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The advancement of computational resources has allowed researchers to run convection-permitting regional climate model (CPRCM) simulations. A pioneering effort promoting a multimodel ensemble of such simulations is the CORDEX Flagship Pilot Studies (FPS) on "Convective Phenomena over Europe and the Mediterranean" over an extended Alps region. In this study, the Distribution Added Value metric is used to determine the improvement of the representation of all available FPS hindcast simulations for the daily mean near-surface wind speed. The analysis is performed on normalized empirical probability distributions and considers station observation data as the reference. The use of a normalized metric allows for spatial comparison among the different regions (coast and inland), altitudes and seasons. This approach permits a direct assessment of the added value between the CPRCM simulations against their global driving reanalysis (ERA-Interim) and respective coarser resolution regional model counterparts. In general, the results show that CPRCMs add value to their global driving reanalysis or forcing regional model, due to better-resolved topography or through better representation of ocean-land contrasts. However, the nature and magnitude of the improvement in the wind speed representation vary depending on the model, the season, the altitude, or the region. Among seasons, the improvement is usually larger in summer than winter. CPRCMs generally display gains at low and medium-range altitudes. In addition, despite some shortcomings in comparison to ERA-Interim, which can be attributed to the assimilation of wind observations on the coast, the CPRCMs outperform the coarser regional climate models, both along the coast and inland. [ABSTRACT FROM AUTHOR]

Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNAIle for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 103-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance. Aminoacyl-tRNA synthetases translate the genetic code. These enzymes harbor signature catalytic motifs dating from their ancient ancestors. A natural variation of one of the stated motifs was discovered and linked to antibiotic hyper-resistance. [ABSTRACT FROM AUTHOR]

There is a growing body of literature supporting the utilization of machine learning (ML) to improve diagnosis and prognosis tools of cardiovascular disease. The current study was to investigate the impact that the ML framework may have on the sensitivity of predicting the presence or absence of congenital heart disease (CHD) using fetal echocardiography. A comprehensive fetal echocardiogram including 2D cardiac chamber quantification, valvar assessments, assessment of great vessel morphology, and Doppler-derived blood flow interrogation was recorded. The postnatal echocardiogram was used to ascertain the diagnosis of CHD. A random forest (RF) algorithm with a nested tenfold cross-validation was used to train models for assessing the presence of CHD. The study population was derived from a database of 3910 singleton fetuses with maternal age of 28.8 ± 5.2 years and gestational age at the time of fetal echocardiography of 22.0 weeks (IQR 21–24). The proportion of CHD was 14.1% for the studied cohort confirmed by post-natal echocardiograms. Our proposed RF-based framework provided a sensitivity of 0.85, a specificity of 0.88, a positive predictive value of 0.55 and a negative predictive value of 0.97 to detect the CHD with the mean of mean ROC curves of 0.94 and the mean of mean PR curves of 0.84. Additionally, six first features, including cardiac axis, peak velocity of blood flow across the pulmonic valve, cardiothoracic ratio, pulmonary valvar annulus diameter, right ventricular end-diastolic diameter, and aortic valvar annulus diameter, are essential features that play crucial roles in adding more predictive values to the model in detecting patients with CHD. ML using RF can provide increased sensitivity in prenatal CHD screening with very good performance. The incorporation of ML algorithms into fetal echocardiography may further standardize the assessment for CHD. [ABSTRACT FROM AUTHOR]

A recently launched project under the auspices of the World Climate Research Program's (WCRP) Coordinated Regional Downscaling Experiments Flagship Pilot Studies program (CORDEX-FPS) is presented. This initiative aims to build first-of-its-kind ensemble climate experiments of convection permitting models to investigate present and future convective processes and related extremes over Europe and the Mediterranean. In this manuscript the rationale, scientific aims and approaches are presented along with some preliminary results from the testing phase of the project. Three test cases were selected in order to obtain a first look at the ensemble performance. The test cases covered a summertime extreme precipitation event over Austria, a fall Foehn event over the Swiss Alps and an intensively documented fall event along the Mediterranean coast. The test cases were run in both "weather-like" (WL, initialized just before the event in question) and "climate" (CM, initialized 1 month before the event) modes. Ensembles of 18–21 members, representing six different modeling systems with different physics and modelling chain options, was generated for the test cases (27 modeling teams have committed to perform the longer climate simulations). Results indicate that, when run in WL mode, the ensemble captures all three events quite well with ensemble correlation skill scores of 0.67, 0.82 and 0.91. They suggest that the more the event is driven by large-scale conditions, the closer the agreement between the ensemble members. Even in climate mode the large-scale driven events over the Swiss Alps and the Mediterranean coasts are still captured (ensemble correlation skill scores of 0.90 and 0.62, respectively), but the inter-model spread increases as expected. In the case over Mediterranean the effects of local-scale interactions between flow and orography and land–ocean contrasts are readily apparent. However, there is a much larger, though not surprising, increase in the spread for the Austrian event, which was weakly forced by the large-scale flow. Though the ensemble correlation skill score is still quite high (0.80). The preliminary results illustrate both the promise and the challenges that convection permitting modeling faces and make a strong argument for an ensemble-based approach to investigating high impact convective processes. [ABSTRACT FROM AUTHOR]

To study the inhibitory effects on bacterial adhesion of a newly devised, hydrophilic heparinized catheter to be used in patients with malignant obstructive jaundice, a randomized controlled study of indwelling endoprostheses was performed, using implantable port-connected heparinized catheters (n = 25) and silicone catheters (n = 21). Catheters withdrawn from patients were cultured for bacteria and examined by electron microscopy for the presence of adherent organisms. In vitro examination of the two type of catheters exposed to suspensions of Eschericia coli and Staphylococcus aureus was performed using electron microscopy and a luminometer. The formation of a biofilm coated with glycocalyces was found in silicone catheters, but not in the heparinized catheters. In vitro experiments demonstrated little bacterial adhesion to the heparinized surface, but significant formation of biofilm on the silicone surface. Anionically charged heparinized catheters have inhibitory effects on bacterial adhesion, and the surface charge of the catheter may be a factor in inhibiting this adhesion. [ABSTRACT FROM AUTHOR]

Background: The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates.Methods: Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data.Results: The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed.Interpretation: The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the possibility of preserving ovarian function by ovarian shielding to reduce the irradiation dose in total body irradiation (TBI). The subjects in the study were females aged less than 40 years, who were undergoing allogeneic hematopoietic stem cell transplantation using a TBI-based regimen and who desired to have children after transplantation. For ovarian shielding, abdominal computed tomography (CT) and skin marking were performed in both the supine and prone positions, prior to the TBI. A pair of columnar blocks was placed just above the patient's body. Thus far three patients have been treated. The serum estradiol level decreased to an undetectable level (<8.5 pg/ml) after transplantation and the follicle-stimulating hormone (FSH) level increased above 90 mIU/ml in all patients and they became amenorrheic. However, regular menstruation recovered in patients no. 1 and 2 about 800 and 370 days after transplantation, respectively, with a decrease in the serum FSH level. Menstruation did not recover in patient no. 3, and serum estradiol was transiently detected above 20 pg/ml. The preservation of ovarian function was made possible by ovarian shielding. However, a longer follow-up is needed to know if normal pregnancy and delivery can occur.Bone Marrow Transplantation (2006) 37, 583–587. doi:10.1038/sj.bmt.1705279; published online 30 January 2006 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented with the aim to preserve ovarian function by ovarian shielding while undergoing TBI for hematopoietic stem cell transplantation.