gebhart/patrepeval huggingface dataset:
Synthesis of Sulfaphenazole Derivatives and Their Use as Inhibitors and Tools for Comparing the Active Sites of Human Liver Cytochromes P450 of the 2C Subfamily (2001)

Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH(2) and H (of the SO(2)NH function) substituents of SPA with various R(1) and R(2) groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC(50) < 1 microM) were only observed for SPA derivatives having the SO(2)NH function and a relatively small R(1) substituent (R(1) = NH(2), CH(3)). Any increase in the size of R(1) led to a moderate decrease of the affinity, and the N-alkylation of the SO(2)NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R(1) and R(2) substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R(1) substituent. One of the new compounds (R(1) = methyl, R(2) = propyl) inhibited all human CYP 2Cs with IC(50) values between 10 and 20 microM, while another one (R(1) = allyl, R(2) = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R(1) = R(2) = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R(1) = CH(3), R(2) = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R(1) = NH(2), R(2) = (CH(2))(2)CH(CH(3))(2)) appears to be particularly interesting for that purpose as its IC(50) value for CYP 2C8 is low (3 microM) and 20-fold smaller than those found for CYP 2C9 and 2C19.
Imaging of Surface Charge and the Mechanism of Desorption Electrospray Ionization Mass Spectrometry (2009)

Distributions of charge deposited on surfaces in desorption electrospray ionization mass spectrometry (DESI-MS) were investigated using a static charge measurement apparatus, which gives an output voltage proportional to the local surface charge density. By scanning the probe along the surface and taking measurements at fixed intervals, a contour image of relative charge density reflecting the charge distribution on the surface can be plotted. Through the measured charge distribution and the derived charge density gradient, the motion of charged droplets in the DESI experiment can be inferred. Measurements taken under various DESI operating conditions, including spray pressure, angle, flow rate, and sprayer tip-to-surface distance, show that charge is spread over an area of a few square centimeters under typical conditions; effective desorption occurs from a much smaller area (∼1 mm2) of highest charge density. Higher sheath gas pressures and smaller sprayer tip-to-surface distances lead to concentration of charge distribution into a smaller area, whereas smaller spray angles favor charge distribution over a larger area. The appearance of the highest charge density in front of the DESI sprayer tip and near the MS inlet suggests that charged droplets are moved toward the MS inlet by pneumatic forces and by the vacuum suction, in agreement with results of earlier simulations. The present observations are consistent with previous studies using other techniques and support the accepted droplet splashing DESI mechanism.
DOTAP (and Other Cationic Lipids): Chemistry, Biophysics, and Transfection; (2004)

Cationic lipid-mediated nucleic acid and protein delivery is becoming increasingly popular for in vitro and in vivo applications. While the chemistry of cationic lipid carriers is moving very rapidly, and more and more sophisticated molecules are being developed, it is worthwhile to look back to understand what has been achieved in the field of cationic lipids and why in some cases delivery based on cationic lipids works and in other cases it does not. For this purpose, DOTAP is one of the best candidates; it is the most widely used cationic lipid, it is relatively cheap, and it is efficient in both in vitro and in vivo applications. The vast amount of data that have accumulated on DOTAP and related molecules could provide invaluable clues to biophysical, structural, and biological mechanisms of transfection by cationic lipids. While many issues of cationic lipid transfection still remain unclear, this review will attempt to address mainly the following issues: (1) interplay of physicochemical parameters of DOTAP formulations; (2) impact of physicochemical parameters on transfection (lipofection) efficiency by cationic reagents, in vitro and in vivo; (3) structure-activity relationships of cationic lipid formulations in cell culture and in the living organism. In addition, in vivo applications of cationic lipids are reviewed, and the problems of local versus systemic administration of lipoplexes are discussed.
Direct measurement of the two-point field correlation function (1996)

The space-shift-variant two-point correlation function of a transversely spatially localized optical field of arbitrary coherence at a remote plane is measured with a novel interferometric technique. The method permits reconstruction of the correlation function by a simple resorting of the measured data. In the case of a coherent field the experimentally measured correlation function is shown to factorize, as expected, and the field amplitude and phase are also reconstructed.
The Intravaginal Slingplasty Operation, a Minimally Invasive Technique for Cure of Urinary Incontinence in the Female (1996)

The aim was to evaluate the intravaginal slingplasty operation, a minimally invasive technique for cure of urinary incontinence. Fifty-four unselected patients, aged from 26 to 79 years, mainly with mixed incontinence symptoms, underwent this procedure. It works by tightening the suburethral vagina ('hammock'), and by creating an artificial pubourethral neoligament. Where indicated, repair of uterine prolapse (24 cases), or infracoccygeal sacropexy (17 cases) was also performed. Almost all patients were discharged on the day of, or day after surgery, without requirement for postoperative catheterization, and returned to fairly normal activities, including jobs, within 7 to 14 days. At a mean follow-up time of 15 months, the cure rates for preoperative symptoms were, frequency 88%, nocturia 77%, urge incontinence 89%, stress incontinence (SI) 85%, symptoms of abnormal emptying, 77%, and reduction of mean residual urine from 67.5 mL to 32 mL. The objective cure rate (exercise pad testing) for stress incontinence was 88.6%; taking the group as a whole, urine loss was reduced from a mean of 11.6 g preoperatively to a mean of 0.5 g postoperatively. Urodynamically diagnosed detrusor instability was not a predictor of surgical failure in this study. According to the concepts presented here, symptoms of urinary dysfunction are mainly symptomatic manifestations of abnormal laxity in the vagina or its supporting ligaments. The surgical methods used to correct these defects are fairly simple, safe and easily learnt by an practising gynaecologist.
Designed Human Serum Hyaluronidase 1 Variant, HYAL1ΔL, Exhibits Activity up to pH 5.9 (2009)

Hyaluronidases from diverse species and sources have different pH optima. Distinct mechanisms with regard to dynamic structural changes, which control hyaluronidase activity at varying pH, are unknown. Human serum hyaluronidase 1 (HYAL1) is active solely below pH 5.1. Here we report the design of a HYAL1 variant that degrades hyaluronan up to pH 5.9. Besides highly conserved residues in close proximity of the active site of most hyaluronidases, we identified a bulky loop formation located at the end of the substrate binding crevice of HYAL1 to be crucial for substrate hydrolysis. The stretch between cysteine residues 207 and 221, which normally contains 13 amino acids, could be replaced by a tetrapeptide sequence of alternating glycine serine residues, thereby yielding an active enzyme with an extended binding cleft. This variant exhibited hyaluronan degradation at elevated pH. This is indicative for appropriate substrate binding and proper positioning being decisively affected by sites far off from the active center.
Integration of biaxial planar gradient coils and an RF microcoil for NMR flow imaging (2005)

A package of two planar gradient coils combined with an RF coil was microfabricated for low-field MRI measurements of velocity flow profiles. The package generates orthogonal gradients in the radial and velocity encoding directions for standard flow imaging experiments. A commercial 0.6 T superconductive magnet was used to test coil performance. For comparison flow imaging was also performed using a commercial set of gradient coils. Velocity profiles were obtained for several volumetric flow rates of water in tubes with inner diameters of 1.02 mm and 1.4 mm. Velocity resolution was 0.13 mm s−1, comparable to that achieved with commercial gradient coils. The quality of the velocity profile was sufficient for viscosity calculations, and thus permits future utilization of this coil package in the design of a portable MRI viscometer.
F-19 MR imaging of glucose metabolism in the rabbit. (1988)

Noninvasive metabolic magnetic resonance (MR) imaging reflecting glucose metabolism in the aldose-reductase-sorbitol (ARS) pathway was performed in the rabbit head; after administration of the fluorinated glucose analogue 3-fluoro-3-deoxy-D-glucose (3FD-glucose), fluorine-19 images were generated. Images of 3FD-glucose showed significant 3FD-glucose uptake by adipose tissue, indicating its buffering effects in case of excess loads of glucose. Images of 3-fluoro-3-deoxy-D-sorbitol (3FD-sorbitol) demonstrated the spatial distribution of aldose reductase activities and significant sorbitol accumulation in the lens. Images of 3-fluoro-3-deoxy-D-fructose (3FD-fructose) showed preferential uptake of fructose by muscle tissue. The extremely low toxicity of 3FD-glucose indicates promise for its clinical application in metabolic imaging.
The Predominant Mechanism by Which Ribavirin Exerts Its Antiviral Activity In Vitro against Flaviviruses and Paramyxoviruses Is Mediated by Inhibition of IMP Dehydrogenase (2005)

It is not yet clear to what extent depletion of intracellular GTP pools contributes to the antiviral activity of ribavirin. Therefore, the antiviral activities of (i) ribavirin, (ii) its 5-ethynyl analogue, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), and (iii) mycophenolic acid (MPA) (a compound that inhibits only cellular IMP dehydrogenase activity) were studied on the replication of flaviviruses and paramyxoviruses. In addition, the effects of these three compounds on intracellular GTP pools were assessed. A linear correlation was observed over a broad concentration range between the antiviral activities of ribavirin, EICAR, and MPA and the effects of these compounds on GTP pool depletion. When the 50% effective concentrations (EC50s) for the antiviral activities of ribavirin, EICAR, and MPA were plotted against the respective EC50 values for GTP pool depletion, a linear correlation was calculated. These data provide compelling evidence that the predominant mechanism of action of ribavirin in vitro against flavi- and paramyxoviruses is based on inhibition of cellular IMP dehydrogenase activity.
Functional evaluation of the genes involved in malonate decarboxylation by Acinetobacter calcoaceticus (1999)

The genomic locus containing the potential repressor gene mdcY (inactivated by a putative IS3 element) and the mdcLMACDEGBH genes from Acinetobacter calcoaceticus was cloned and sequenced. In order to evaluate the biochemical function of the protein components, the genes were expressed independently and their activities predicted by database analysis. The mdcA gene product, the alpha subunit, was found to be malonate/acetyl-CoA transferase and the mdcD gene product, the beta subunit, was found to be malonyl-CoA decarboxylase. The mdcE gene product, the gamma subunit, may play a role in subunit interaction to form a stable complex or as a codecarboxylase. The mdcC gene product, the delta subunit, was an acyl-carrier protein, which has a unique CoA-like prosthetic group. Various combinations of malonate decarboxylase subunits allowed us to estimate their contribution to malonyl-CoA decarboxylase activity. The prosthetic group was identified as carboxymethylated 2'-(5"-phosphoribosyl)-3'-dephospho-CoA by mass spectrometry. The mdcH gene product was determined to have malonyl-CoA/dephospho-CoA acyltransferase activity. Using database analysis mdcLM, mdcG, mdcB and mdcI were estimated to be the genes for a malonate transporter, a holo-acyl carrier synthase, protein for the formation of precursor of the prosthetic group and a regulatory protein, respectively. From the data shown above we propose a metabolic pathway for malonate in A. calcoaceticus.
Cognitive Carpentry: A Blueprint for How to Build a Person (1995)

From the Publisher:
In his groundbreaking new book, John Pollock establishes an outpost at the crossroads where artificial intelligence meets philosophy. Specifically, he proposes a general theory of rationality and then describes its implementation in OSCAR, an architecture for an autonomous rational agent he claims is the AI system capable of performing reasoning that philosophers would regard as epistemically sophisticated.
A sequel to Pollock's How to Build a Person, this volume builds upon that theoretical groundwork for the implementation of rationality through artificial intelligence. Pollock argues that progress in AI has stalled because of its creators' reliance upon unformulated intuitions about rationality. Instead, he bases the OSCAR architecture upon an explicit philosophical theory of rationality, encompassing principles of practical cognition, epistemic cognition, and defeasible reasoning. One of the results is the world's first automated defeasible reasoner capable of reasoning in a rich, logical environment.
Underlying Pollock's thesis is a conviction that the tenets of artifical intelligence and those of philosophy can be complementary and mutually beneficial. And, while members of both camps have in recent years grown skeptical of the very possibility of symbol processing AI, Cognitive Carpentry establishes that such an approach to AI can be successful. 
A Bradford Book
The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease (2008)

Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmic levels of beta-catenin has been observed. Apparently Abeta binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/beta-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/beta-catenin signaling, including the activation of M1 muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR alpha, gamma agonists, nicotine and some antioxidants, results in neuroprotection against Abeta. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.
Leukemia Inhibitory Factor Is an Anti-Inflammatory and Analgesic Cytokine (1998)

The mRNA for leukemia inhibitory factor (LIF), a neuroimmune signaling molecule, is elevated during skin inflammation produced by intraplantar injection of complete Freund's adjuvant (CFA). Moreover, although LIF knock-out mice display normal sensitivity to cutaneous mechanical and thermal stimulation compared with wild-type mice, the degree of CFA-induced inflammation in mice lacking LIF is enhanced in spatial extent, amplitude, cellular infiltrate, and interleukin (IL)-1beta and nerve growth factor (NGF) expression. Conversely, local injection of low doses of recombinant LIF diminishes mechanical and thermal hypersensitivity as well as the IL-1beta and NGF expression induced by CFA. These data show that upregulation of LIF during peripheral inflammation serves a key, early anti-inflammatory role and that exogenous LIF can reduce inflammatory hyperalgesia.
Air-Stable Surface-Passivated Perovskite Quantum Dots for Ultra-Robust, Single- and Two-Photon-Induced Amplified Spontaneous Emission (2015)

We demonstrate ultra-air- and photostable CsPbBr3 quantum dots (QDs) by using an inorganic-organic hybrid ion pair as the capping ligand. This passivation approach to perovskite QDs yields high photoluminescence quantum yield with unprecedented operational stability in ambient conditions (60 ± 5% lab humidity) and high pump fluences, thus overcoming one of the greatest challenges impeding the development of perovskite-based applications. Due to the robustness of passivated perovskite QDs, we were able to induce ultrastable amplified spontaneous emission (ASE) in solution processed QD films not only through one photon but also through two-photon absorption processes. The latter has not been observed before in the family of perovskite materials. More importantly, passivated perovskite QD films showed remarkable photostability under continuous pulsed laser excitation in ambient conditions for at least 34 h (corresponds to 1.2 × 10(8) laser shots), substantially exceeding the stability of other colloidal QD systems in which ASE has been observed.
Power switch characterization for fine-grained dynamic voltage scaling (2008)

Dynamic voltage scaling (DVS) provides power savings for systems with varying performance requirements. One low overhead implementation of DVS uses PMOS power switches to connect DVS blocks to one of the available V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DD</sub> supplies. While power switches have been analyzed extensively for leakage power gating, proper design of power switches for DVS is less well understood. This paper characterizes power switches for DVS in terms of V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DD</sub> -switching delay and V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DD</sub> -switching energy. We show the impact of these switching overheads on a novel fine-grained DVS architecture and present an RC model that allows fast estimation of the overhead. Measurements of a DVS multiplier and adder on a 90 nm CMOS test chip validate the model. Our model and measurements confirm that power switched DVS can provide sufficiently low overhead to give energy savings with only one clock cycle spent at a lower voltage, making this approach a flexible and enticing option for embedded portable systems.
Digital Imaging in Pathology: Whole-Slide Imaging and Beyond (2011)

Digital imaging in pathology has undergone an exponential period of growth and expansion catalyzed by changes in imaging hardware and gains in computational processing. Today, digitization of entire glass slides at near the optical resolution limits of light can occur in 60 s. Whole slides can be imaged in fluorescence or by use of multispectral imaging systems. Computational algorithms have been developed for cytometric analysis of cells and proteins in subcellular locations by use of multiplexed antibody staining protocols. Digital imaging is unlocking the potential to integrate primary image features into high-dimensional genomic assays by moving microscopic analysis into the digital age. This review highlights the emerging field of digital pathology and explores the methods and analytic approaches being developed for the application and use of these methods in clinical care and research settings.
Visual reinforcement learning for object recognition in robotics (2016)

In recent years, unmanned systems reached a maturity level that resulted in the adoption of robotic system for both civil and military usages. As the amount of unmanned systems increases, the amount of visual information that is being sent to the end user increases, and the need to develop the unmanned systems ability to autonomously alert the user on predefined events is being emphasized. This ability is mainly based on their capability to detect and classify the objects in their field of operation. Recent studies shows that the mechanism behind the recognition process in the human brain includes continuous generation of predictions based on prior knowledge about the world. These predictions enable rapid generation of hypothesis that biases the outcome of the recognition process in situation of uncertainty. In addition, the visual system continuously updating its knowledge about the world based on visual feedback. In our work, we formed an architecture that is based on the concepts behind these top-down prediction and learning processes of the human visual system, together with state of the art bottom-up object recognition models, e.g. deep CNNs. We show that imitating these top-down reinforcement learning mechanisms, together with the state of the art bottom-up feed-forward algorithm, creates an accurate and continuously improving target recognition model.
Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. (1998)

The molecular signaling events by which leptin exerts its functions in vivo are not well delineated. Here, we show a novel leptin signaling mechanism that requires phosphoinositide 3-kinase (PI 3-kinase)-dependent activation of cyclic nucleotide phosphodiesterase 3B (PDE3B) and subsequent suppression of cAMP levels. In pancreatic beta cells, leptin causes the activation of PDE3B, which leads to marked inhibition of glucagon-like peptide-1-stimulated insulin secretion. The effect of leptin is abolished when insulin secretion is induced with cAMP analogues that cannot be hydrolyzed by PDE3B. Selective inhibitors of PDE3B and PI 3-kinase completely prevent the leptin effect on insulin secretion and cAMP accumulation. The results demonstrate that one of the physiological effects of leptin, suppression of insulin secretion, is mediated through activation of PDE3B and suggest PDE3B as a mediator of leptin action in other tissues.
Forward genetics in mammaliancells: functional approaches to gene discovery (1999)

Definitive proof of function in biological systems requires genetic analysis. Only when the loss of a particular protein corresponds to the loss of a specific function can one be sure that the protein truly affects the function. Changing the pattern of gene expression through random mutagenesis or by introducing expression libraries, followed by selection of mutant or variant cells and identification of a missing or overexpressed protein, has the power to reveal or confirm the roles of specific components of signaling pathways and to provide mutant cell lines and cDNA reagents to be used in defining detailed mechanisms through structure-function analyses. These examples of forward genetics contrast with reverse genetic approaches, where the function of a known gene product is explored by knockout or replacement. Here we review a broad range of techniques that have been used to alter gene expression randomly in mammalian cells, with examples of specific discoveries that have resulted from these applications of forward genetics.