The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. To evaluate the biological and clinical relevance of p53 loss, human somatic cell gene targeting was used to delete ...the TP53 gene in the non-tumorigenic epithelial cell line, MCF-10A. In all four p53-/- clones generated, cells acquired the capability for epidermal growth factor-independent growth and were defective in appropriate downstream signaling and cell cycle checkpoints in response to DNA damage. Interestingly, p53 loss induced chromosomal instability leading to features of transformation and the selection of clones with varying phenotypes. For example, p53-deficient clones were heterogeneous in their capacity for anchorage-independent growth and invasion. In addition, and of clinical importance, the cohort of p53-null clones showed sensitivity to chemotherapeutic interventions that varied depending not only on the type of chemotherapeutic agent, but also on the treatment schedule. In conclusion, deletion of the TP53 gene from MCF-10A cells eliminated p53 functions, as well as produced p53-/- clones with varying phenotypes possibly stemming from the distinct chromosomal changes observed. Such a model system will be useful to further understand the cancer-specific phenotypic changes that accompany p53 loss, as well as help to provide future treatment strategies for human malignancies that harbor aberrant p53.
Assessing population-level consequences for marine mammals exposed to disturbance requires knowledge of their metabolism. We provide an overview of the magnitude and variation in marine mammal ...metabolism, and the intrinsic and extrinsic factors and behaviors that influence metabolism to assist with choosing a reliable metabolic rate for future bioenergetic models.
Abstract
Over the past several decades, scientists have constructed bioenergetic models for marine mammals to assess potential population-level consequences following exposure to a disturbance, stressor, or environmental change, such as under the Population Consequences of Disturbance (pCOD) framework. The animal's metabolic rate (rate of energy expenditure) is a cornerstone for these models, yet the cryptic lifestyles of marine mammals, particularly cetaceans, have limited our ability to quantify basal (BMR) and field (FMR) metabolic rates using accepted ‘gold standard’ approaches (indirect calorimeter via oxygen consumption and doubly labeled water, respectively). Thus, alternate methods have been used to quantify marine mammal metabolic rates, such as extrapolating from known allometric relationships (e.g. Kleiber's mouse to elephant curve) and developing predictive relationships between energy expenditure and physiological or behavioral variables. To understand our current knowledge of marine mammal metabolic rates, we conducted a literature review (1900–2023) to quantify the magnitude and variation of metabolic rates across marine mammal groups. A compilation of data from studies using ‘gold standard’ methods revealed that BMR and FMR of different marine mammal species ranges from 0.2 to 3.6 and 1.1 to 6.1 x Kleiber, respectively. Mean BMR and FMR varied across taxa; for both measures odontocete levels were intermediate to higher values for otariids and lower values of phocids. Moreover, multiple intrinsic (e.g. age, sex, reproduction, molt, individual) and extrinsic (e.g. food availability, water temperature, season) factors, as well as individual behaviors (e.g. animal at water’s surface or submerged, activity level, dive effort and at-sea behaviors) impact the magnitude of these rates. This review provides scientists and managers with a range of reliable metabolic rates for several marine mammal groups as well as an understanding of the factors that influence metabolism to improve the discernment for inputs into future bioenergetic models.
Context. Quasi-periodic pulsations (QPPs) are time variations in the energy emission during a flare that are observed on both the Sun and other stars and thus have the potential to link the physics ...of solar and stellar flares. Aims. We characterise the QPPs detected in an X-ray flare on the solar analogue, EK Draconis, which was observed by XMM-Newton. Methods. We used wavelet and autocorrelation techniques to identify the QPPs in a detrended version of the flare. We also fitted a model to the flare based on an exponential decay combined with a decaying sinusoid. The flare is examined in multiple energy bands. Results. A statistically significant QPP is observed in the X-ray energy band of 0.2–12.0 keV with a periodicity of 76 ± 2 min. When this energy band is split, a statistically significant QPP is observed in the low-energy band (0.2–1.0 keV) with a periodicity of 73 ± 2 min and in the high-energy band (1.0–12.0 keV) with a periodicity of 82 ± 2 min. When fitting a model to the time series the phases of the signals are also found to be significantly different in the two energy bands (with a difference of 1.8 ± 0.2 rad) and the high-energy band is found to lead the low-energy band. Furthermore, the first peak in the cross-correlation between the detrended residuals of the low- and high-energy bands is offset from zero by more than 3σ (4.1 ± 1.3 min). Both energy bands produce statistically significant regions in the wavelet spectrum, whose periods are consistent with those listed above. However, the peaks are broad in both the wavelet and global power spectra, with the wavelet showing evidence for a drift in period with time, and the difference in period obtained is not significant. The offset in the first peak in the cross-correlation of the detrended residuals of two non-congruent energy bands (0.5−1.0 keV and 4.5−12.0 keV) is found to be even larger (10 ± 2 min). However, the signal-to-noise in the higher of these two energy-bands, covering the range 4.5−12.0 keV, is low. Conclusions. The presence of QPPs similar to those observed on the Sun, and other stars, suggests that the physics of flares on this young solar analogue is similar to the physics of solar flares. It is possible that the differences in the QPPs detected in the two energy bands are seen because each band observes a different plasma structure. However, the phase difference, which differs more significantly between the two energy bands than the period, could also be explained in terms of the Neupert effect. This suggests that QPPs are caused by the modulation of the propagation speeds of charged particles.
Temporal variability in flux and spectral shape is ubiquitous in the X-ray sky and carries crucial information about the nature and emission physics of the sources. The EPIC instrument on board the
...XMM-Newton
observatory is the most powerful tool for studying variability even in faint sources. Each day, it collects a large amount of information about hundreds of new serendipitous sources, but the resulting huge (and growing) dataset is largely unexplored in the time domain. The project called Exploring the X-ray transient and variable sky (EXTraS) systematically extracted all temporal domain information in the
XMM-Newton
archive. This included a search and characterisation of variability, both periodic and aperiodic, in hundreds of thousands of sources spanning more than eight orders of magnitude in timescale and six orders of magnitude in flux, and a search for fast transients that were missed by standard image analysis. All results, products, and software tools have been released to the community in a public archive. A science gateway has also been implemented to allow users to run the EXTraS analysis remotely on recent XMM datasets. We give details on the new algorithms that were designed and implemented to perform all steps of EPIC data analysis, including data preparation, source and background modelling, generation of time series and power spectra, and search for and characterisation of different types of variabilities. We describe our results and products and give information about their basic statistical properties and advice on their usage. We also describe available online resources. The EXTraS database of results and its ancillary products is a rich resource for any kind of investigation in almost all fields of astrophysics. Algorithms and lessons learnt from our project are also a very useful reference for any current and future experiment in the time domain.
Purpose
The majority of colorectal cancer surgeries are performed electively, and treatment is often decided at the multidisciplinary team conference. Although the average 30-day mortality rate is ...low, there is substantial population heterogeneity from young, healthy patients to frail, elderly patients. The individual risk of surgery can vary widely, and tailoring treatment for colorectal cancer may lead to better outcomes. This requires prediction of risk that is accurate and available prior to surgery.
Methods
Data from the Danish Colorectal Cancer Group database was transformed into the Observational Medical Outcomes Partnership Common Data Model. Models were developed to predict the risk of mortality within 30, 90, and 180 days after colorectal cancer surgery using only covariates decided at the multidisciplinary team conference. Several machine-learning models were trained, but due to superior performance, a Least Absolute Shrinkage and Selection Operator logistic regression was used for the final model. Performance was assessed with discrimination (area under the receiver operating characteristic and precision recall curve) and calibration measures (calibration in large, intercept, slope, and Brier score).
Results
The cohort contained 65,612 patients operated for colorectal cancer in the period from 2001 to 2019 in Denmark. The Least Absolute Shrinkage and Selection Operator model showed an area under the receiver operating characteristic for 30-, 90-, and 180-day mortality after colorectal cancer surgery of 0.871 (95%
CI
: 0.86–0.882), 0.874 (95%
CI
: 0.864–0.882), and 0.876 (95%
CI
: 0.867–0.883) and calibration in large of 1.01, 0.98, and 1.01, respectively.
Conclusion
The postoperative short-term mortality prediction model showed excellent discrimination and calibration using only preoperatively known predictors.
Context. X-ray catalogues provide a wealth of information on many source types, ranging from compact objects to galaxies, clusters of galaxies, stars, and even planets. Thanks to the huge volume of ...X-ray sources provided in the 3XMM catalogue, along with many source specific products, many new examples from rare classes of sources can be identified. Aims. Through visualising spectra and lightcurves from about 80 observations included in the incremental part of the 3XMM catalogue, 3XMM-DR5, as part of the quality control of the catalogue, we identified two new X-ray sources, 3XMM J183333.1+225136 and 3XMM J184916.1+652943, that were highly variable. This work aims to investigate their nature. Methods. Through simple model fitting of the X-ray spectra and analysis of the X-ray lightcurves of 3XMM J183333.1+225136 and 3XMM J184916.1+652943, along with complementary photometry from the XMM-Newton Optical Monitor, Pan-STARRS and the Stella/WiFSIP and Large Binocular Telescope (LBT) spectra, we suggest that the two sources might be magnetic cataclysmic variables (CVs) of the polar type and we determine some of their properties. Results. Both CVs have very hard spectra, showing no soft excess. They are both situated in the local neighbourhood, located within ~1 kpc. 3XMM J183333.1+225136 has an orbital period of 2.15 h. It shows features in the lightcurve that may be a total eclipse of the white dwarf. 3XMM J184916.1+652943 has an orbital period of 1.6 h. Given that only a small sky area was searched to identify these CVs, future sensitive all sky surveys such as the eROSITA project should be very successful at uncovering large numbers of such sources.
The objective of this study was to investigate the relationship between baseline resting heart rate and incidence of heart failure (HF) and global and regional left ventricular (LV) dysfunction.
The ...association of resting heart rate to HF and LV function has not been well described in an asymptomatic multi-ethnic population.
Resting heart rate was measured in participants in the MESA (Multi-Ethnic Study of Atherosclerosis) trial at inclusion. Incident HF was registered (n = 176) during follow-up (median 7 years) in those who underwent cardiac magnetic resonance imaging (n = 5,000). Changes in ejection fraction (ΔEF) and peak circumferential strain (Δεcc) were measured as markers of developing global and regional LV dysfunction in 1,056 participants imaged at baseline and 5 years later. Time to HF (Cox model) and Δεcc and ΔEF (multiple linear regression models) were adjusted for demographics, traditional cardiovascular risk factors, calcium score, LV end-diastolic volume, and mass in addition to resting heart rate.
Cox analysis demonstrated that for 1 beat/min increase in resting heart rate, there was a 4% greater adjusted relative risk for incident HF (hazard ratio: 1.04; 95% CI: 1.02 to 1.06; p < 0.001). Adjusted multiple regression models demonstrated that resting heart rate was positively associated with deteriorating εcc and decrease in EF, even when all coronary heart disease events were excluded from the model.
Elevated resting heart rate was associated with increased risk for incident HF in asymptomatic participants in the MESA trial. Higher heart rate was related to development of regional and global LV dysfunction independent of subclinical atherosclerosis and coronary heart disease. (Multi-Ethnic Study of Atherosclerosis MESA; NCT00005487).
Abstract Chronic recurrent multifocal osteomyelitis (CRMO) is characterized by reduced activation of protein kinases ERK1 and 2 in monocytes resulting in impaired IL-10 expression. IL10 and its ...homologs IL19 and IL20 are organized in the IL10 cluster on chromosome 1q32. IL-10 and IL-19 are immune-regulatory cytokines, while IL-20 acts in a pro-inflammatory manner. The NLRP3 inflammasome, a multi-protein complex forming in response to innate stimuli, mediates IL-1β cleavage and release. Here, we investigated IL-10-related cytokine expression in CRMO monocytes, underlying molecular events, and effects on inflammatory responses. We observed reduced anti-inflammatory IL-10 and IL-19 expression, and enhanced IL-20 expression in CRMO monocytes. Reduced IL-10 and IL-19 expression was associated with impaired Sp-1 recruitment to regulatory regions, contributing to NLRP3 inflammasome activation, which may induce inflammatory bone-loss. Our findings underscore the importance of balanced receptor-, cell-, and tissue-specific cytokine expression for immune homeostasis, providing additional arguments for cytokine blocking strategies in CRMO.
Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is widely used to diagnose and manage patients with heart failure. We aimed to investigate associations between NT-proBNP levels and ...development of global and regional myocardial impairment, dyssynchrony, and risk of developing myocardial scar over time. Methods and Results We included 2416 adults (45-84 years) without baseline clinical cardiovascular disease from MESA (Multi-Ethnic Study of Atherosclerosis). NT-proBNP was assessed at baseline (2000-2002). Cardiac magnetic resonance-measured left ventricular parameters were assessed at baseline and year 10 (2010-2012). Tagged cardiac magnetic resonance and myocardial dyssynchrony were assessed. We used linear and logistic regression models to study the relationships between quartiles of NT-proBNP levels and outcome variables. Left ventricular parameters decreased over time. After 10-year follow-up and adjusting for cardiovascular disease risk factors, people in the highest quartile had significantly greater decline in left ventricular ejection fraction (-1.60%; 95% CI, -2.26 to -0.94;
<0.01) and smaller decline in left ventricular end systolic volume index (-0.47 mL/m
; 95% CI, -1.18 to 0.23;
<0.01) compared with those in the lowest quartile. Individuals in the highest quartile had more severe risk factor adjusted global, mid, and apical regional dyssynchrony compared with those in the lowest, second, and third quartiles (all
-trend<0.05). Compared with the lowest-quartile group, the adjusted odds ratios for having myocardial scar was 1.3 (95% CI, 0.7-2.2) for quartile 2; 1.2 (95% CI, 0.6-2.3) for quartile 3; and 2.7 (95% CI, 1.4-5.5) for quartile 4 (
-trend=0.012) for the total sample. Conclusions Among participants without baseline clinical cardiovascular disease, higher baseline NT-proBNP concentration was significantly associated with subclinical changes in developing myocardial dysfunction, more severe cardiac dyssynchrony, and higher odds of having myocardial scar over a 10-year period independent of traditional cardiovascular disease risk factors.
The Swift Gamma Ray Burst satellite routinely provides prompt positions for GRBs and their afterglows on timescales of a few hundred seconds. However, with a pointing accuracy of only a few ...arcminutes, and a systematic uncertainty on the star-tracker solutions to the World Coordinate System of 3–4 arcsec, the precision of the early XRT positions is limited to 3–4 arcsec at best. This is significant because operationally, the XRT detects >95% of all GRBs, while the UVOT detects only the optically brightest bursts, ~30% of all bursts detected by BAT; thus early and accurate XRT positions are important because for the majority of bursts they provide the best available information for the initial ground-based follow-up campaigns. Here we describe an autonomous way of producing more accurate prompt XRT positions for GRBs and their afterglows, based on UVOT astrometry and a detailed mapping between the XRT and UVOT detectors. The latter significantly reduces the dominant systematic error – the star-tracker solution to the World Coordinate System. This technique, which is limited to times when there is significant overlap between UVOT and XRT PC-mode data, provides a factor of 2 improvement in the localisation of XRT refined positions on timescales of less than a few hours. Furthermore, the accuracy achieved is superior to astrometrically corrected XRT PC mode images at early times (for up to 24 h), for the majority of bursts, and is comparable to the accuracy achieved by astrometrically corrected X-ray positions based on deep XRT PC-mode imaging at later times.
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