gebhart/patrepeval huggingface dataset:
Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects (2006)

Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.
Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice (2005)

In order to examine the effect of estrogen on facial pain, we first compared the face-rubbing evoked by a formalin injection in the lip of aromatase-knockout (ArKO) mice, lacking endogenous estrogen production, 17 beta-estradiol-treated ArKO mice (ArKO-E2) and wild-type (WT) littermates. During the 'acute' phase of pain the time spent rubbing was similar in the three groups, whereas during the following 'interphase' and the second phase of pain, grooming was increased in ArKO mice. Estradiol-treatment restored a behaviour similar to WT group. To better understand estrogens modulation on pain processes, we examined changes in 5-HT and CGRP innervations of trigeminal nucleus caudalis (TNC) in ArKO, ArKO-E2 and WT groups sacrificed during the interphase. Whereas serotonin and CGRP immunoreactivities were comparable in WT and ArKO non-injected control groups, our data showed that 9 min after formalin injection, the density of serotoninergic terminals increased significantly in WT, but not in ArKO mice, while that of CGRP-immunoreactive fibers was lower in WT than in ArKO mice on the injected side. Estradiol-treatment only partially reversed these changes in ArKO-E2 mice. We conclude that estrogen deprivation in ArKO mice can be responsible for increased nociceptive response and that it is accompanied by transmitter changes favouring pro- over anti-nociceptive mechanisms in TNC during interphase of the formalin model. That estradiol-treatment completely reverses the behavioural abnormality suggests that estrogens absence produces chiefly functional activation-dependent changes. However, the fact that the immunohistochemical abnormalities were not totally normalized by estradiol-treatment suggested that some permanent developmental alterations may occur in ArKO mice.
Characterization of Multidrug-Resistant Salmonella enterica Serovar Typhimurium Isolated in Japan (2001)

A total of 221 isolates of multidrug-resistant Salmonella enterica serovar Typhimurium in Japan were characterized in the present study. The results revealed that clonal serovar Typhimurium definitive phage type 104 strains prevailed and that these strains had drug resistance patterns, integron types, and pulsed-field gel electrophoresis patterns similar to those predominant among isolates in Western countries.
Reduced antibody response to streptavidin through site‐directed mutagenesis (2001)

Abstract Streptavidin provides an effective receptor for biotinylated tumoricidal molecules, including radionuclides, when conjugated to an antitumor antibody and administered systemically. Ideally, one would like to administer this bacterial protein to patients repeatedly, so as to maximize the antitumor effect without eliciting an immune response. Therefore, we attempted to reduce the antigenicity of streptavidin by mutating surface residues capable of forming high energy ionic or hydrophobic interactions. A crystallographic image of streptavidin was examined to identify residues with solvent‐exposed side chains and residues critical to streptavidin's structure or function, and to define loops. Mutations were incorporated cumulatively into the protein sequence. Mutants were screened for tetramer formation, biotin dissociation, and reduced immunoreactivity with pooled patient sera. Patient antisera recognized one minor continuous epitope with binding locus at residue E101 and one major discontinuous epitope involving amino acid residues E51 and Y83. Mutation of residues E51, Y83, R53, and E116 reduced reactivity with patient sera to &lt;10% that of streptavidin, but these mutations were no less antigenic in rabbits. Mutant 37, with 10 amino acid substitutions, was only 20% as antigenic as streptavidin. Rabbits immunized with either streptavidin or mutant 37 failed to recognize the alternative antigen. Biotin dissociated from mutant 37 four to five times faster than from streptavidin. Residues were identified with previously undescribed impact on biotin binding and protein folding. Thus, substitution of charged, aromatic, or large hydrophobic residues on the surface of streptavidin with smaller neutral residues reduced the molecule's ability to elicit an immune response in rabbits.
Pseudomonas aeruginosa-induced infection and degradation of human wound fluid and skin proteins ex vivo are eradicated by a synthetic cationic polymer (2004)

&lt;I&gt;Objectives&lt;/I&gt;: Antimicrobial peptides are important effectors of innate immunity. Bacteria display multiple defence mechanisms against these peptides. For example, &lt;I&gt;Pseudomonas aeruginosa&lt;/I&gt; releases potent proteinases that inactivate the human cathelicidin LL-37. Hence, in conditions characterized by persistent bacterial colonization, such as in &lt;I&gt;P. aeruginosa&lt;/I&gt;-infected skin wounds, there is a need for efficient means of reducing bacterial load. Here, the effect of the cationic molecule polyhexamethylenebiguanide (PHMB) was evaluated. &lt;I&gt;Methods&lt;/I&gt;: Infection models in human wound fluid and human skin were established. Radial diffusion methods, bacterial growth and bactericidal assays were used for determination of effects of PHMB on bacteria in the presence of plasma, wound fluid or human skin. At the protein and tissue levels, SDS-PAGE, light microscopy and scanning electron microscopy were used to study the effects of &lt;I&gt;P. aeruginosa&lt;/I&gt; infection before and after addition of PHMB. &lt;I&gt;Results&lt;/I&gt;: PHMB killed common ulcer-derived bacteria in the presence of human wound fluid. Furthermore, elastase-expressing &lt;I&gt;P. aeruginosa&lt;/I&gt; completely degraded wound fluid proteins as well as human skin during infection &lt;I&gt;ex vivo&lt;/I&gt;. The infection, and consequent protein degradation, was reversed by PHMB. &lt;I&gt;Conclusions&lt;/I&gt;: The &lt;I&gt;ex vivo&lt;/I&gt; infection models presented here should be helpful in the screening of novel antimicrobials and constitute a prerequisite for future clinical studies.
Investigating and Engineering Enzymes by Genetic Selection (2001)

Natural enzymes have arisen over millions of years by the gradual process of Darwinian evolution. The fundamental steps of evolution-mutation, selection, and amplification-can also be exploited in the laboratory to create and characterize protein catalysts on a human timescale. In vivo genetic selection strategies enable the exhaustive analysis of protein libraries with 10(10) different members, and even larger ensembles can be studied with in vitro methods. Evolutionary approaches can consequently yield statistically meaningful insight into the complex and often subtle interactions that influence protein folding, structure, and catalytic mechanism. Such methods are also being used increasingly as an adjunct to design, thus providing access to novel proteins with tailored catalytic activities and selectivities.
Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents (2004)

Peripheral arterial occlusive disease (PAOD) is now recognized as a combination of clinical syndromes that are associated with significant morbidity and mortality. The primary pathophysiology of PAOD is impaired perfusion to the lower extremity. Effective pharmacotherapy designed to increase perfusion in PAOD is lacking, and revascularization options are suboptimal. New and more efficacious therapies that improve blood flow are definitely needed, and thus designing, describing, and validating these new therapies in preclinical PAOD models will be essential. This study describes the various preclinical PAOD models presently in use, correlates the models to human PAOD, and reviews the available end points that can be used to detect a response to therapy.
Growth factor-induced delayed early response genes. (1992)

Growth factors induce the sequential expression of cellular genes whose products are thought to mediate long-term responses to the growth factors. In mouse 3T3 fibroblastic cells, the first genes to be expressed (immediate-early genes) are activated within minutes after the addition of platelet-derived growth factor, fibroblast growth factor, or serum. By cDNA cloning, we have identified genes that are activated after a delay of a few hours and several hours prior to serum-induced DNA replication. Activation of these delayed early response genes requires new protein synthesis, presumably the synthesis of immediate-early transcription factors described previously. Partial or complete sequencing of 13 different delayed early cDNAs, representing about 40% of the 650 primary cDNA isolates, revealed that 8 were related to known gene sequences and 5 were not. Among the former are cDNAs encoding nonhistone chromosomal proteins [HMGI(Y) and HMGI-C], adenine phosphoribosyltransferase (APRT), a protein related to human macrophage migration inhibitory factor (MIF), a protein of the major intrinsic protein (MIP) family homologous to the integral membrane protein of human erythrocytes, and cyclin CYL1. In 3T3 cells, the delayed early gene response to growth factors appears to be at least as complex as the immediate-early gene response previously described.
2-Pyridone Ring Formation through the Photoreaction of Arenecarbothioamides with Unsaturated Carboxylic Acids (2002)

Irradiation of arenecarbothioamides with 2,4-hexadienoic acid in benzene gives 2-pyridone derivatives in moderate yields.The corresponding benzo-fused 2-pyridone derivative was also obtained by use of o-vinylbenzoic acid as dienoic acid equivalent.2-Pyridones are one of the important classes of heterocyclic compounds that can be found in many biologically active natural products and pharmaceuticals. 2 Therefore, considerable effort has been devoted to the development of synthetic methodology directed at the efficient preparation of 2-pyridone derivatives. 3 In the course of our systematic study on photochemistry of the arenecarbothioamide-alkene system, 4 we found that photoreaction of arenecarbothioamides with 3-furan-2-ylacrylic acid in benzene proceeds via key intermediate 4-amino-3-butenoi acid to give 2,3-diaryl-2-pyrrolin-5-one (scheme 1). 5 From the Ar C S NH 2 hv benzene O COOH S Ar NH 2 COOH O O
Direct Observation of Hydrogen Molecules Adsorbed onto a Microporous Coordination Polymer (2004)

Trapped hydrogen molecules in the nanochannels of a copper coordination polymer were successfully observed by the synchrotron powder-diffraction method. The adsorbed molecules are located near one corner of the rectangular nanochannels, and the pockets of the pore walls are suited to the size of the hydrogen molecules (see picture). These results could provide guidelines for the design of hydrogen-storage materials.
Poorly Soluble Marketed Drugs Display Solvation Limited Solubility (2007)

We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 microM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.
Notch and Wingless Regulate Expression of Cuticle Patterning Genes (1999)

The cell surface receptor Notch is required during Drosophila embryogenesis for production of epidermal precursor cells. The secreted factor Wingless is required for specifying different types of cells during differentiation of tissues from these epidermal precursor cells. The results reported here show that the full-length Notch and a form of Notch truncated in the amino terminus associate with Wingless in S2 cells and in embryos. In S2 cells, Wingless and the two different forms of Notch regulate expression of Dfrizzled 2, a receptor of Wg; hairy, a negative regulator of achaete expression; shaggy, a negative regulator of engrailed expression; and patched, a negative regulator of wingless expression. Analyses of expression of the same genes in mutant N embryos indicate that the pattern of gene regulations observed in vitro reflects regulations in vivo. These results suggest that the strong genetic interactions observed between Notch and wingless genes during development of Drosophila is at least partly due to regulation of expression of cuticle patterning genes by Wingless and the two forms of Notch.
Palladium-catalysed vinylation of organic halides under solid–liquid phase transfer conditions (1984)

Heck-type reactions involving organic halides proceed readily at or near room temperature when performed under solid–liquid phase transfer conditions.
Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant (2013)

The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.
Activation by Autophosphorylation or cGMP Binding Produces a Similar Apparent Conformational Change in cGMP-dependent Protein Kinase (1998)

Binding of cyclic nucleotide to or autophosphorylation of cGMP-dependent protein kinase (PKG) activates this kinase, but the molecular mechanism of activation for either process is unknown. Activation of PKG by cGMP binding produces a conformational change in the enzyme (Chu, D.-M., Corbin, J. D., Grimes, K. A., and Francis, S. H. (1997) J. Biol. Chem. 272, 31922-31928; Zhao, J., Trewhella, J., Corbin, J., Francis, S., Mitchell, R., Brushia, R., and Walsh, D. (1997) J. Biol. Chem. 272, 39129-31936). In the present studies, activation of type Ibeta PKG by either autophosphorylation or cGMP-binding alone causes (i) an electronegative charge shift on ion exchange chromatography, (ii) a similar increase ( approximately 3.5 A) in the Stokes radius as determined by gel filtration chromatography, and (iii) a similar decrease in the mobility of the enzyme on native gel electrophoresis. Consistent with these results, cGMP binding increases the rate of phosphoprotein phosphatase-1 catalyzed dephosphorylation of PKG which is autophosphorylated only at Ser-63 (not activated); however, dephosphorylation of PKG that is highly autophosphorylated (activated) is not stimulated by cGMP. The combined results suggest that activation of PKG by either autophosphorylation or cGMP binding alone produces a similar apparent elongation of the enzyme, implying that either process activates the enzyme by a similar molecular mechanism.
SYNTHESIS AND CONFIGURATION OF DIHYDROSPHINGOSINE1,2 (1953)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSYNTHESIS AND CONFIGURATION OF DIHYDROSPHINGOSINE1,2Herbert E. Carter, David Shapiro, and J. Bradley HarrisonCite this: J. Am. Chem. Soc. 1953, 75, 4, 1007–1008Publication Date (Print):February 1, 1953Publication History Published online1 May 2002Published inissue 1 February 1953https://pubs.acs.org/doi/10.1021/ja01100a522https://doi.org/10.1021/ja01100a522research-articleACS PublicationsRequest reuse permissionsArticle Views34Altmetric-Citations28LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Design, Synthesis, and Biological Evaluation of Novel 3-Aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor (VEGF-R) Inhibitors (2008)

In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.
Calculation of steady flow pressure loss coefficients for pipe junctions (2001)

Abstract Pipe junctions are found in many engineering systems. It is often desirable to predict the pressures within such systems. Steady flow pressure loss coefficients can be defined that attempt to characterize the effects of the junction on the flow. These coefficients are usually established experimentally, but empirical and analytical expressions exist that allow some of the loss coefficients for junctions to be calculated. In the paper, simple expressions are presented that allow all of the loss coefficients for a three pipe T-junction, with any lateral branch angle or area ratio, to be calculated. The coefficients obtained using these expressions are compared with measured values. The steady flow pressure loss coefficients calculated in this way have been applied to the simulation of the propagation of a shock wave through a T-junction. Predictions of the mean pressure levels show good correlation with measurements.
The yellow fever 17D vaccine virus: molecular basis of viral attenuation and its use as an expression vector (1997)

The yellow fever (YF) virus is the prototype flavivirus. The use of molecular techniques has unraveled the basic mechanisms of viral genome structure and expression. Recent trends in flavivirus research include the use of infectious clone technology with which it is possible to recover virus from cloned cDNA. Using this technique, mutations can be introduced at any point of the viral genome and their resulting effect on virus phenotype can be assessed. This approach has opened new possibilities to study several biological viral features with special emphasis on the issue of virulence/attenuation of the YF virus. The feasibility of using YF virus 17D vaccine strain, for which infectious cDNA is available, as a vector for the expression of heterologous antigens is reviewed.
Derivation of Cloned Human Blastocysts by Histone Deacetylase Inhibitor Treatment After Somatic Cell Nuclear Transfer with β-Thalassemia Fibroblasts (2011)

Derivation of embryonic stem cells from patient-specific cloned blastocysts by somatic cell nuclear transfer (SCNT) holds promise for both regenerative medicine and cell-based drug discovery. However, the efficiency of blastocyst formation after human SCNT is very low. The developmental competence of SCNT embryos has been previously demonstrated in several species to be enhanced by treatment with histone deacetylase inhibitors, such as trichostatin A (TSA), to increase histone acetylation. In this study, we report that treatment of SCNT embryos with 5 nM TSA for 10 h following activation incubation increased the developmental competence of human SCNT embryos constructed from β-thalassemia fibroblast cells. The efficiency of blastocyst formation from SCNT human embryos treated with TSA was approximately 2 times greater than that from untreated embryos. Cloned blastocysts were confirmed to be generated through SCNT by DNA and mitochondrial DNA fingerprinting analyses. Further, treatment of SCNT embryos with TSA improved the acetylation of histone H3 at lysine 9 in a manner similar to that observed in in vitro fertilized embryos.
Growth of high mobility GaN and AlGaN/GaN high electron mobility transistor structures on 4H-SiC by ammonia molecular-beam epitaxy (2001)

Ammonia molecular-beam epitaxy has been used to grow high-quality epilayers of GaN and AlGaN/GaN heterostructure field-effect transistor (HFET) structures on insulating 4H-SiC. The growth process, which used a magnetron sputter epitaxy deposited buffer layer of AlN, has been described previously. Ex situ pretreatment of the SiC substrate was found to be unnecessary. For a single 2.0 μm thick silicon doped epilayer, a room temperature (RT) electron mobility of 500 cm2/Vs was measured at a carrier density of 6.6×1016 cm−3. For the HFET structure, a room temperature mobility of 1300 cm2/Vs at a sheet carrier density of 3.3×1012 cm−2 was observed, increasing to 11 000 cm2/Vs at 77 K. The surface morphology of the layers indicated a coalesced mesa structure similar to what we observed for growth on sapphire, but with a lower overall defect density and correspondingly larger grain size. The observation of well-resolved Shubnikov de Haas oscillations at fields as low as 3 T indicated a relatively smooth interface.