined into a perinatal French deprivation index (P-FDep) for the main analysis. P-FDep was categorised into five equal groups (deprivation groups 1-5) for comparison with other research and into 10 equal groups (deprivation groups 1-10) for more granular analyses, with group 1 being the least and group 5 (or group 10) the most deprived group. The rate in the most deprived compared with the least deprived group for P-FDep was 1.71 (95% confidence interval 1.60 to 1.83) times higher, based on the analysis of deprivation groups 1-5. A mortality gradient existed across the groups, translating into 2496 excess deaths (23.3%) when the rate in the least deprived group was applied to all areas. The gradient was more marked when deprivation groups 1-10 were used (relative risk 1.88, 95% CI 1.71 to 2.07 for the highest to the lowest deprived group). Compared with 2001-08 (neonatal mortality rate 2.39 per 1000), the rate remained constant in the least deprived areas, but worsened in the most deprived areas (+10.1% and +11.7% for groups 4 and 5, respectively), increasing the relative risks between the highest and lowest groups, which were 1.54 (95% CI 1.46 to 1.62) for deprivation groups 1-5 and 1.67 (1.55 to 1.79) for deprivation groups 1-10, in 2001-08.ConclusionsIn this study, the socioeconomic level of the mother's place of residence was strongly associated with the neonatal mortality rate. The data showed that inequalities have widened, contributing to the increase in the neonatal mortality rate.
Journal Article
The Transcriptional Response of Caenorhabditis elegans to Ivermectin Exposure Identifies Novel Genes Involved in the Response to Reduced Food Intake
We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short-term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms.
Journal Article