1,468 research outputs found
The dehydration of N-acetylglucosamine (GlcNAc) to enantiopure dihydroxyethyl acetamidofuran (Di-HAF)
The first multi-gram synthesis of enantiopure dihydroxyethyl acetamidofuran (Di-HAF) is reported. Under optimized conditions, GlcNAc dehydrates in pyridine in the presence of phenylboronic acid and triflic acid to afford Di-HAF in 73% yield and 99.3% ee in just 30 minutes. This protocol opens the door for further research on this bio-renewable building block which is now available as a chiral pool synthon. A plausible mechanism of its formation and of the subsequent dehydration of Di-HAF into well-known 3-acetamido-5-acetylfuran (3A5AF) is proposed.</p
Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization.
Inflammation contributes to atherosclerosis and coronary artery disease (CAD). In order to
help identify therapeutic targets, it is important to ascertain whether biomarkers associated
with CAD risk are causal. In a recent meta-analysis of clinical trials, neutrophil-to lymphocyte ratio (NLR) was associated with increased cardiovascular risk 1
. We investigate a
potential causal nature of this relationship by performing Mendelian randomization (MR)
analyse
Learning Sub-Sampling and Signal Recovery with Applications in Ultrasound Imaging
Limitations on bandwidth and power consumption impose strict bounds on data
rates of diagnostic imaging systems. Consequently, the design of suitable (i.e.
task- and data-aware) compression and reconstruction techniques has attracted
considerable attention in recent years. Compressed sensing emerged as a popular
framework for sparse signal reconstruction from a small set of compressed
measurements. However, typical compressed sensing designs measure a
(non)linearly weighted combination of all input signal elements, which poses
practical challenges. These designs are also not necessarily task-optimal. In
addition, real-time recovery is hampered by the iterative and time-consuming
nature of sparse recovery algorithms. Recently, deep learning methods have
shown promise for fast recovery from compressed measurements, but the design of
adequate and practical sensing strategies remains a challenge. Here, we propose
a deep learning solution termed Deep Probabilistic Sub-sampling (DPS), that
learns a task-driven sub-sampling pattern, while jointly training a subsequent
task model. Once learned, the task-based sub-sampling patterns are fixed and
straightforwardly implementable, e.g. by non-uniform analog-to-digital
conversion, sparse array design, or slow-time ultrasound pulsing schemes. The
effectiveness of our framework is demonstrated in-silico for sparse signal
recovery from partial Fourier measurements, and in-vivo for both anatomical
image and tissue-motion (Doppler) reconstruction from sub-sampled medical
ultrasound imaging data
Scattering theory of interface resistance in magnetic multilayers
The scattering theory of transport has to be applied with care in a diffuse
environment. Here we discuss how the scattering matrices of heterointerfaces
can be used to compute interface resistances of dirty magnetic multilayers.
First principles calculations of these interface resistances agree well with
experiments in the CPP (current perpendicular to the interface plane)
configuration.Comment: submitted to J. Phys. D (special issue at the occasion of Prof. T.
Shinjo's 60th birthday
Tigecycline in critically ill patients on continuous renal replacement therapy: a population pharmacokinetic study
Background: Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking.
Methods: Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT.
Results: A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45–94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI.
Conclusions: Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT.
Trial registration: EudraCT, 2012–005617-39. Registered on 7 August 2013
Inactivation of the Saccharomyces cerevisiae SKY1 gene induces a specific modification of the yeast anticancer drug sensitivity profile accompanied by a mutator phenotype
The therapeutic potential of the highly active anticancer agent cisplatin
is severely limited by the occurrence of cellular resistance. A better
understanding of the molecular pathways involved in cisplatin-induced cell
death could potentially indicate ways to overcome cellular
unresponsiveness to the drug and thus lead to better treatment results. We
used the budding yeast Saccharomyces cerevisiae as a model organism to
identify and characterize novel genes involved in cisplatin-induced cell
kill, and found that SKY1 (SR-protein-specific kinase from budding yeast)
is a cisplatin sensitivity gene whose disruption conferred cisplatin
resistance. In cross-resistance studies, we observed resistance of yeast
sky1 Delta cells (i.e., cells from which the SKY1 gene had been disrupted)
to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and
daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil.
Furthermore, these cells did not display reduced platinum accumulation,
DNA platination or doxorubicin accumulation, indicating that the
resistance is unrelated to decreased drug import or increased drug export.
Based on the modification of the anticancer drug sensitivity profile and
our finding that sky1 Delta cells display a mutator phenotype, we propose
that Sky1p might play a significant role in specific repair and/or
tolerance pathways. Disruption of the S. cerevisiae SKY1 gene would thus
result in deregulation of such mechanisms and, consequently, lead to
altered drug sensitivity
Estimation of the basic reproduction number for Streptococcus equi spp. equi outbreaks by meta-analysis of strangles outbreak reports
Background Streptococcus equi spp. equi (S. equi), the cause of strangles in horses, is considered a highly contagious pathogen affecting equines and the equine industry worldwide. Fundamental epidemiological characteristics of outbreaks, such as the basic reproduction number (R-0), are not well described. Objectives Estimate R-0 for S. equi in equine populations from outbreak data. Study design Systematic review and meta-analysis of published and unpublished data. Methods A literature search for outbreak reports was carried out. Depending on data available in the reports, the early epidemic growth rate or final attack rate (AR) approach was used to estimate the basic reproduction number for that outbreak. Other recorded outbreak characteristics were the type of housing (group vs. individual). An overall estimate for R-0 was computed by meta-analysis. Results Data from eight outbreaks were extracted from peer-reviewed publications. Data from two additional, non-published outbreaks was also included in the meta-analysis. A conservative estimate for R-0 was 2.2 (95% confidence interval [CI] 1.9-2.5). A less conservative estimate, including outbreaks with a 100% AR for which a lower limit R-0 was estimated, was 2.7 (95% CI 2.1-3.3). Main limitations Few papers describing longitudinal incidence data were found so most estimates were based on the outbreaks' final size. Several outbreaks had a 100% attack rate and could therefore only be included as a lower limit estimate in the meta-analysis. The reported result therefore may be an underestimation. Conclusions This estimate for R-0 for S. equi informs parameters for future mathematical modelling, quantifies desired preventive vaccine coverage and helps evaluate the effect of prevention strategies through future modelling studies
Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities
Amino Alcohol Coordination in Ruthenium(II)-Catalysed Asymmetric Transfer Hydrogenation of Ketones
Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump
Imatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is
successfully used in the treatment of chronic myelogenous leukemia and
gastrointestinal stromal tumors. However, the intended chronic oral
administration of imatinib may lead to development of cellular resistance
and subsequent treatment failure. Indeed, several molecular mechanisms
leading to imatinib resistance have already been reported, including
overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib
is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug
pump that is frequently overexpressed in human tumors. Using a panel of
well-defined BCRP-overexpressing cell lines, we provide the first evidence
that imatinib is a substrate for BCRP, that it competes with mitoxantrone
for drug export, and that BCRP-mediated efflux can be reversed by the
fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the
gastrointestinal tract, BCRP might not only play a role in cellular
resistance of tumor cells but also influence the gastrointestinal
absorption of imatinib
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