gebhart/patrepeval huggingface dataset:
New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus (2023)

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive <i>Enterococcus faecalis</i>, <i>Enterococcus faecium</i> and multidrug resistant (MDR) <i>Staphylococcus aureus</i> strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> (best compound MICs: range, 1-4 μg/mL). Lead compound <b>7a</b> was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of <b>7a</b> in complex with <i>Pseudomonas aeruginosa</i> GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of <b>7a</b> and <b>7h</b> showed potent antibacterial activity against over 100 MDR and non-MDR strains of <i>A. baumannii</i> and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of <b>7a</b> in a mouse model of vancomycin-intermediate <i>S. aureus</i> thigh infection was also demonstrated.
A novel prostate cancer subtyping classifier based on luminal and basal phenotypes (2023)

Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.
Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase (2016)

To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.
Novel protein therapeutic joint retention strategy based on collagen‐binding Avimers (2017)

Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross-linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra-articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein-protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen-binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen-binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra-articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL-1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL-1 receptor. In vitro, IL-1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra-articular IL-1-induced IL-6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL-1Ra_M26 and native IL-1Ra inhibited IL-6 output when co-administered with the IL-1 challenge, only IL-1Ra_M26 inhibited when administered 1 week prior to IL-1 challenge. Collagen-binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238-1247, 2018.
Viability of Oxide Fiber Coatings in Ceramic Composites for Accommodation of Misfit Stresses (1996)

The C and BN fiber coatings used in most ceramic composites perform a less obvious but equally essential function, in addition to crack deflection; they accommodate misfit stresses due to interfacial fracture surface roughness. Coatings substituted for them must also perform that function to be effective. However, in general, oxides are much less compliant materials than C and BN, which raises the question of the feasibility of oxide substitutes. The viability of oxide coatings for accommodating misfit stresses in Nicalon fiber/SiC composites was investigated by calculating the maximum misfit stresses as functions of coating properties and geometries. Control of interfacial fracture path was also briefly considered. The implications regarding composite properties were examined by calculating properties for composites with mechanically viable oxide coatings.
STATISTICAL APPROACHES TO HUMAN BRAIN MAPPING BY FUNCTIONAL MAGNETIC RESONANCE IMAGING (1996)

Proper use of functional neuro-imaging through effective experimental design and modern statistical analysis provides new insights in current brain research. This tutorial has two aims: to describe aspects of this technology to applied statisticians and to provide some statistical ideas to neuroscientists unfamiliar with quantitative analytic methods that accommodate randomness. Introductory background material and ample references to current literature on the physics of magnetic resonance imaging, Fourier methods for image reconstruction and measures of image quality are included. Two of the statistical approaches mentioned here are extensions of established methods for longitudinal data analysis to the frequency domain. A recent case study provides real-world instances of approaches, problems and open questions encountered in current functional neuro-imaging research and an introduction to the analysis of spatial time series in this context.
Big Area Additive Manufacturing and Hardware-in-the-Loop for Rapid Vehicle Powertrain Prototyping: A Case Study on the Development of a 3-D-Printed Shelby Cobra (2016)

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;Rapid vehicle powertrain development has become a technological breakthrough for the design and implementation of vehicles that meet and exceed the fuel efficiency, cost, and performance targets expected by today’s consumer. Recently, advances in large scale additive manufacturing have provided the means to bridge hardware-in-the-loop with preproduction mule chassis testing. This paper details a case study from Oak Ridge National Laboratory bridging the powertrain-in-the-loop development process with vehicle systems implementation using big area additive manufacturing (BAAM). For this case study, the use of a component-in-the-loop laboratory with math-based models is detailed for the design of a battery electric powertrain to be implemented in a printed prototype mule. The ability for BAAM to accelerate the mule development process via the concept of computer-aided design to part is explored. The integration of the powertrain and the opportunities and challenges of doing so are detailed in this work. The results of the mule-vehicle chassis dynamometer testing are presented. Lastly, the ability to integrate more complex powertrains is discussed.&lt;/div&gt;&lt;/div&gt;
Fraction of expired oxygen: an additional safety approach to monitor oxygen delivery to the heart lung machine oxygenator (2021)

Monitoring the FEO<sub>2</sub> is a more reliable way to verify O<sub>2</sub> delivery to an oxygenator. An alarm can be set on the FEO<sub>2</sub> monitor to alert the perfusionist if the FEO<sub>2</sub> falls below a predetermined threshold so any issue with O<sub>2</sub> delivery will always be recognized.
Correlation matching method for high-precision position detection of optical vortex using Shack–Hartmann wavefront sensor (2012)

We propose a new method for realizing high-spatial-resolution detection of singularity points in optical vortex beams. The method uses a Shack-Hartmann wavefront sensor (SHWS) to record a Hartmanngram. A map of evaluation values related to phase slope is then calculated from the Hartmanngram. The position of an optical vortex is determined by comparing the map with reference maps that are calculated from numerically created spiral phases having various positions. Optical experiments were carried out to verify the method. We displayed various spiral phase distribution patterns on a phase-only spatial light modulator and measured the resulting singularity point using the proposed method. The results showed good linearity in detecting the position of singularity points. The RMS error of the measured position of the singularity point was approximately 0.056, in units normalized to the lens size of the lenslet array used in the SHWS.
Arylzinc Species by Microwave Assisted Grignard Formation—Transmetalation Sequence: Application in the Negishi Coupling. (2006)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Characterization of bovine herpesvirus 1 UL49 homolog gene and product: bovine herpesvirus 1 UL49 homolog is dispensable for virus growth (1995)

The sequence of the bovine herpesvirus 1 (BHV-1) gene that is homologous to the herpes simplex virus UL49 gene was determined. The BHV-1 UL49 homolog open reading frame consists of 774 bp and is capable of encoding 258 amino acids. Northern (RNA) blot analysis showed that the BHV-1 UL49 homolog is transcribed into a 1.1-kb RNA which is coterminal with the transcripts of an upstream UL49.5 homolog gene. Rabbit antisera produced against synthetic peptides of the predicted UL49 homolog gene product recognized a polypeptide of 33 to 35 kDa in both virus-infected cells and isolated virions. Further analysis by unionic-detergent partition of isolated virions suggested that the UL49 homolog gene product is a virion tegument protein. Indirect immunofluorescence assay revealed that the UL49 homolog gene product was predominantly localized in the nuclei of BHV-1-infected cells. A mutant virus with the UL49 homolog gene deleted was produced, and it was able to replicate in noncomplementing cells. Nevertheless, the yield of mutant virus was significantly reduced. The results from this study suggest that the BHV-1 UL49 homolog gene encodes a nuclear protein which constitutes a tegument component in mature virions and that it is dispensable for virus growth in cell culture.
Nucleophilic addition to diene and arene-metal complexes (1981)

Abstract
<title>Advanced strategies for spatially resolved analyte mapping with distributed fiber optic sensors for environmental and process applications</title> (1999)

The evolution of approaches to simultaneous real-time acquisition of analytical data from multiple locations is analyzed. Greatest emphasis is placed on optical time-of- flight (OTOF) chemical detection when the measurements are taken along the length of a single continuous extended-length 'distributed' sensing element. The attractive features of such distributed sensing element fabricated by immobilization of chemically sensitive reagents directly into the original cladding of a conventional plastic-clad silica (PCS) optical fiber are demonstrated. Several signal generation and processing methods are devised to address the requirements for spatially resolved chemical sensing. These requirements include high signal levels, a fairly uniform detection limit over the length of the sensing fiber, measurements with dynamically quenched fluorophores, and high spatial resolution. Applications of OTOF distributed chemical sensors for spatially resolved analyte mapping for environmental and process applications are discussed.
Frequency noise and phase-locking of a quantum cascade laser-pumped, 1.073THz molecular laser using a 1560nm frequency comb (2019)

We report the measurement of the frequency noise power spectral density (PSD) of a THz molecular laser (ML) pumped by a mid-infrared (MIR) quantum cascade laser (QCL). This is obtained by beating the ML frequency with the harmonic of the repetition rate of a 1560nm frequency comb (FC). We find a frequency noise PSD <; 10Hz <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> /Hz (-95dBc/Hz) at 100kHz from the carrier, limited by the noise of the QCL current driver. We also show that it is possible to actively phase-lock the QCLpumped ML to the FC repetition rate harmonic by controlling the QCL drive current.
Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist (2022)

The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.
Purification of Cells and Their Parts (2000)

Arrhythmias result from abnormalities of impulse initiation or impulse conduction or a combination of both. Abnormal impulse initiation results from either automaticity or triggered activity. Automaticity can further be subdivided into (1) automaticity caused by the normal automatic mechanism (a normal property of cardiac cells in the sinus node, in some parts of the atria, in the atrioventricular junctional region, and in the His-Purkinje system) and (2) automaticity caused by an abnormal mechanism (resulting from a decrease in membrane potential of cardiac fibers, which normally have a high level of membrane potential). Triggered activity is caused by afterdepolarizations, which are second depolarizations that occur either during repolarization (referred to as early afterdepolarizations) or after repolarization is complete or nearly complete (referred to as delayed afterdepolarizations). Abnormal impulse conduction results in reentrant excitation. Usually a combination of slowed conduction and unidirectional conduction block provides the conditions necessary for reentry to occur.
Implementing network file system policies with FileWall (2006)

Managing network file systems in large deployments is a critical challenge facing administrators today. Network file systems are widely used, are standardized, and provide acceptable performance. These systems are designed for the least common denominator of functionality, across all deployments to enable widespread use across diverse client systems. Unfortunately, specific deployment scenarios require different policies that govern file system access. The rigid structure of current network file systems makes modifying policies and mechanisms equally difficult. In this paper, we present a novel approach to implement network file system policies through message transformation, external to clients and servers. We present FileWall, a file system proxy, through which administrators can easily extend network file system policies for monitoring, access control, maintenance, and semantic extensions. We also present a policy specification language, FWL, which allows administrators to specify policies in a few lines, without being encumbered with implementation details. We have implemented FileWall using the Click modular router framework for the NFS protocol, and present solutions for four real-world administrative problems using our system — maintaining per-client file system statistics, implementing temporal access control, improving file handle security, and supporting client transparent failover. Through our evaluation, we show that FileWall imposes minimal delays, the interposition overheads are low, and the performance of FileWall is comparable to a simple network tunnel.
Nature of the 1/f noise in 6H-SiC (1994)

The phenomenon of 1/f noise in SiC has been studied in detail for the first time. Spectral noise density dependences for n-type 6H-SiC samples with doping level Nd-Na approximately=1017 cm-3 were measured at 300-600 K over the frequency range from 20 Hz to 20 kHz. The value of the Hooge parameter alpha for 1/f noise is in the range from 5*10-5 to 10-3. A low value of a indicates a rather high degree of structural perfection of the material. The value of the 1/f noise depends rather weakly on temperature in the range 300-450 K. The sources of the 1/f noise are distributed uniformly in the channel of SiC JFETs used for studying low-frequency noise in 6H-SiC. For all samples, two local levels can be plainly observed from noise measurements. A frequency-dependent decrease of the 1/f noise was observed on the injection of minority carriers (holes) with very small concentration. Holes have been injected into the n-channel of FETs due to the forward bias on the gate p+-n junction. The change in the low-frequency noise due to the appearance of the holes is qualitatively similar to the illumination-induced modification of 1/f noise in n-GaAs and n-Si observed and explained theoretically earlier. It is supposed that bulk 1/f noise in n-SiC is due to fluctuations in the occupancy of the levels that form the density-of-states tail near the conduction band edge.
Alkyne adducts of paramagnetic and diamagnetic tripalladium clusters supported by dppm ligands (2008)

The unsaturated redox-active cluster [Pd 3 (dppm) 3 (CO)] n + (n = 0,1, or 2) reacts with ethylene dicarboxylic esters and a variety of terminal acetylenes (but not PhC≡CPh) in all three charge states. In particular, the radical cations [Pd 3 (dppm) 3 (CO)(RC≡CR′)] .+ can be produced by several routes: one-electron electrochemical reduction of the dication adducts, comproportionation of the neutral and dicationic adducts, as well as the direct complexation of alkyne to the known radical cation [Pd 3 (dppm) 3 (CO)] .+ . Compared with the latter, each of the adducts have significantly extended lifetimes and classify as persistent radicals in solution. The alkyne adducts have been characterized by voltammetry (cyclic and rotating disk electrode), by UV – vis titrations and by MALDI-TOF mass spectra from dithranol matrices. Isotropic solution EPR spectra of the adducts with R = R′ = MeOC(O) and EtOC(O), as well as those with R′ = H and R = C 6 H 5 , FC 6 H 4 , HC≡CC 6 H 4 , and EtO have been obtained. Full line shape fitting simulations demonstrate that all display coupling to six different 31 P (I = 1/2) and to one to three 106 Pd (I = 5/2) nuclei. The A( 31 P) values range from a low of 3.0 × 10 4 to a high of 180.5 × 10 4 cm –1 ; this variation is caused by changes in the contribution of P s orbitals to the SOMO resulting from structural distortions of the Pd 3 P 6 core upon alkyne coordination.Key words: electrochemistry, redox state, electron paramagnetic resonance, catalytic model, palladium, bridging phosphine.
A novel population of interleukin 21-producing pre-follicular T helper cells develop spontaneously in young naïve mice (LYM3P.743) (2014)

Abstract Interleukin 21 is a cytokine vital for driving the proliferation of antigen-stimulated B cells within the germinal center and their subsequent differentiation into antibody-secreting plasmablasts and plasma cells. IL21 is predominately produced by a subset of activated CD4+ T cells known as T follicular helper cells. These cells develop at the T cell-B cell border and express ICOS, PD1, CD44, CXCR5 and BCL6. While this cell type has been identified, the processes that ultimately result in TFH differentiation are poorly understood. Here we use a novel IL21-venus fluorescent protein reporter mouse to investigate the signals and pathways involved in the earliest stages of development of TFH cells and production of IL21. We identify and characterize a naturally occurring population of ICOShi CD44hi CD4+ T cells that produce IL21 and are present within 4 weeks of age in naïve healthy C57BL/6J mice. These T cells show characteristics of TFH cells, including the upregulation of Bcl6 and Sostdc1, but lack surface staining for CXCR5 and PD1 and, surprisingly, develop in the absence of B cells. Therefore, these spontaneously arising cells actively producing IL21 appear to identify the earliest precursor to the mature TFH state.
Deinking of Dry-toned Prints from NexPress Digital Production Presses (2006)

The output of 4/5-color digital presses of the Kodak NexPress product family and of other digital presses is increasing rapidly. Printed paper from these presses represent an increasing portion of waste paper beside other dry toner based output devices like office printers, copiers, faxes and multifunctional devices.Worldwide app. half of the paper is recycled - in Europe even more. The environmental legislation in Germany requests, that a recycling process like that of paper results in recycled products for the same application as far as possible technically as well as commercially. For paper that means that the recycling of paper used in commercial printing or offices ends in paper for the same applications and not just in e.g. brown kraft paper.Therefore printed paper from digital output devices like digital production presses has to be deinkable with the technologies already established in the paper mills for the conventional printing technologies existing as they are still providing the majority of printed paper.Some product development groups targeting the recyclability of their printed products since some time and we report - as an example - deinking results which show, that the prints from the Kodak NexPress family of digital presses match the deinking standards existing so far. This is valid for four-color prints as well as for prints produced in a five-color press applying additional clear toner and optional image glossing.