gebhart/patrepeval huggingface dataset:
5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines:  A Novel Class of Nonsteroidal Human Progesterone Receptor Agonists (1998)

The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
Distances between active site probes in glutamine synthetase from Escherichia coli: fluorescence energy transfer in free and in stacked dodecamers (1986)

Probes for fluorescence energy transfer measurements were introduced into active sites of dodecameric glutamine synthetase from Escherichia coli by substituting appropriate ATP analogues for ATP in the autoinactivation reaction of this enzyme with L-Met-(S)-sulfoximine and Mn2+ [Maurizi, M. R., & Ginsburg, A. (1986) Biochemistry (preceding paper in this issue)]. Two fluorescent donors, 8-mercapto-ATP alkylated with either 5-[[[(iodoacetyl)amino]ethyl]amino]naphthalene-1-sulfonic acid (AEDANS-ATP) or 1,N6-etheno-2-aza-ATP (aza-epsilon-ATP), and two acceptors, 6-mercaptopurine ribonucleotide triphosphate or 8-mercapto-ATP alkylated with the chromophore 4'-[[4-(dimethylamino)-phenyl]azo]-2-iodoacetanilide (6-Y- or 8-Y-ATP), were used. Fluorescence emissions of enzyme derivatives with 1 or 2 equiv of fluorescent donor per dodecamer and either an acceptor (Y) or ADP at the remaining active sites were compared at pH 7.0. The results, together with the known geometry of the enzyme, indicate that active site probes in the dodecamer are widely separated and that energy transfer occurs from a single donor to two or three acceptors on adjacent subunits. The calculated distance between equidistant active site probes on heterologously bonded subunits within the same hexagonal ring is 56-60 A. Probes on isologously bonded subunits are no closer than 60 A and may be as far apart as 78 A. Thus, active sites are away from the 6-fold axis of symmetry toward the outer edges of the dodecamer and are located greater than or equal to 30 A from the plane separating the hexagonal rings. During Zn2+-induced stacking of the same enzyme derivatives along the 6-fold axes of symmetry, additional quenches of fluorescent probes were dependent on the presence of acceptors on separate dodecamers. The Zn2+-induced face to face aggregation of dodecamers in the presence of 46 microM ZnCl2 and 9 mM MgCl2 at pH 7.0 had an Arrhenius activation energy of 22.3 +/- 0.2 kcal/mol and a second-order rate constant at 25 degrees C of approximately 10(5) M-1 s-1 at early stages. Time-dependent fluorescence quenches correlated well with the degree of linear polymer formation and reached maximum values of 47-70% quench when the average n-mer was six dodecamers. After correction for unquenched polymer ends, a fluorescent donor and an acceptor probe in layered dodecamers were estimated to be approximately 36 A apart--an average value if there is some twisting of single strands.(ABSTRACT TRUNCATED AT 400 WORDS)
Mapping Maize Sequences to Chromosomes Using Oat-Maize Chromosome Addition Materials, (2001)

Oat- (Avena sativa) maize (Zea mays) chromosome additions are produced by crossing maize and oat. During early embryo development maize chromosomes are preferentially eliminated, and oat plants are often recovered that retain a single maize chromosome. Each of the 10 maize chromosomes recently has been isolated as a separate oat-maize addition. We describe here the mapping of 400 maize sequences to chromosomes using polymerase chain reaction and DNA from the oat-maize addition material. Fifty of the sequences were from cloned markers that had been previously mapped by linkage analysis, and our results were consistent with those obtained using Southern-blot analysis. Previously unmapped expressed sequence tags and sequence tagged sites (350) were mapped to chromosomes. Maize gene sequences and expression data are rapidly being accumulated. Coupling this information with positional information from high throughput mapping programs provides plant biologists powerful tools for identifying candidate genes of interest.
Botulinum toxin. From poison to medicine. (1993)

Although thousands of people in the world each year continue to be poisoned with botulinum toxin-food-borne, infantile, or wound botulism-the neurotoxin is now sufficiently understood to allow it to be used as a medicinal agent to paralyze specific muscles, giving temporary symptomatic relief from a variety of dystonic neurologic disorders. I review some of the epidemiologic, clinical, and pathophysiologic aspects of botulinum toxin and how the neurotoxin may act as a poison or a medicine.
Conversion of the Alzheimer's beta-amyloid precursor protein (APP) Kunitz domain into a potent human neutrophil elastase inhibitor. (1991)

Site-specific mutagenesis techniques have been used to construct active site variants of the Kunitz-type protease inhibitor domain present in the Alzheimer's beta-amyloid precursor protein (APP-KD). Striking alteration of its protease inhibitory properties were obtained when the putative P1 residue, arginine, was replaced with the small hydrophobic residue valine. The altered protein was no longer inhibitory toward bovine pancreatic trypsin, human Factor XIa, mouse epidermal growth factor-binding protein, or bovine chymotrypsin, all of which are strongly inhibited by the unaltered APP-KD (Sinha, S., Dovey, H. F., Seubert, P., Ward, P. J., Blacher, R. W., Blaber, M., Bradshaw, R. A., Arici, M., Mobley, W. C., and Lieberburg, I. (1990) J. Biol. Chem. 265, 8983-8985). Instead, the P1-Val-APP-KD was a potent inhibitor of human neutrophil elastase, with a Ki = 0.8 nM, as estimated by the inhibition of the activity of human neutrophil elastase measured using a chromogenic substrate. It also inhibited the degradation of insoluble elastin by the enzyme virtually stoichiometrically. Replacement of the P1' (Ala) and P2' (Met) residues of P1-Val-MKD with the corresponding residues (Ser, Ile) from alpha 1-proteinase inhibitor resulted in an inactive protein, underscoring the mechanistic differences between the serpins from the Kunitz-type protease inhibitor family. These results confirm the importance of the P1 arginine residue of APP-KD in determining inhibitory specificity, and are also the first time that a single amino acid replacement has been shown to generate a specific potent human neutrophil elastase inhibitor from a human KD sequence.
The potential neural mechanisms of acute indirect vibration. (2011)

There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception suggesting neural enhancement. Nevertheless, the neural mechanism(s) of vibration and its potentiating effect have received little attention. One proposal suggests that spinal reflexes enhance muscle contraction through a reflex activity known as tonic vibration stretch reflex (TVR), which increases muscle activation. However, TVR is based on direct, brief, and high frequency vibration (>100 Hz) which differs to indirect vibration, which is applied to the whole body or body parts at lower vibration frequency (5-45 Hz). Likewise, muscle tuning and neuromuscular aspects are other candidate mechanisms used to explain the vibration phenomenon. But there is much debate in terms of identifying which neural mechanism(s) are responsible for acute vibration; due to a number of studies using various vibration testing protocols. These protocols include: different methods of application, vibration variables, training duration, exercise types and a range of population groups. Therefore, the neural mechanism of acute vibration remain equivocal, but spinal reflexes, muscle tuning and neuromuscular aspects are all viable factors that may contribute in different ways to increasing muscular performance. Additional research is encouraged to determine which neural mechanism(s) and their contributions are responsible for acute vibration. Testing variables and vibration applications need to be standardised before reaching a consensus on which neural mechanism(s) occur during and post-vibration. Key pointsThere is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception, but little attention has been given to the neural mechanism(s) of acute indirect vibration.Current findings suggest that acute vibration exposure may cause a neural response, but there is little consensus on identifying which neural mechanism(s) are specifically responsible. This is due to a number of studies using various vibration testing protocols (i.e.varying frequencies, amplitudes, durations, and methods of application).Spinal reflexes, muscle tuning and neuromuscular aspects and central motor command are all viable neuromechanical factors that may contribute at different stages to transiently increasing muscular performance.Additional research is encouraged to determine when (pre, during and post) the different neural mechanism(s) respond to direct and indirect vibration stimuli.
A Bayesian approach to digital matting (2005)

This paper proposes a new Bayesian framework for solving the matting problem, i.e. extracting a foreground element from a background image by estimating an opacity for each pixel of the foreground element. Our approach models both the foreground and background color distributions with spatially-varying sets of Gaussians, and assumes a fractional blending of the foreground and background colors to produce the final output. It then uses a maximum-likelihood criterion to estimate the optimal opacity, foreground and background simultaneously. In addition to providing a principled approach to the matting problem, our algorithm effectively handles objects with intricate boundaries, such as hair strands and fur, and provides an improvement over existing techniques for these difficult cases.
Integrated-optic acoustically-tunable filters for WDM networks (1990)

The background needed to understand the integrated-optic collinear acoustically tunable optical filters (ATOFs) and the fabrication and performance of both simple and multielement acoustooptic tunable filters is presented. The most important sources of crosstalk between channels simultaneously selected by a single device are discussed. ATOFs have the combined virtues of narrow passband (subnanometer bandwidth), broad tuning range (hundreds of nanometers have been demonstrated), and simultaneous independent multiple-channel filtering. The theory and practice of collinear integrated optic acoustooptic filters is presented. Devices which involve higher-order integration are discussed, including multiple-state filters for enhanced sidelobe suppression and polarization-independent configurations. Various sources of interchannel crosstalk are derived and demonstrated in multiwavelength filtering experiments.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Computational studies and peptidomimetic design for the human p53–MDM2 complex (2004)

The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6--8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a beta-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.
IL‐6 and IL‐1β in Fever: Studies Using Cytokine‐Deficient (Knockout) Micea (1998)

Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.
Analysis and Purification of Human Lymphoblastoid (Namalwa) Interferon Using a Monoclonal Antibody (1982)

Highly purified interferon-alpha (IFN-alpha) prepared from a human lymphoblastoid line (Namalwa) was analysed by gel filtration and polyacrylamide gel electrophoresis (PAGE). Gel filtration separated the IFN-alpha into two peaks (A and B). All the components of peak A were retained by a monoclonal antibody (NK2) column, but some of those from peak B were not retained. The IFN that was not bound was active on mouse cells and could be resolved into two major bands by PAGE. The bound fraction (about 75% of the interferon protein) was purified by means of the monoclonal antibody column, although complete purification of crude interferon was not achieved in one passage.
Lattice Model of Polymer Melt Intercalation in Organically-Modified Layered Silicates (1997)

A mean-field, lattice-based model of polymer melt intercalation in organically-modified mica-type silicates (OLS) has been developed. In general, an interplay of entropic and energetic factors determines the outcome of polymer intercalation. Free energy curves and their dependence on energetic and entropic factors suggest three possible equilibrium statesimmiscible, intercalated, and exfoliatedall of which have been experimentally observed. The entropic penalty of polymer confinement may be compensated for by the increased conformational freedom of the surfactant chain as the layers separate. When the total entropy change is small, small changes in the system's internal energy will determine if intercalation is thermodynamically possible. Complete layer separation, though, depends on the establishment of very favorable polymer−OLS interactions to overcome the penalty of polymer confinement. For alkylammonium-modified layered silicates, a favorable energy change is accentuated by maximizing the magnitude and number of favorable polymer−surface interactions while minimizing the magnitude and number of unfavorable apolar interactions between the polymer and the functionalizing alkyl surfactants.
COX-2 Inhibitory Effects of Naturally Occurring and Modified Fatty Acids (2001)

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.
Targeting the Epigenome in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease (2009)

Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases activates inflammatory genes, whereas histone deacetylation results in inflammatory gene repression. Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes, but mainly by recruiting histone deacetylase-2 (HDAC2) to activated inflammatory genes. HDAC2 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma. In chronic obstructive pulmonary disease (COPD), there is resistance to the antiinflammatory actions of corticosteroids, which is explained by reduced activity and expression of HDAC2. This can be reversed by a plasmid vector, which restores HDAC2 levels, but may also be achieved by low concentrations of theophylline. Oxidative stress causes corticosteroid resistance by reducing HDAC2 activity and expression by activation of phosphoinositide-3-kinase-delta, resulting in HDAC2 phosphorylation via a cascade of kinases. Theophylline reverses corticosteroid resistance by directly inhibiting oxidant-activated PI3Kdelta and is mimicked by PI3Kdelta knockout or by selective inhibitors. Other treatments may also interact in this pathway, making it possible to reverse corticosteroid resistance in patients with COPD, as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate. Other histone modifications, including methylation, tyrosine nitration, and ubiquitination may also affect histone function and inflammatory gene expression, and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies, particularly in corticosteroid-resistant inflammation.
Mutually Interpenetrating Sheets and Channels in the Extended Structure of [Cu(4,4′‐bpy)Cl] (1995)

Bis-monodentate 4,4′-bipyridine ligands link μ2-chloro-bridged Cu1 dimers to form an extended structure containing channels that are of comparable size to those in some zeolites (drawing on the right; dark spheres, Cu; large shaded spheres, Cl).
Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis (2002)

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta cell mass via activation of beta cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of beta-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of beta cell mass in vivo.
Stir bar sorptive extraction (SBSE), a novel extraction technique for aqueous samples: Theory and principles (1999)

The theory and practice of a novel approach for sample enrichment, namely the application of stir bars coated with the sorbent polydimethylsiloxane (PDMS) and referred to as stir bar sorptive extraction (SBSE) are presented. Stir bars with a length of 10 and 40 mm coated with 55 and 219 μL of PDMS liquid phase, respectively were applied. The 10-mm stir bars are best suited for stirring sample volumes from 10 up to 50 mL whereas 40-mm stir bars are more ideal for sample volumes up to 250 mL. Depending on sample volume and the stirring speed, typical stirring times for equilibration are between 30 and 60 min. The performance of SBSE is illustrated with the analysis of volatile and semivolatile micropollutants from aqueous samples. Detection limits using mass selective detection are in the low ng/L range for a wide selection of analytes from the EPA priority pollutant lists including analytes ranging in volatility from 1,1,1-trichloroethane to chrysene. For the extraction of selected compounds from 200-mL samples, detection limits below 0.1 ng/L are reached in the selected ion monitoring mode. A comparison between SBSE and solid-phase microextraction is made. ©1999 John Wiley & Sons, Inc. J Micro Sep 11: 737–747, 1999