gebhart/patrepeval huggingface dataset:
Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918. (1996)

We sought to develop an assay for measuring the inhibition of P-glycoprotein (Pgp) function in whole blood as an indicator of in vivo drug activity. Since the CD56(+) subset of peripheral blood lymphocytes (PBLs) has been shown to express functional Pgp, the changes in rhodamine 123 (R123) uptake by CD56(+) PBLs from GG918-treated and untreated whole blood were used as the basis for these studies. In an ex vivo study, heparin-treated whole blood was obtained from normal volunteers, and GG918 and R123 were added at various concentrations for time course analyses of dye loading. GG918 concentrations from 2.5 to 800 nm were tested in incubations ranging from 15 min to 3 h prior to R123 addition. R123 loading times ranged from 0 to 80 min. Flow cytometric analyses of the CD56(+) PBLs indicated that the resolution of Pgp inhibition was dependent on inhibitor concentration and time of R123 loading and independent of the R123 concentrations tested. In this ex vivo assay model, a dose-dependent response was seen for GG918 with a 2-fold increase in cellular R123 intensity being produced at a drug concentration of 80 nm. When this assay method was applied to blood samples from volunteers dosed p.o. with GG918, similar shifts in R123 fluorescence of the CD56(+) PBLs were observed with significant increases in R123 intensity occurring at serum concentrations as low as 40 nm. In contrast to assays in which target cell populations are enriched prior to testing, the addition of the substrate (R123) directly to the blood sample combined with the segregation of the target cells by specific immunofluorescence provides the investigator an indication of in situ activity of circulating drug. Thus, CD56(+) PBLs may prove useful as a surrogate target for monitoring multidrug resistance inhibitor activity in situ.
Detecting Cancer Metastases on Gigapixel Pathology Images (2017)

Each year, the treatment decisions for more than 230,000 breast cancer patients in the U.S. hinge on whether the cancer has metastasized away from the breast. Metastasis detection is currently performed by pathologists reviewing large expanses of biological tissues. This process is labor intensive and error-prone. We present a framework to automatically detect and localize tumors as small as 100 x 100 pixels in gigapixel microscopy images sized 100,000 x 100,000 pixels. Our method leverages a convolutional neural network (CNN) architecture and obtains state-of-the-art results on the Camelyon16 dataset in the challenging lesion-level tumor detection task. At 8 false positives per image, we detect 92.4% of the tumors, relative to 82.7% by the previous best automated approach. For comparison, a human pathologist attempting exhaustive search achieved 73.2% sensitivity. We achieve image-level AUC scores above 97% on both the Camelyon16 test set and an independent set of 110 slides. In addition, we discover that two slides in the Camelyon16 training set were erroneously labeled normal. Our approach could considerably reduce false negative rates in metastasis detection.
A value for n-person games (1988)

At the foundation of the theory of games is the assumption that the players of a game can evaluate, in their utility scales, every “prospect” that might arise as a result of a play. In attempting to apply the theory to any field, one would normally expect to be permitted to include, in the class of “prospects,” the prospect of having to play a game. The possibility of evaluating games is therefore of critical importance. So long as the theory is unable to assign values to the games typically found in application, only relatively simple situations—where games do not depend on other games—will be susceptible to analysis and solution.
Estimation based on entropy matching for generalized Gaussian PDF modeling (1999)

A novel method for estimating the shape factor of a generalized Gaussian probability density function (PDF) is presented and assessed. It relies on matching the entropy of the modeled distribution with that of the empirical data. The entropic approach is suitable for real-time applications and yields results that are accurate also for low values of the shape factor and small data sample. Modeling of wavelet coefficients for entropy coding is addressed and experimental results on true image data are reported and discussed.
Kernel PLS variants for regression (2003)

Abstract. We focus on covariance criteria for finding a suitable subspace for regression in a reproducing kernel Hilbert space: kernel principal component analysis, kernel partial least squares and kernel canonical correlation analysis, and we demonstrate how this fits within a more general context of subspace regression. For the kernel partial least squares case some variants are considered and the methods are illustrated and compared on a number of examples. 1
这并非是一场博弈 ISO9001：2015中“基于风险思想”是风险管理还是预防措施——这有关系吗？ (2015)

目前已经发布的ISO9001：2015（DIS）提出了“基于风险思想”，而针对这一国际标准草案所涉及的关于风险方面新主题的认识，大家似乎分为以下两个不同阵营：一些人认为，这一“基于风险思想”对于以前的ISO9001来讲，是一个全新的主题。
Stable transfer of intact high molecular weight DNA into plant chromosomes. (1996)

In conjunction with an enhanced system for Agrobacterium-mediated plant transformation, a new binary bacterial artificial chromosome (BIBAC) vector has been developed that is capable of transferring at least 150 kb of foreign DNA into a plant nuclear genome. The transferred DNA appears to be intact in the majority of transformed tobacco plants analyzed and is faithfully inherited in the progeny. The ability to introduce high molecular weight DNA into plant chromosomes should accelerate gene identification and genetic engineering of plants and may lead to new approaches in studies of genome organization.
Transfer and expression of the lacZ gene in rat brain neurons mediated by herpes simplex virus mutants. (1990)

Three mutants of herpes simplex virus type 1 (HSV-1) were used to deliver and express the Escherichia coli lacZ gene in cells of the rat central nervous system. Because the lacZ gene was inserted in place of the genes encoding one of the immediate-early viral proteins ICP0 or ICP4 or the early viral protein thymidine kinase, these mutants were compromised or defective in their ability to replicate. All mutant vectors exhibited reduced pathogenesis in animals as compared to the wild type HSV-1 strain KOS. In all cases lacZ was under the control of immediate-early or early viral promoters that are active in the early phase of infection. Expression of beta-galactosidase was observed in cortical neurons following stereotactic inoculation of mutant viruses into adult rat brains; distinct patterns of expression were observed with each mutant vector. Injection of the ICP0 mutant in the frontal cortex and caudate nucleus resulted in beta-galactosidase expression in a substantial number of cells around the inoculation site and at some distance from it for 14 days, with maximum expression after 3 days. The ICP0 vector appeared to have reached the ipsilateral and contralateral cingulate cortex by retrograde transport. Following inoculations of the ICP4 and thymidine kinase vectors into the same brain regions, only a few cells in areas immediately adjacent to the injection track expressed beta-galactosidase and they did so for only a few days. These herpes virus-derived vectors provide a means for the in situ delivery and expression of specific genes in neurons in the central nervous system with little adverse effect on animals.
Effects of Interleukin‐1 and Interleukin‐2 on Mammary Gland Leukocyte Populations and Histology during the Early Nonlactating Period (1993)

Eight Jersey cows free of intramammary infection (IMI) with major mastitis pathogens were intramammarily infused with interleukin (IL)-1, IL-2, or phosphate-buffered saline (PBS) after the last milking prior to drying off. Rectal temperatures were monitored hourly through 6 hours after infusion and at 24-hour intervals thereafter. Quarter secretions were collected 7 days prior to drying off, at drying off, and on days 1, 2, 3, 4, 7, and 14 of the nonlactating period. Cows were slaughtered and mammary tissues were collected at 7 (3 cows) and 14 (5 cows) days after treatment. The infusion of 10 micrograms of IL-1 produced an elevation in rectal temperature that was significantly higher than that of cows receiving IL-2 or PBS at 4, 5, and 6 hours after treatment, whereas cows receiving 1.0 mg of IL-2 exhibited no change in rectal temperature. Somatic cell counts (SCC) in mammary glands infused with IL-1 or IL-2 remained significantly elevated over PBS-infused control glands through day 4 after treatment. Neutrophils predominated in secretions of IL-1-treated glands, and macrophages and lymphocytes predominated in IL-2-treated glands. The mammary involution process was accelerated by IL-2, and tissues exhibited reductions in alveolar epithelial and luminal areas and increases in connective tissue stroma and degree of leukocytosis compared with IL-1 and control glands. Concentrations of plasma cells producing IgG1, IgG2, IgA, and IgM also were greatest following IL-2 infusion. Results suggest that IL-2 is superior to IL-1 in stimulating an increase in mammary mononuclear cell populations and in accelerating involution during the early nonlactating period.
Palladium(II)‐Catalyzed CH Activation/CC Cross‐Coupling Reactions: Versatility and Practicality (2009)

In the past decade, palladium-catalyzed C-H activation/C-C bond-forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming C-C bonds from C-H bonds: Pd(II)/Pd(0), Pd(II)/Pd(IV), Pd(0)/Pd(II)/Pd(IV), and Pd(0)/Pd(II) catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of C-H bonds with organometallic reagents through a Pd(II)/Pd(0) catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.
General and Mild Preparation of 2-Aminopyridines (2010)

A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to SNAr chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses the phosphonium salt, PyBroP, as a means of substrate activation.
LC/MS applications in drug development (1999)

The combination of high-performance liquid chromatography and mass spectrometry (LC/MS) has had a significant impact on drug development over the past decade. Continual improvements in LC/MS interface technologies combined with powerful features for structure analysis, qualitative and quantitative, have resulted in a widened scope of application. These improvements coincided with breakthroughs in combinatorial chemistry, molecular biology, and an overall industry trend of accelerated development. New technologies have created a situation where the rate of sample generation far exceeds the rate of sample analysis. As a result, new paradigms for the analysis of drugs and related substances have been developed. The growth in LC/MS applications has been extensive, with retention time and molecular weight emerging as essential analytical features from drug target to product. LC/MS-based methodologies that involve automation, predictive or surrogate models, and open access systems have become a permanent fixture in the drug development landscape. An iterative cycle of “what is it?” and “how much is there?” continues to fuel the tremendous growth of LC/MS in the pharmaceutical industry. During this time, LC/MS has become widely accepted as an integral part of the drug development process. This review describes the utility of LC/MS techniques for accelerated drug development and provides a perspective on the significant changes in strategies for pharmaceutical analysis. Future applications of LC/MS technologies for accelerated drug development and emerging industry trends are also discussed. © 1999 John Wiley & Sons, Inc., Mass Spec Rev 18: 187–279, 1999
Intact Antibody Characterization Using Orbitrap Mass Spectrometry (2015)

Recent innovations and improvement in Orbitrap technology have enabled routine Orbitrap MS-based analysis of intact monoclonal antibody and related products. In this chapter, LC-MS and LC-MS/MS solutions that include sample preparation, Orbitrap instrumentation and data processing are introduced for routine intact antibody mass measurement as well as subunit sequencing and fragment structure analysis. Measurement of antibody molecular mass under both denatured and native conditions are described with recommendations for best practice and key Orbitrap MS parameters. The results demonstrate accurate and reproducible measurement of molecular mass and relative abundance of glycoforms. The intact subunit sequencing and middle-down approaches efficiently dissociate the light chain and the heavy chain, leading to 67% backbone fragmentation for the intact light chain, and 52% and 32% backbone fragmentation for the single chain Fc (scFc) and Fd′ fragments (Fab-domains of heavy chain), respectively. The use of complementary dissociation methods, ETD and HCD, not only improves sequence coverage, but also allows the confident identification and localization of sequence modifications including glycosylation. The improved resolution and scan speed in the new generation Orbitrap mass spectrometers enable the practical utility of online LC in conjunction with subunit or middle-down MS/MS in a high-throughput format. The methods presented here can be used routinely in biopharmaceutical applications.
Heterogeneous Single-Walled Carbon Nanotube Catalyst Discovery and Optimization (2002)

High-throughput methods are utilized in the discovery and optimization of heterogeneous catalyst formulations that promote single-walled carbon nanotube (SWNT) synthesis. Catalyst compositions, substrates, and reaction conditions are varied to efficiently investigate SWNT growth by chemical vapor deposition (CVD). A robotic microarray printer is employed to print libraries of the liquid-based catalyst precursors onto various substrates. After CVD, the catalyst arrays are qualitatively screened for yield via electron microscopy. More comprehensive characterization of candidate catalysts is further investigated with confocal Raman spectroscopy (CRS). Detailed CRS mapping reveals information concerning the printed catalyst and nanotube homogeneity in the microarrays. This powerful characterization approach allows for the high-throughput screening of nanotube type, diameter distribution, and purity within the microarrays. The methodology described has enabled the efficient exploration of synthesis parameters, which has led to the identification of SWNT catalysts with various activities.
Optimization of a nicotine degrading enzyme for potential use in treatment of nicotine addiction (2019)

Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.
Spread Spectrum Applications in Unmanned Aerial Vehicles (1994)

This thesis is part of an ongoing Naval Postgraduate School research project to develop unmanned aerial vehicles (UAVs) using current off the shelf (COTS) technology. This thesis specifically evaluated a spread spectrum UHF data link between a UAV and ground terminal. The command and control (C2) process and its role as the fundamental premise of the warfare commander were discussed. A review of the Pioneer Remotely Piloted Vehicle (RPV), which gained such wide recognition during Operations Desert Storm and Desert Shield, was provided to the reader for familiarization with the workings of a generic UAV. An investigation of two common spread spectrum techniques and there associated benefits was made. A link budget calculation was made. The choice of a spread spectrum radio transceiver was reviewed. The requirements and design of the UAV and ground terminal antenna were discussed. A link budget analysis was performed. An atmospheric pat propagation prediction was performed. The details of an actual flight test and the data gathered were examined. Future changes to enhance the data link performance and increase its capabilities were introduced. The COTS spread spectrum data link will enhance the role of the UAV in its command and control mission for the warfare commander.
Adiabatic Markovian Dynamics (2010)

We propose a theory of adiabaticity in quantum markovian dynamics based on a decomposition of the Hilbert space induced by the asymptotic behavior of the Lindblad semigroup. A central idea of our approach is that the natural generalization of the concept of eigenspace of the Hamiltonian in the case of markovian dynamics is a noiseless subsystem with a minimal noisy cofactor. Unlike previous attempts to define adiabaticity for open systems, our approach deals exclusively with physical entities and provides a simple, intuitive picture at the Hilbert-space level, linking the notion of adiabaticity to the theory of noiseless subsystems. As two applications of our theory, we propose a general framework for decoherence-assisted computation in noiseless codes and a dissipation-driven approach to holonomic computation based on adiabatic dragging of subsystems that is generally not achievable by nondissipative means.
The effect of density on the properties of high molecular weight polyethylenes (1977)

Abstract Ultrahigh molecular weight polyethylene has been crystallized at various pressures (0–330 MN m −2 ) to material of a wide range of specific gravities (0.928–0.967). Tensile measurements illustrate that the properties of these materials are dependent on specific gravity (sg), in that the yield stress increases linearly with sg. Low sg (0.928–0.944) materials exhibit higher yields stress than low molecular weight materials of the same sg but the opposite is true for higher sg material. Low sg material also extends uniformly after yielding while above a sg of 0.944 necking becomes more marked. Orientation hardening is observed with all these materials above 200% extension and is more marked than with low molecular weight polymers. Differential scanning calorimetry (DSC) analysis of the pressure crystallized materials indicate that in the range 200–400 MN m −2 two phases are present, i.e., chain‐folded and chain‐extended lamellas. Increasing or decreasing the pressure changes the crystalline component to chain‐extended or chain‐folded morphologies, respectively. The reorganization of the crystalline components on drawing is discussed.
The Transgenic Expression of Human CD39 on Murine Islets Inhibits Clotting of Human Blood (2006)

Platelet activation is believed to play an important role in the triggering of thrombosis of human blood by pig islets. We used a transgenic mouse model to investigate whether overexpression of CD39 (ecto nucleoside triphosphate diphosphohydrolase 1 [ENTPD1], EC 3.6.1.5), an ectonucleotidase that degrades the platelet agonists ATP, could interfere with this process. Islets isolated from CD39 transgenic mice showed 2.4-fold higher NTPDase activity than wild-type controls. When incubated with human blood, these islets significantly delayed clotting time compared to wild type islets (7.9 +/- 0.89 min versus 4.3 +/- 0.77 min, P = 0.007). Importantly, expression of human CD39 in the islets of transgenic mice had no deleterious effect on glucose metabolism. These results suggest that transgenic expression of human CD39 does not interfere with islet function and may be a useful strategy to inhibit thrombosis induced by intraportal administration of islet xenografts.
Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes (2000)

Ribozymes are catalytic RNA molecules that can be designed to cleave specific RNA sequences. To investigate the potential use of synthetic stabilized ribozymes for the treatment of chronic hepatitis C virus (HCV) infection, we designed and synthesized hammerhead ribozymes targeting 15 conserved sites in the 5' untranslated region (UTR) of HCV RNA. This region forms an internal ribosome entry site that allows for efficient translation of the HCV polyprotein. The 15 synthetic ribozymes contained modified nucleotides and linkages that stabilize the molecules against nuclease degradation. All 15 ribozymes were tested for their ability to reduce expression in an HCV 5' UTR/luciferase reporter system and for their ability to inhibit replication of an HCV-poliovirus (HCV-PV) chimera. Treatment with several ribozymes resulted in significant down-regulation of HCV 5' UTR/luciferase reporter expression (range 40% to 80% inhibition, P <.05). Moreover, several ribozymes showed significant inhibition (>90%, P <.001) of chimeric HCV-PV replication. We further show that the inhibitory activity of ribozymes targeting site 195 of HCV RNA exhibits a sequence-specific dose response, requires an active catalytic ribozyme core, and is dependent on the presence of the HCV 5' UTR. Treatment with synthetic stabilized anti-HCV ribozymes has the potential to aid patients who are infected with HCV by reducing the viral burden through specific targeting and cleavage of the viral genome.
Making Antibodies by Phage Display Technology (1994)

Antibody fragments of predetermined binding specificity have recently been constructed from repertoires of antibody V genes, bypassing hybridoma technology and even immunization. The V gene repertoires are harvested from populations of lymphocytes, or assembled in vitro, and cloned for display of associated heavy and light chain variable domains on the surface of filamentous bacteriophage. Rare phage are selected from the repertoire by binding to antigen; soluble antibody fragments are expressed from infected bacteria; and the affinity of binding of selected antibodies is improved by mutation. The process mimics immune selection, and antibodies with many different binding specificities have been isolated from the same phage repertoire. Thus human antibody fragments have been isolated with specificities against both foreign and self antigens, including haptens, carbohydrates, secreted and cell surface proteins, viral coat proteins, and intracellular antigens from the lumen of the endoplasmic reticulum and the nucleus. Such antibodies have potential as reagents for research and in therapy.