gebhart/patrepeval huggingface dataset:
Polyproline-Rod Approach to Isolating Protein Targets of Bioactive Small Molecules:  Isolation of a New Target of Indomethacin (2007)

Identification of protein targets of bioactive small molecules has been a technical hurdle of chemical genetics. Here we report a polyproline-rod approach to isolating protein targets of small molecules from cell lysates. The results indicate that insertion of a long, rigid polyproline helix between a small-molecule bait and a biotin tag boosts the capacity of affinity purification and thereby permits isolation of low-abundance or low-affinity proteins. In the course of the proof-of-concept experiments, we isolated glyoxalase 1 (GLO1) as a new target of indomethacin, a widely used antiinflammatory drug. Molecular biological experiments suggest that inhibition of GLO1 enzyme activity is related to the clinically recognized beneficial side effects of the indomethacin family of nonsteroidal antiinflammatory drugs.
Increasing the Functional Residual Capacity May Reverse Obstructive Sleep Apnea (1988)

We describe the reversal of obstructive sleep apnea with a 0.5 L increase in the functional residual capacity (FRC) in a patient with sleep apnea syndrome. The patient had been treated with medroxyprogesterone acetate for 8 months. The increase in FRC was obtained by applying a constant negative extrathoracic pressure (NEP) with a poncho-type respirator. With pulmonary inflation, there was a dramatic decrease in the apnea index and the percent apnea time, and an improvement in sleep architecture. At all sleep stages, the desaturation duration was shorter with NEP. The exact mechanisms by which pulmonary expansion improved sleep apnea in this patient remain unclear; lung volume dependence of upper airway patency and the improvements in apnea-induced desaturation may be contributing factors. Our observation illustrates that lung volumes may be an important factor in the pathophysiology of obstructive sleep apnea, especially in the apnea onset and in the apneic-induced desaturation.
Signaling Role of Intracellular Iron in NF-κB Activation (2003)

Iron chelators inhibit endotoxin-induced NF-kappaB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-kappaB activation. The present study tested this hypothesis. Analysis of Fe(59)-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low molecular weight (LMW).Fe(59) complex ([LMW.Fe](i)) at </=2 min returning to the basal level within 15 min. The [LMW.Fe](i) response preceded IkappaB kinase (IKK) (>/=15 min) and NF-kappaB (>/=30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxypyridin-4-one and N,N'-bis-2-hydroxybenzylethylenediamine-N,N'-diacetic acid) abrogated the [LMW.Fe](i) response and IKK and NF-kappaB activation. The [LMW.Fe](i) response was also observed in tumor necrosis factor alpha (TNFalpha)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-gamma but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFalpha. Both [LMW.Fe](i) response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-containing oxidases), l-N(6)-(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant negative mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of (.)NO and O(2)() in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO(-), 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO(-) alone induced both [LMW.Fe](i) response and IKK activation. Finally, direct addition of ferrous iron to cultured HMs activated IKK and NF-kappaB. These results support a novel signaling role for [LMW.Fe](i) in IKK activation, which appears to be induced by ONOO(-) and selectively operative in macrophages.
Biological and serological characterization of Campylobacter jejuni lipopolysaccharides with deviating core and lipid A structures (1995)

Lipopolysaccharides from Campylobacter jejuni were tested for their ability to induce toxic lethality in galactosamine-sensitized mice, pyrogenicity in rabbits and tumour necrosis factor (TNF) secretion from mouse peritoneal macrophages. Compared with those of Salmonella LPS, lethal toxicity was 50% lower, pyrogenicity was 30- to 50-fold lower, and ability to induce TNF was 100-fold lower. C. jejuni LPS and lipid A exhibited higher phase-transition temperatures than those of Salmonella preparations, and thus the former have lower fluidity at 37°C. This lower fluidity of acyl chains may influence the biological activities of C. jejuni LPS, but acyl chain characteristics and diaminoglucose replacing glucosamine in the hydrophilic lipid A backbone may also influence the supramolecular structure of lipid A, thereby affecting biological activities. Although diaminoglucose is present in the backbone of C. jejuni lipid A, antigenically the latter resembled classical lipid A of the Enterobacteriaceae when tested with anti-lipid A antibodies. Chemical investigations suggested the presence of glucuronic acid in an acid labile linkage in the inner core region, thus producing a structurally unusual region in C. jejuni LPS.
A Novel FRP-Concrete Composite Construction for the Infrastructure (1995)

A novel composite column is proposed that is similar to the classic concrete-filled steel tubes, except that steel has been replaced with Fiber Reinforced Plastic (FRP) shapes. The FRP tube, while an integral part of the structure, is also the pour form for concrete. The tube may be a filament-wound pipe or a multi-layer FRP shape with a layer of longitudinal fibers sandwiched between two layers of circumferential fibers. The principle behind the proposed system is the same as in fiber-wrapping practice where concrete core is both protected and confined by a fiber jacket. A new passive confinement model is proposed for external confinement of concrete columns with fiber-wraps or FRP tubes. The model accounts for the varying lateral expansion of concrete (Poisson's effect), and the non-ductile behavior of fiber composites. Results are compared with recent studies of fiber-wrapped columns.
High-molecular-weight kininogen is exclusively membrane bound on endothelial cells to influence activation of vascular endothelium (1995)

An important biologic function of high-molecular-weight kininogen (HK) is to deliver bradykinin (BK) to its cellular receptors. Internalization and degradation of HK may provide a mechanism by which endothelial cells modulate the production of BK and control its activities. Therefore, we investigated the binding and subsequent distribution of biotinylated-HK (biotin-HK) associated with human umbilical vein endothelial cells (HUVEC). HUVEC bound 3 to 4 times more HK and with greater avidity at 1 to 3 hours at 37 degrees C than at 4 degrees C (Bmax = 1.0 +/- 0.02 x 10(7) molecules/cell, kd = 7 +/- 3 nmol/L v Bmax = 2.6 +/- 0.2 x 10(6) molecules/cell, kd = 46 +/- 8 nmol/L). However, there was no evidence that the difference was caused by internalization of HK at the higher temperature. First, the same amount of biotin-HK was associated with nonpermeabilized and permeabilized HUVEC using buffers containing 20 to 50 mumol/L zinc ion in the absence or presence of 2 mmol/L calcium ion. Second, binding of biotin-HK to HUVEC was approximately 92% reversible at 1 hour when the cells were maintained at both 37 degrees C and 4 degrees C. Third, neither chloroquine nor primaquine altered the amount of biotin-HK bound to HUVEC. Fourth, biotin-HK bound to HUVEC was almost completely removed by pronase. Fifth, the nonpermeable dye, crystal violet, almost completely quenched the fluorescence signal emitted by HUVEC-associated fluorescein isothiocyanate (FITC) HK. Finally, the localization of HUVEC-bound FITC-HK was restricted to the membrane as shown by laser scanning confocal microscopy. The expression of HK binding sites had an absolute requirement for metabolic energy, but was not dependent on new protein synthesis. Membrane-bound HK contributed to the anticoagulant nature of endothelial cells by blocking human alpha-thrombin binding and its resultant induction of prostacyclin formation. These studies indicate that HK is not internalized by HUVEC, but remains primarily on cell surfaces to be accessible for BK liberation and to modulate the binding and actions of alpha-thrombin.
Current status of immunotherapy (2016)

The successful use of immune checkpoint inhibitors has been big breakthrough in the development of cancer immunotherapy. Anti-CTLA-4 monoclonal antibody, ipilimumab, is the first-approved immune checkpoint inhibitor and has shown durable objective responses for advanced melanoma beyond the effect of dacarbazine. Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, are other immune checkpoint inhibitors that have demonstrated more effective results than conventional drugs in clinical trials for a variety of advanced solid tumors including melanoma, non-small cell lung carcinoma and renal carcinoma. These studies have indicated that the enhancement of anti-cancer immunity by controlling the immune suppressive environment in cancer tissues is an important issue for the development of cancer immune-therapy. Accordingly, in recent years, the enthusiasm for research of cancer immunology has shifted to studies regarding the formation of the immune suppressive environment, immune suppression mechanisms in cancer tissues and the molecules and cells involved in these pathways. Novel findings from these studies might lead to the development of cancer immunotherapy based on control of the immune suppressive environment.
Factored axis-aligned filtering for rendering multiple distribution effects (2014)

Monte Carlo (MC) ray-tracing for photo-realistic rendering often requires hours to render a single image due to the large sampling rates needed for convergence. Previous methods have attempted to filter sparsely sampled MC renders but these methods have high reconstruction overheads. Recent work has shown fast performance for individual effects, like soft shadows and indirect illumination, using axis-aligned filtering. While some components of light transport such as indirect or area illumination are smooth, they are often multiplied by high-frequency components such as texture, which prevents their sparse sampling and reconstruction. We propose an approach to adaptively sample and filter for simultaneously rendering primary (defocus blur) and secondary (soft shadows and indirect illumination) distribution effects, based on a multi-dimensional frequency analysis of the direct and indirect illumination light fields. We describe a novel approach of factoring texture and irradiance in the presence of defocus blur, which allows for pre-filtering noisy irradiance when the texture is not noisy. Our approach naturally allows for different sampling rates for primary and secondary effects, further reducing the overall ray count. While the theory considers only Lambertian surfaces, we obtain promising results for moderately glossy surfaces. We demonstrate 30x sampling rate reduction compared to equal quality noise-free MC. Combined with a GPU implementation and low filtering over-head, we can render scenes with complex geometry and diffuse and glossy BRDFs in a few seconds.
Function-Blocking ERBB3 Antibody Inhibits the Adaptive Response to RAF Inhibitor (2014)

ERBB3/HER3 expression and signaling are upregulated in mutant BRAF melanoma as an adaptive, prosurvival response to FDA-approved RAF inhibitors. Because compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, cotargeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here, we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 activation of ERBB3 and downstream signaling in RAF-inhibited melanoma cells. Targeting mutant BRAF in combination with huHER3-8 decreased cell proliferation and increased cell death in vitro, and decreased tumor burden in vivo, compared with targeting either mutant BRAF or ERBB3 alone. Furthermore, the likelihood of a durable tumor response in vivo was increased when huHER3-8 was combined with RAF inhibitor PLX4720. Together, these results offer a preclinical proof of concept for the application of ERBB3-neutralizing antibodies to enhance the efficacy of RAF inhibitors in melanoma to delay or prevent tumor regrowth. As ERBB3 is often upregulated in response to other kinase-targeted therapeutics, these findings may have implications for other cancers as well.
Multiple Functions of the Douglas Fir Beetle Pheromone 3-Methyl-2-Cyclohexen-1-0ne1,2 (1973)

The known differences in response by Dendroctonus pseudotsugae Hopkins to its pheromone 3-methyl-2-cyclohexen-1-one (MCH) correspond with differences in concentration of the substance. When combined with other pheromones of D. pseudotsugae and host-plant volatiles, a low concentration of MCH elicits increased arrestment and stridulation of males and increased flight attraction of both sexes, whereas a high concentration of MCH inhibits the normal positive response of both sexes to these other pheromones and host plant volatiles. Since differential release of MCH apparently occurs during natural beetle behavior, these effects are suggested as multiple functions of the pheromone.
Optical brain imaging in vivo: techniques and applications from animal to man (2007)

Optical brain imaging has seen 30 years of intense development, and has grown into a rich and diverse field. In-vivo imaging using light provides unprecedented sensitivity to functional changes through intrinsic contrast, and is rapidly exploiting the growing availability of exogenous optical contrast agents. Light can be used to image microscopic structure and function in vivo in exposed animal brain, while also allowing noninvasive imaging of hemodynamics and metabolism in a clinical setting. This work presents an overview of the wide range of approaches currently being applied to in-vivo optical brain imaging, from animal to man. Techniques include multispectral optical imaging, voltage sensitive dye imaging and speckle-flow imaging of exposed cortex, in-vivo two-photon microscopy of the living brain, and the broad range of noninvasive topography and tomography approaches to near-infrared imaging of the human brain. The basic principles of each technique are described, followed by examples of current applications to cutting-edge neuroscience research. In summary, it is shown that optical brain imaging continues to grow and evolve, embracing new technologies and advancing to address ever more complex and important neuroscience questions.
Synthesis and anti-HIV Activity of New Fused Chromene Derivatives Derived from 2-Amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2- c]chromene-3-carbonitrile (2013)

A new series of pyrano-chromene and pyrimido pyrano-chromene derivatives were synthesized starting from 2-amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (6). The structures of the synthesized compounds were elucidated by spectral data. Compounds 6-11, 13-15 and 18 have been selected for an inhibitory activity screening against HIV-1 and HIV-2 in MT-4 cells.
Retention of cleaved synaptosome-associated protein of 25 kDa (SNAP-25) in neuromuscular junctions: a new hypothesis to explain persistence of botulinum A poisoning (1999)

Botulinum neurotoxins can block neurotransmitter release for several months. The molecular mechanism of these toxins' action is known, but the persistence of neuromuscular paralysis that they cause is unexplained. At frog neuromuscular junctions, application of botulinum toxin type A caused paralysis and reduced the C-terminus immunoreactivity of SNAP-25, but not that of the remaining N-terminus fragment. Botulinum toxin type C caused paralysis and reduced syntaxin immunoreactivity without affecting that of SNAP-25. Co-application of botulinum A and C reduced syntaxin immunoreactivity, and that of both C and N termini of SNAP-25. Application of hydroxylamine to de-palmitoylate SNAP-25 resulted in a slight reduction of the immunoreactivity of SNAP-25 N terminus, while it had no effect on immunoreactivity of botulinum A cleaved SNAP-25. In contrast, application of hydroxylamine to nerve terminals where syntaxin had been cleaved by botulinum C caused a considerable reduction in SNAP-25 N-terminus immunoreactivity. Hence the retention of immunoreactive SNAP-25 at the neuromuscular junction depends on its interactions with syntaxin and plasma membrane. Persistence of cleaved SNAP-25 in nerve terminals may prevent insertion of new SNAP-25 molecules, thereby contributing to the longevity of botulinum A effects.Key words: SNAP receptor, neurotoxin, dystonia, botulism, torticollis.
Size and Surface Functionalization of Iron Oxide Nanoparticles Influence the Composition and Dynamic Nature of Their Protein Corona (2014)

Nanoparticles (NPs) adsorb proteins when in the biological matrix, and the resulted protein corona could affect NP-cell interactions. The corona has a dynamic nature with the adsorbed proteins constantly exchanging with the free proteins in the matrix at various rates. The rapidly exchanging proteins compose the soft corona, which responds more dynamically to environment changes than the hard corona established by the ones with slow exchange rates. In the present study, the corona formed on the superparamagnetic iron oxide NPs (SPIONs) in human serum was studied by flow field-flow fractionation and ultracentrifugation, which rapidly differentiated the corona proteins based on their exchange rates. By varying the surface hydrophobicity of the SPIONs with a core size around 10 nm, we found out that, the more hydrophobic surface ligand attracted proteins with higher surface hydrophobicity and formed a more dynamic corona with a larger portion of the involved proteins with fast exchange rates. Increasing the core diameter of the SPIONs but keeping the surface ligand the same could also result in a more dynamic corona. A brief investigation of the effect on the cellular uptake of SPIONs using one selected corona protein, transferrin, was conducted. The result showed that, only the stably bound transferrin could significantly enhance cellular uptake, while transferrin bound in a dynamic nature had negligible impact. Our study has led to a better understanding of the relationship between the particle properties and the dynamic nature of the corona, which can help with design of nanomaterials with higher biocompatibility and higher efficacy in biosystems for biomedical applications.
Catecholamines and pinealectomy-induced convulsions in the gerbil (Meriones unguiculatus). (1982)

Within three hours after surgery nine out of ten pineal-ectomized gerbils will convulse; dopamine (DA) levels in the telencephalon of the gerbils do not change after pinealectomy (PX), however, norepinephrine (NE) concentrations decrease in the telencephalon from 1-12 hours after PX (Philo and Reiter, 1980). Administration of L-dihydroxyphenylalanine (L-DOPA, 50 mg/kg) will prevent the convulsions and maintain normal levels of norepinephrine. Administration of alpha-methyl-p-tyrosine (alpha MPT, 250 mg/kg), a tyrosine hydroxylase inhibitor, increases the number of convulsions. Injections of L-DOPA counter the facilitatory actions of alpha MPT on PX-induced convulsions. Studies with the monoamine oxidase inhibitor pargyline indicate a decrease in production of norepinephrine after PX in the gerbil. The diminished levels of neurotransmitter apparently facilitate the onset of convulsions caused by the epileptogenic stimulus of PX.
Fc gamma R(CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. Role of Ca2+ in Fc gamma R(CD16)-induced transcription and expression of lymphokine genes. (1989)

In this study, we present evidence that interaction of Fc gamma R(CD16) with ligands (immune complexes or anti-CD16 antibodies) induces a rapid rise in [Ca2+]i and fast production of both inositol 1,4,5 triphosphate (IP3) and IP4 in homogeneous NK cell preparations. Part of the initial [Ca2+]i rise observed upon stimulation of NK cells with either anti-CD16 antibodies alone or after their crosslinking at the cell membrane depends on Ca2+ mobilization from intracellular stores, but sustained [Ca2+]i levels are maintained, after the initial spike, through influx of extracellular Ca2+. The [Ca2+]i rise is mediated, at least in part, by increases in IP3 after receptor-induced hydrolysis of membrane polyphosphoinositides (PPI). The role of extracellular Ca2+ in Fc gamma R(CD16)-dependent induction of lymphokine gene expression has been tested by evaluating production, mRNA accumulation and transcription of IFN-gamma and TNF in NK cells stimulated with Fc gamma R(CD16) ligands and/or rIL-2 in the presence of EGTA. Under these conditions, accumulation and transcription of both IFN-gamma and TNF mRNA induced by CD16 ligands, but not that induced by rIL-2, is completely abolished and neither cytokine can be detected at significant levels in the supernatant fluids of cells so treated. These data confirm that NK cell activation by specific ligands occurs through mechanisms distinct from those induced by IL-2, and indicate that extracellular Ca2+ represents a stringent requirement for cytokine production induced in NK cells through specific (Fc gamma R) stimulation. Our data also indicate that the [Ca2+]i rise induced upon Fc gamma R(CD16) crosslinking, though necessary, is not sufficient per se to induce activation of lymphokine genes, compatible with the hypothesis that Fc gamma R(CD16) crosslinking generates additional transducing signals that synergize with IL-2 to maximally activate NK cells.
Qubit-Assisted Transduction for a Detection of Surface Acoustic Waves near the Quantum Limit (2017)

We demonstrate ultrasensitive measurement of fluctuations in a surface-acoustic-wave (SAW) resonator using a hybrid quantum system consisting of the SAW resonator, a microwave (MW) resonator, and a superconducting qubit. The nonlinearity of the driven qubit induces parametric coupling, which up-converts the excitation in the SAW resonator to that in the MW resonator. Thermal fluctuations of the SAW resonator near the quantum limit are observed in the noise spectroscopy in the MW domain.
Coalbed Methane Production (1993)

Coal, "the black rock that burns," is the subject of song, story, and legend. The earliest literature citation of coal (combustible bodies, some of which by inference must be coal) is credited to Aristotle in his treatise "Meteorology," which may date near the middle of the fourth century B.C. Theophrastus, a student of Aristotle, at what is probably a slightly later date provides descriptions of different forms of coal based on their behavior in combustion, identifies areas of occurrence, and states that it was used by smiths (footnote by Hoover to Agricola, 1556).Though the Greek philosophers are responsible for the earliest known literature citations, China and perhaps other parts of eastern Asia are usually believed to have preceded the Mediterranean area in recognition of coal as a peculiar material with usable properties. Inouye (1913) states that although there is no authentic record of the history of the Fu-shun coal field in southern Manchuria, "it is said that the coal was used as fuel … for copper smelting in times as remote as 2,000 or even 3,000 years ago."Fires through most of man's history have been fed by "traditional fuels"—wood, straw, dung, and other plant materials. That coal could be of complementary usage is recorded in the remains of funeral pyres in Wales, dated about 3,000 years ago (Lindbergh and Proverse, 1977). However, the versatility of coal was not widely appreciated, and the discovery and use of charcoal satisfied most needs of primitive metal-working.By the end of the