gebhart/patrepeval huggingface dataset:
Structural Insights into Novel 15-Prostaglandin Dehydrogenase Inhibitors (2021)

We discovered SW033291 in a high throughput chemical screen aimed at identifying 15-prostaglandin dehydrogenase (15-PGDH) modulators. The compound exhibited inhibitory activity in in vitro biochemical and cell-based assays of 15-PGDH activity. We subsequently demonstrated that this compound, and several analogs thereof, are effective in in vivo mouse models of bone marrow transplant, colitis, and liver regeneration, where increased levels of PGE2 positively potentiate tissue regeneration. To better understand the binding of SW033291, we carried out docking studies for both the substrate, PGE2, and an inhibitor, SW033291, to 15-PGDH. Our models suggest similarities in the ways that PGE2 and SW033291 interact with key residues in the 15-PGDH-NAD+ complex. We carried out molecular dynamics simulations (MD) of SW033291 bound to this complex, in order to understand the dynamics of the binding interactions for this compound. The butyl side chain (including the sulfoxide) of SW033291 participates in crucial binding interactions that are similar to those observed for the C15-OH and the C16-C20 alkyl chain of PGE2. In addition, interactions with residues Ser138, Tyr151, and Gln148 play key roles in orienting and stabilizing SW033291 in the binding site and lead to enantioselectivity for the <i>R</i>-enantiomer. Finally, we compare the binding mode of (<i>R</i>)-S(O)-SW033291 with the binding interactions of published 15-PGDH inhibitors.
L-Arginine for the Treatment of Centrally Obese Subjects: A Pilot Study (2014)

L-Arginine may be effective at reducing central adiposity in obese patients.
Development of a Thermogelling Ophthalmic Formulation of Cysteine (2006)

Preliminary studies carried out with cysteine 2% solution showed that pH adjusted to isoelectrical pH (i.e., 4.9) led to enhance stability during autoclaving and ensured no significant degradation during at least 14 days if stored at 2-8 degrees C protected from light. Optimized formulations combined either cysteine(2%)/Poloxamer407(16.5%) or cysteine(2%)/Poloxamer407(20%)/Poloxamer188(5%) and were characterized by an adequate temperature of gelification (TG) (25.9 degrees C and 26.9 degrees C, respectively), an important gel strength (5.1daN and 5.3daN, respectively) and a drastic increase in the apparent viscosity between 24 degrees C and 32 degrees C (multiplication factor of 78 and 77-fold, respectively). Cysteine addition produced only slight but significant decrease in temperature of gelification and increase in gel strength.
Segmentation of the Face and Hands in Sign Language Video Sequences Using Color and Motion Cues (2004)

We present a hand and face segmentation methodology using color and motion cues for the content-based representation of sign language video sequences. The methodology consists of three stages: skin-color segmentation; change detection; face and hand segmentation mask generation. In skin-color segmentation, a universal color-model is derived and image pixels are classified as skin or nonskin based on their Mahalanobis distance. We derive a segmentation threshold for the classifier. The aim of change detection is to localize moving objects in a video sequences. The change detection technique is based on the F test and block-based motion estimation. Finally, the results from skin-color segmentation and change detection are analyzed to segment the face and hands. The performance of the algorithm is illustrated by simulations carried out on standard test sequences.
Adaptive name matching in information integration (2003)

Identifying approximately duplicate database records that refer to the same entity is essential for information integration. The authors compare and describe methods for combining and learning textual similarity measures for name matching.
Identification of Subtypes in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Reveals a Gene Signature Prognostic of Outcome (2010)

PURPOSE Human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression (HER2 positivity) defines a clinically challenging subgroup of patients with breast cancer (BC) with variable prognosis and response to therapy. We aimed to investigate the heterogeneous biologic appearance and clinical behavior of HER2-positive tumors using molecular profiling. PATIENTS AND METHODS Hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stage, histologic grade, and estrogen receptor (ER) status was used to construct a HER2-derived prognostic predictor that was further evaluated in several large independent BC data sets. RESULTS Unsupervised analysis identified three subtypes of HER2-positive tumors with mixed stage, histologic grade, and ER status. One subtype had a significantly worse clinical outcome. A prognostic predictor was created based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2-positive BC across multiple independent BC data sets and identify a sizable HER2-positive group with long disease-free survival and low mortality. Significant correlation to prognosis was also observed in basal-like, ER-negative, lymph node-positive, and high-grade tumors, irrespective of HER2 status. The predictor included genes associated with immune response, tumor invasion, and metastasis. CONCLUSION The HER2-derived prognostic predictor provides further insight into the heterogeneous biology of HER2-positive tumors and may become useful for improved selection of patients who need additional treatment with new drugs targeting the HER2 pathway.
Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin (1998)

Nasal administration of peptide antigens has been shown to induce T cell tolerance. We have investigated the potential for peptide therapy of the autoimmune response to myelin antigens in experimental autoimmune encephalomyelitis (EAE). Three major encephalitogenic epitopes were studied for their ability to induce nasal tolerance to myelin antigens. These included epitopes Ac1-9 and 89-101 of myelin basic protein (MBP) and 139-151 from proteolipid protein (PLP). Peptide Ac1-9 from MBP effectively suppressed responses to both MBP epitopes, following immunization with whole myelin (linked suppression). The N-terminal epitope failed, however, to modify the response to epitope 139-151 of PLP. The second MBP epitope (89-101) was poorly tolerogenic for the immune response to any naturally processed myelin epitope. By contrast, PLP[139-151] was able to induce bystander suppression of T cells responsive to both itself and the two epitopes from MBP. Furthermore, this epitope suppressed EAE induced with peptides derived from MBP and was capable of treating ongoing disease. The mechanism of bystander suppression, mediated by PLP[139-151], did not correlate with an overt switch from the T helper 1 to the T helper 2 phenotype. These results demonstrate how a complex autoimmune disease may be controlled by treatment with a single peptide epitope and reveal a hierarchy in the suppressive properties of different myelin antigens.
Purification of kidney epithelial cell growth inhibitors. (1980)

Two high molecular weight growth inhibitors have been isolated from the culture medium of BSC-1 cells, epithelial cells of African green monkey kidney. The purified kidney epithelial cell growth inhibitors, at ng/ml concentrations, reversibly arrest the growth of BSC-1 cells in the G1 phase of the cell cycle. Their action is selective; they are most active on BSC-1 cells, are less active as inhibitors of the growth of rat lung and human breast epithelial cells, and do not inhibit the growth of 3T3 mouse embryo fibroblasts ad human skin fibroblasts in culture. Their growth inhibitory action on BSC-1 cell cultures is counteracted by epidermal growth factor or calf serum.
Dendritic cells directly modulate B cell growth and differentiation (1999)

Journal Article Dendritic cells directly modulate B cell growth and differentiation Get access Bertrand Dubois, Bertrand Dubois Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Jean-Michel Bridon, Jean-Michel Bridon Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Jérôme Fayette, Jérôme Fayette Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Clarisse Barthélémy, Clarisse Barthélémy Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Jacques Banchereau, Jacques Banchereau Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Christophe Caux, Christophe Caux Schering-Plough, Laboratory for Immunological Research, Dardilly, France Search for other works by this author on: Oxford Academic Google Scholar Francine Brière Francine Brière Schering-Plough, Laboratory for Immunological Research, Dardilly, France Correspondence: Dr. Francine Brière, Schering-Plough Laboratoryforlmmu-nological Research, 27 chemin des peupliers, BP11, 69571, Dardilly, France. E-mail: Francine.Briere@spcorp.com Search for other works by this author on: Oxford Academic Google Scholar Journal of Leukocyte Biology, Volume 66, Issue 2, August 1999, Pages 224–230, https://doi.org/10.1002/jlb.66.2.224 Published: 01 August 1999 Article history Received: 13 April 1999 Accepted: 19 April 1999 Published: 01 August 1999
Cloning and molecular characterization of the B subunit of Escherichia coli heat-labile enterotoxin (1983)

We have constructed a plasmid containing the gene for production of the B subunit of the heat-labile enterotoxin (LT-B) from a human isolate of Escherichia coli, strain H10407. The 0.8-kilobase gene fragment encoding synthesis of LT-B was cloned onto plasmid pBR322 after sequential digestion of the enterotoxin plasmid of strain H10407 with restriction endonucleases PstI and HindIII. LT-B was isolated by agarose affinity chromatography from cell lysates of recombinant clones expressing the B subunit. The B subunit was isolated in its oligomeric form, was structurally identical to native B subunit when examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, dissociated to monomeric B in the presence of 5 M guanidine, was immunologically identical to native B subunit in an enzyme-linked immunosorbent assay, and contained no demonstrable A subunit in any of the assays.
Port Placement for Endoscopic Cardiac Surgery Based on Robot Dexterity Optimization (2006)

Accurate and proper placement of ports during robotically-assisted endoscopic surgery is critical to the success of the procedure. Improper placement of ports can lead to robot collisions, the inability to reach the surgical site, the inability to manipulate the tools properly, or collisions between the tools inside the patient’s body. In current practice, port placement methods do not consider the ability of the robot to manoeuvre the tools. Furthermore, there is a lack of guidance on what the position of the robot or the configuration of its arms should be. This paper proposes to choose the best port location and determine the position of the base and arms of the robot such that its performance is maximized. Performance measures developed in the past to optimize robot design and manipulation are used to optimize the placement of ports when using a surgical manipulator for artery dissection during coronary bypass surgery.
Synthesis, Reactions and Antimicrobial Activity of 2-Amino-4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile (2005)

A novel 2-amino-4-(8-quinolinol-5-yl)-1- (p-tolyl)-pyrrole-3-cabonitrile (2) was obtained by the reaction of 2-[2-bromo-1-(8-hydroxyquinolin-5-yl)-ethylidene]-malononitrile (1) with p-toluidene. The new synthon compound (2) could be annelated to the corresponding pyrrolo[2,3-d]pyrimidines (4, 6, 7, 26-28), triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (10, 29, 30), pyrrolo[2,3-c]pyrazoles (11-15), pyrrolo[1,2-a]pyrrolo[3,2-e] pyrimidine (17) and imidazo[1,2-c]pyrrolo[3,2-e]pyrimidines (18-25) via the reaction with some reagents such as acetic anhydride, formamide, triethyl orthoformate, hydrazine hydrate, hydroxylamine, ethylenediamine, carbon disulfide and phosphorus oxychloride. Chemical and spectroscopic evidences for the structures of these compounds are presented. The antifungal and antibacterial activity of the newly synthesized comounds were evaluated.
Hit to Lead Account of the Discovery of a New Class of Inhibitors of Pim Kinases and Crystallographic Studies Revealing an Unusual Kinase Binding Mode (2009)

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.
A simple method to characterize substrate current in MOSFET's (1984)

Experimental verification of substrate current characteristics is thoroughly carried out. V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</inf> - V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DSAT</inf> , instead of V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</inf> , is shown to be the driving force of all hot-electron effects. A simple relationship between substrate current and V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</inf> - V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DSAT</inf> is found. This relationship provides a convenient tool to characterize the substrate current or the channel electric field, and, hence, all hot-electron effects. Measurements of I <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SUB</inf> /I <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</inf> and V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</inf> - V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DSAT</inf> at two bias points and any one channel length are sufficient to fully characterize the substrate currents for all channel lengths V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</inf> 's and V <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">G</inf> 's for a given technology.
Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. (1990)

The debrisoquine/sparteine-type polymorphism is a clinically important inherited variation of drug metabolism characterized by two phenotypes, the extensive metabolizer and the poor metabolizer (PM). Five to 10 percent of individuals in Caucasian populations are of the PM phenotype and have deficient metabolism of debrisoquine and over 25 other drugs. Our previous studies have revealed absence of cytochrome P450IID6 protein and aberrant splicing of IID6 premRNA in livers of PMs. Moreover, two mutant alleles of the P450IID6 gene locus (CYP2D6) were identified by restriction fragment length analysis to be associated with the PM phenotype. However, the mutations of the CYP2D6 gene causing absent P450IID6 protein have not been defined. Here we report the cloning and sequencing of two types of mutant alleles of CYP2D6 isolated from genomic libraries of three PM individuals. One allele (29-A) was characterized by a single nucleotide deletion in the 5th exon with consequent frameshift and was observed in one individual only. The other type of mutant allele (29-B) was present in all three PM individuals and its sequence contained multiple mutations, notably four base changes causing amino acid changes in exons 1, 2 and 9, and a point mutation at the consensus sequence of the splice site of the 3rd intron. To understand the significance of the individual mutations, chimeric genes were constructed between the wild-type IID6 gene and the mutant 29-B allele or site-specific mutations were introduced into the IID6-cDNA and these DNA constructs were transiently expressed in COS-1 cells. The mutations in exon 1 resulted in a functionally deficient IID6 protein and the mutation at the splice site in absent IID6 protein, whereas the mutations in exons 2 and 9 were of no consequence for IID6 function. Only the mutation at the splice site thus explains the absence of P450IID6 protein in livers of PM individuals and appears to be a common cause of polymorphic drug oxidation.
The kinetics of 1,4-butanediol diglycidyl ether crosslinking of dermal sheep collagen (2000)

Dermal sheep collagen was crosslinked with 1,4-butanediol diglycidyl ether (BDDGE) or modified with glycidyl isopropyl ether (PGE). The reduction in amine groups as a function of time was followed to study the overall reaction kinetics of collagen with either BDDGE or PGE. Linearization of the experimental data resulted in a reaction order of 2 with respect to the amine groups in the PGE masking reaction, whereas a reaction order of 2.5 was obtained in the BDDGE crosslinking reaction. The reaction orders were independent of the pH in the range of 8.5-10.5 and the reagent concentration (1-4 wt %). The reaction order with respect to epoxide groups was equal to 1 for both reagents. As expected, the reaction rate was favored by a higher reagent concentration and a higher solution pH. Because the BDDGE crosslinking reaction occurs via two distinct reaction steps, the content of pendant epoxide groups in the collagen matrix was determined by treating the collagen with either O-phosphoryl ethanolamine or lysine methyl ester. The increase in either phosphor or primary amine groups was related to the content of pendant groups. Crosslinking at pH 9.0 resulted in a low reaction rate but in a high crosslink efficacy, especially after prolonged reaction times. A maximum concentration of pendant epoxide groups was detected after 50 h. Reaction at pH 10.0 was faster, but a lower crosslinking efficacy was obtained. At pH 10.0, the ratio between pendant epoxide groups and crosslinks was almost equal to 1 during the course of the crosslinking reaction.
Human mast cell carboxypeptidase. Selective localization to MCTC cells (1991)

Two murine mAb were prepared against human mast cell carboxypeptidase (HMC-CP) purified from human skin, and were termed CP1 and CP2, respectively. Double immunohistochemical labeling of Carnoy's-fixed sections of human skin, lung, and gastrointestinal tissue with CP1 and CP2, respectively, and with a murine monoclonal antitryptase antibody demonstrated that HMC-CP was selectively present in a subset of human mast cells. Double labeling experiments with CP1 and CP2, respectively, and a murine anti-chymase mAb demonstrated the presence of HMC-CP in the tryptase-positive, chymase-positive mast cell type (MCTC) only. Immunohistochemical labeling of peripheral blood leukocytes resulted in staining of monocytes with CP2 but not with CP1. In addition to chymase and a cathepsin-G like proteinase, HMC-CP is another neutral protease that is selectively present in the MCTC tryptase-positive, chymase-positive mast cells type of mast cell, thus extending the biochemical definition of human mast cell heterogeneity.
A Functional Cell Surface Type Receptor Is Required for the Early Action of 1,25-Dihydroxyvitamin D3 on the Phosphoinositide Metabolism in Rat Enterocytes (1989)

1,25-Dihydroxyvitamin D3 (1,25-(OH)2-D3) (0.1 pM to 2 nM) induces a concomitant very rapid (within 5 s) and transient release of inositol trisphosphate and diacylglycerol in enterocytes from 3-month-old rats. This high level is not maintained but declines to a lower level 60 s after stimulation. The stimulating effect is dose-dependent and biphasic with a maximum effect at 10 pM. 1,25-(OH)2-D3 induces a rapid (within 10 s) accumulation of inositol bisphosphate and its effect on inositol monophosphate is delayed (120 s). The primary action of 1,25-(OH)2-D3 is to initiate hydrolysis of phosphatidyl 4,5-bisphosphate to yield inositol trisphosphate and diacylglycerol. In contrast, 1,25-(OH)2-D3, for any of the concentrations and the incubation time periods tested, has no effect on inositol trisphosphate and diacylglycerol formation in enterocytes from 16-day-old rats at a time when specific binding sites for 1,25-(OH)2-D3 cannot be detected. In conclusion, the early (within 5-60 s) effects of 1,25-(OH)2-D3 on small intestinal epithelium may be mediated via the phosphoinositide transduction system and require the presence of functioning cell membrane-type receptors.
Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics (2008)

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents.