gebhart/patrepeval huggingface dataset:
Novel Therapies for Asthma - Advances and Problems (2005)

It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with anti-histamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-gamma are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.
Aspects of solid state 13C CPMAS NMR spectroscopy in coals from the Balkan peninsula (2003)

The cross-polarized magic-angle-spinning NMR (CPMAS-NMR) technique was used in this work to assess the carbon distribution in coals of different rank (peat, lignite, xylite, sub-bituminous coal) from important deposits in Greece and Bulgaria. The technique is assumed to be only semiquantitative due to a number of interferences, such as spinning side bands (SSB) in the spectra, paramagnetic species in the samples, and low or remote protonation of aromatic carbons. The Bulgarian sub-bituminous coal shows the greatest amounts of aromatic structures. The lignite sample from the Drama basin Northern Greece, is relatively unaltered and largely unlettered, and shows the greatest amounts of aliphatic groups. The 13C-NMR spectra of Pliocene lignites from endemic areas in Serbia and Montenegro and Bosnia, taken from published papers, show significantly more intense resonance's for methoxyl phenolic, and polysaccharide moieties compared to the Drama lignite NMR spectrum. Xylite reveals high contents of carbohydrates.
Selective Amino Acid Substitutions Convert the Creatine Transporter to a γ-Aminobutyric Acid Transporter (2007)

The creatine transporter (CRT) is a member of a large family of sodium-dependent neurotransmitter and amino acid transporters. The CRT is closely related to the gamma-aminobutyric acid (GABA) transporter, GAT-1, yet GABA is not an effective substrate for the CRT. The high resolution structure of a prokaryotic homologue, LeuT has revealed precise details of the substrate binding site for leucine (Yamashita, A., Singh, S. K., Kawate, T., Jin, Y., and Gouaux, E. (2005) Nature 437, 215-223). We have now designed mutations based on sequence comparisons of the CRT with GABA transporters and the LeuT structural template in an attempt to alter the substrate specificity of the CRT. Combinations of two or three amino acid substitutions at four selected positions resulted in the loss of creatine transport activity and gain of a specific GABA transport function. GABA transport by the "gain of function" mutants was sensitive to nipecotic acid, a competitive inhibitor of GABA transporters. Our results show LeuT to be a good structural model to identify amino acid residues involved in the substrate and inhibitor selectivity of eukaryotic sodium-dependent neurotransmitter and amino acid transporters. However, modification of the binding site alone appears to be insufficient for efficient substrate translocation. Additional residues must mediate the conformational changes required for the diffusion of substrate from the binding site to the cytoplasm.
X-ray molecular structures of Mn(CO)5(O2CCF3) and Mn(CO)3(C5H5N)2(O2CCF3) (1981)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTX-ray molecular structures of Mn(CO)5(O2CCF3) and Mn(CO)3(C5H5N)2(O2CCF3)F. Albert Cotton, Donald J. Darensbourg, and Brian W. S. KolthammerCite this: Inorg. Chem. 1981, 20, 4, 1287–1291Publication Date (Print):April 1, 1981Publication History Published online1 May 2002Published inissue 1 April 1981https://pubs.acs.org/doi/10.1021/ic50218a064https://doi.org/10.1021/ic50218a064research-articleACS PublicationsRequest reuse permissionsArticle Views96Altmetric-Citations22LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Pharmacotherapy, Pharmacogenomics, and The Future of Alcohol Dependence Treatment, Part 2 (2004)

In addition to existing drug treatments for alcohol dependence, many other medications are under investigation, particularly for specific types of alcoholism. Pharmacogenomics is expected to play an important role in this research effort.
Pathways of glycine betaine synthesis in two extremely halophilic bacteria, Actinopolyspora halophila and Ectothiorhodospira halochloris (2001)

Glycine betaine is a solute which is able to restore and maintain the osmotic balance of living cells. In this thesis, the glycine betaine synthesis in two extremely halophilic bacteria Actinopolyspora halophila and Ectothiorhodospira halochloris is investigated.\n\nA. halophila synthesized remarkably high intracellular concentrations of glycine betaine. The highest glycine betaine concentration, determined at 24% (w/v) NaCl, was 33% of the cellular dry weight.\n\nThe data presented in this work indicate that the de novo synthesis of glycine betaine proceeds via the threefold methylation of glycine. S-adenosylmethionine acts as the methyl group donor in the reactions. The genes encoding this pathway were cloned and successfully expressed in Escherichia coli. In E. halochloris, glycine sarcosine N-methyltransferase (GSMT) and sarcosine dimethylglycine N-methyltransferase (SDMT) catalyze the reaction sequence. In A. halophila all three methylation reactions appear to be catalyzed by a fusion protein. The methyltransferases from the two bacteria show high sequence homology.\n\nFurthermore, it was demonstrated that in addition to the glycine methylation pathway, A. halophila has the ability to oxidize choline to glycine betaine. Choline was first oxidized to betaine aldehyde in a reaction in which H2O2-generation and oxygen consumption are coupled. Betaine aldehyde was oxidized further to glycine betaine in a reaction in which NAD(P)+ was reduced.\n\nThe GSMT and SDMT of E. halochloris were expressed in E. coli, purified, and some of their enzymatic properties were characterized. Both enzymes had high substrate specificity and pH optima near physiological pH. No evidence of cofactors was found. The enzymes showed Michaelis-Menten kinetics for their substrates. The apparent Km and Vmax values were determined for all substrates, when the other substrate was present in saturating concentrations. Both enzymes were strongly inhibited by the reaction product S-adenosylhomocysteine. Glycine betaine inhibited the methylation reactions only at high concentrations.\n\nFinally, it was demonstrated that the expression of the E. halochloris methyltransferase genes in E. coli results in glycine betaine accumulation and improves salt tolerance.
Tumor Necrosis Factor (TNF) Receptor Superfamily Member TACI Is a High Affinity Receptor for TNF Family Members APRIL and BLyS (2000)

An expression cloning approach was employed to identify the receptor for B-lymphocyte stimulator (BLyS) and identified the tumor necrosis factor receptor superfamily member TACI as a BLyS-binding protein. Expression of TACI in HEK293T cells confers on the cells the ability to bind BLyS with subnanomolar affinity. Furthermore, a TACI-Fc fusion protein recognizes both the cleaved, soluble form of BLyS as well as the membrane BLyS present on the cell surface of a recombinant cell line. TACI mRNA is found predominantly in B-cells and correlates with BLyS binding in a panel of B-cell lines. We also demonstrate that TACI interacts with nanomolar affinity with the BLyS-related tumor necrosis factor homologue APRIL for which no clear in vivo role has been described. BLyS and APRIL are capable of signaling through TACI to mediate NF-kappaB responses in HEK293 cells. We conclude that TACI is a receptor for BLyS and APRIL and discuss the implications for B-cell biology.
Assessment of the antigenic structure of tick-borne encephalitis virus by the use of synthetic peptides (1993)

The feasibility of using synthetic peptides for the identification of individual monoclonal antibody (MAb)-defined epitopes was assessed on the basis of a structural model of the tick-borne encephalitis (TBE) virus envelope glycoprotein E. For this purpose a series of 19 synthetic peptides was prepared, covering most of the E protein sequence. Each of the peptides was tested by ELISA for reactivity with 19 protein E-specific MAbs raised against TBE virus strain Neudoerfl. Specific reactivity was observed with three MAbs and two peptides (representing amino acids 1 to 22 and 221 to 240, respectively), thus providing new information on the location of the corresponding epitopes. Specificity was confirmed in a competition ELISA by the ability of the peptides to block MAb binding to TBE virus antigen. However, in contrast to the other MAbs, these peptide-reactive MAbs were not blocked by native virus particles in the competition ELISA, indicating that they do not recognize the native conformation of the E protein. These three MAbs also showed increased reactivity with denatured forms of the virus in a dot blot assay. Additionally, they reacted only in ELISA systems in which the virus was directly coated to the solid phase and thereby presumably partially denatured, but not when a capture antibody was used, which preserves the native antigen conformation. We have thus identified two classes of MAbs, those which recognize the native form and those which recognize the denatured form of protein E. The latter may be useful for the analysis of sites probably involved in protein folding and oligomerization.
X-ray structure of wheat germ agglutinin isolectin 3 (1995)

Wheat germ agglutinin isolectin 3 (WGA3) was crystallized from 10 mM acetate buffer at pH 4.9 containing 6 mM CaCl(2) and 4%(v/v) ethanol. The crystal belongs to monoclinic space group P2(1) with unit-cell dimensions a = 44.86, b = 91.02, c = 44.86 A, and beta = 110.22 degrees. The asymmetric unit contains two molecules (V(m) = 2.51 A(3) Da(-1)). The crystal structure was solved by the molecular-replacement method and was refined by the simulated-annealing method. The conventional R value was 0.191 for 19713 reflections [|F(o)| > 3sigma(F)] in the resolution range 8-1.9 A. The r.m.s. deviations from the ideal bond distances and angles were 0.014 A, and 3.0 degrees, respectively, and the estimated coordinate error was 0.2-0.25 A. The two molecules in the asymmetric unit are related by the pseudo twofold symmetry and form a dimer structure. The backbone structures of the two subunits are nearly identical with the r.m.s. difference of 0.36 A for the superposition of equivalent C(alpha) atoms. The dimer structure is very similar to those of isolectins 1 and 2 with the r.m.s. difference of 0.35-0.39 A for the C(alpha) superposition. Since amino-acid residues which differ from those of isolectin 1 or 2 are not involved in the contact between the two subunits, the subunit-subunit interaction is not significantly affected by the replacement of these residues. As a result, the geometry of the sugar-binding sites which are located at the interface between the two subunit molecules is basically conserved among three isolectins.
Purification and Subunit Characterization of the Rat Liver Endocytic Hyaluronan Receptor (1999)

The endocytic hyaluronan (HA) receptor of liver sinusoidal endothelial cells (LECs) is responsible for the clearance of HA and other glycosaminoglycans from the circulation in mammals. We report here for the first time the purification of this liver HA receptor. Using lectin and immuno-affinity chromatography, two HA receptor species were purified from detergent-solubilized membranes prepared from purified rat LECs. In nonreducing SDS-polyacrylamide gel electrophoresis (PAGE), these two proteins migrated at 175- and approximately 300 kDa corresponding to the two species previously identified by photoaffinity labeling of live cells as the HA receptor (Yannariello-Brown, J., Frost, S. J., and Weigel, P. H. (1992) J. Biol. Chem. 267, 20451-20456). These two proteins co-purify in a molar ratio of 2:1 (175:300), and both proteins are active, able to bind HA after SDS-PAGE, electrotransfer, and renaturation. After reduction, the 175-kDa protein migrates as a approximately 185-kDa protein and is not able to bind HA. The 300-kDa HA receptor is a complex of three disulfide-bonded subunits that migrate in reducing SDS-PAGE at approximately 260, 230, and 97 kDa. These proteins designated, respectively, the alpha, beta, and gamma subunits are present in a molar ratio of 1:1:1 and are also unable to bind HA when reduced. The 175-kDa protein and all three subunits of the 300-kDa species contain N-linked oligosaccharides, as indicated by increased migration in SDS-PAGE after treatment with N-glycosidase F. Both of the deglycosylated, nonreduced HA receptor proteins still bind HA.
Genetically Manipulated Bacterial Toxin as a New Generation Mucosal Adjuvant (2001)

Cholera toxin (CT) and heat-labile toxin (LT) of Escherichia coli act as adjuvants for the enhancement of mucosal and serum antibody (Ab) responses to mucosally co-administered protein antigen (Ag). Both LT and CT induce B7-2 expression on antigen-presenting cells (APCs) for subsequent co-stimulatory signalling to CD4+ T cells. CT directly affects CD4+ T cells activated via the TCR-CD3 complex with selective inhibition of Th1 responses whereas LT maintains Th1 cytokine responses with inhibition of interleukin (IL)-4 production. Interestingly, while CT failed to induce mucosal adjuvant activity in the absence of IL-4, LT did so. Nontoxic mutant (m)CTs (S61F and E112K) retain adjuvant properties by inducing CD4+ Th2 cells, which provided effective help for the Ag-specific mucosal immunoglobulin (Ig)A, as well as serum IgG1, IgE and IgA Ab responses. The mCT E112K has been shown to exhibit two distinct mechanisms for its adjuvanticity. Firstly, mCT enhanced the B7-2 expression of APCs. Secondly, this nontoxic CT derivative directly affected CD4+ T cells and selectively inhibited Th1 cytokine responses. Thus, several lines of evidence indicate that enzyme activity can be separated from adjuvant properties of CT and this offers promise for the development of safe delivery of vaccines for mucosal IgA responses.
Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses (1994)

In response to NGF, the Trk receptor tyrosine kinase forms a complex with SHC, a protein that couples receptor tyrosine kinases to p21ras. Complex formation between Trk and SHC, SHC tyrosine phosphorylation, and association of SHC with Grb2 were mediated by autophosphorylation at Y490 in Trk [sequence: see text]. To determine the role of SHC and other Trk substrates in NGF signaling, Trk receptors with mutations in Y490 and Y785 (the PLC-gamma 1 association site) were introduced into PC12nnr5 cells. NGF treatment of PC12nnr5 cells expressing Trk with mutations in either substrate-binding site resulted in normal neurite outgrowth and Erk1 activity and tyrosine phosphorylation. However, PC12nnr5 cells expressing Trk with mutations at both sites failed to stably extend neurites and efficiently induce Erk1 activity and tyrosine phosphorylation in response to NGF. We postulate that Trk receptors can activate Erk1 by either SHC- or PLC-gamma 1-dependent signaling pathways. These results suggest a model whereby Trk receptors utilize at least partially redundant signal transduction pathways to mediate NGF responses.
Setting standards for assessment of ward patients at risk of deterioration (2004)

Improving the care of critically ill patients is a key objective of the Department of Health (DoH, 2000). Research findings and anecdotal evidence suggest that the key indicators of developing critical illness (respiratory rate and fluid balance) are being missed on busy general medical and surgical wards. In order to address this issue, the East Somerset NHS Trust critical care outreach team, in collaboration with ward staff, created the Amber Project. This project aimed to identify clearly patients who were at risk of deterioration and provide qualified nurses with a clear framework and minimum standard for assessment and observation. The project ran from June to September 2003. Results indicated that on the ward using the amber system the frequency of patient observations increased compared to those found on two other general wards. Nursing staff reported feeling more confident with regard to assessment and prioritizing care. Junior medical staff, physiotherapy and nursing staff reported that multiprofessional communication had improved, resulting in identification and treatment of critically ill patients. The authors suggest that the Amber Project, which incorporates the use of a "track and trigger" warning system, has been an effective initiative in identifying patients at risk of developing critical illness on general wards. Its positive impact on the performance and confidence of qualified nurses working in difficult environments has resulted in the extension of the project to all other wards in the hospital.
A 45GHz Doherty power amplifier with 23% PAE and 18dBm output power, in 45nm SOI CMOS (2012)

A 45GHz Doherty power amplifier is implemented in 45nm SOI CMOS. Two-stack FET amplifiers are used as main and auxiliary amplifiers, allowing a supply voltage of 2.5V and high output power. The use of slow-wave coplanar waveguides (CPW) improves the PAE and gain by approximately 3% and 1dB, and reduces the die area by 20%. This amplifier exhibits more than 18dBm saturated output power, with peak power gain of 7dB. It occupies 0.64mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> while achieving a peak PAE of 23%; at 6dB back-off the PAE is 17%.
Antigen‐specific immunotherapy and cancer vaccines (2003)

The specific activation of the immune system to control cancer growth in vivo has been a long-standing goal in cancer immunology and medical oncology. The identification of tumor-associated antigens has provided the basis for new concepts in antigen-specific immunotherapy. The first clinical trials on cancer vaccines were designed to evaluate the toxicity and objectively measurable immunologic effects in relation to clinical developments mostly in patients with metastatic disease. MHC class I- and II-restricted peptide epitopes, antigenic proteins, viral constructs, mini-genes and whole tumor cells have been used either alone or combined with different cytokines (i.e., IL-2, IL-12, GM-CSF), adjuvants (incomplete Freund's adjuvant, montanide, QS21) or with dendritic cells to induce specific immune responses in vivo. Standardized assay systems to evaluate the immunologic effects of cancer vaccines have been established. Clinical developments during and after vaccination were followed in relation to vaccine-induced immune responses. Prognostic tumor features, i.e., homogeneity of tumor antigen and MHC class I/II expression and intratumoral cellular infiltrates, have been identified that may help to select patients who are more likely to benefit from antigen-specific cancer vaccines in the future.
The solid‐state michael addition of indole to 4‐arylidene‐3‐methyl‐5‐pyrazolone (1999)

Abstract The Michael addition reactions of indole to 4‐arylidene‐3‐methyl‐1‐phenyl‐5‐pyrazolone 1 were investigated in the solid state, by which a series of new compounds, 1‐aryl‐1‐(3‐indolyl)‐1‐(3′‐methyl‐1′‐phenyl‐5′‐pyrazolon‐4′‐yl)methanes 2 , were easily obtained. This provides a feasible method of preparing novel compounds containing two heterocyclic groups at the same carbon.
Spectroscopic and kinetic features of allocolchicine binding to tubulin (1989)

Allocolchicine is a structural isomer of colchicine in which colchicine's tropone C ring is replaced with an aromatic ester. In spite of the structural differences between the two ligands, the association parameters for both molecules binding to tubulin are quite similar. The association constant for allocolchicine binding to tubulin was determined by fluorescence titration to be 6.1 x 10(5) M-1 at 37 degrees C, which is about a factor of 5 less than that of the colchicine-tubulin association. In particular, analysis of the kinetics of the association of allocolchicine with tubulin yielded nearly equivalent activation parameters for the two ligands. The activation energy of the allocolchicine binding reaction was found to be 18.4 +/- 1.5 kcal/mol, which is only slightly less than the activation energy for colchicine binding to tubulin. This finding argues against conformational flexibility of the C ring as the structural feature of colchicine responsible for the slow kinetics of colchicinoid-tubulin binding reactions. Tubulin binding promote a dramatic enhancement of allocolchicine fluorescence. Unlike colchicine, the emission energy and intensity of the tubulin-bound allocolchicine fluorescence can be mimicked by solvent, and a general hydrophobic environment for the ligand binding site is indicated. The excitation spectrum of the protein-bound species, however, is shown to possess two bands which center at higher and lower energy than the energy maximum of the spectrum of the ligand in apolar solvents, indicating that properties of the colchicine binding site in addition to a low dielectric constant contribute to the fluorescence of the bound species.(ABSTRACT TRUNCATED AT 250 WORDS)