gebhart/patrepeval huggingface dataset:
Loss of Early Phase of Insulin Release in Humans Impairs Glucose Tolerance and Blunts Thermic Effect of Glucose (1987)

Loss of the early phase of insulin release has been documented in both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes; however, the physiological importance of this loss is unsettled. We created a model of loss of the early phase of insulin release in normal volunteers. Somatostatin (SRIF) was briefly infused (from -5 to 15 min) during intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The thermic response to oral glucose was determined under these conditions by indirect calorimetry. Early insulin release was totally blocked during IVGTT and OGTT by SRIF infusion. During the IVGTT, glucose tolerance was deteriorated in association with loss of the early phase of insulin release as indicated by a decrease in the K value (control 1.9 +/- 0.36 vs. SRIF 1.1 +/- 0.27, P less than .001). Higher plasma glucose concentrations were observed during SRIF tests in the OGTT at 60, 90, 120, 150, and 180 min; total glycemic excursion was larger during the SRIF test (9473 +/- 3089 mg X dl-1 X 5 h-1) when compared with the control condition (6583 +/- 2329 mg X dl-1 X 5 h-1). During the OGTT the total amount of glucose oxidized (control 56 +/- 4.2 vs. SRIF 55 +/- 3.4 g/5 h) was similar in both conditions, suggesting that nonoxidative pathways of glucose disposal were responsible for the deterioration in glucose tolerance. Surprisingly, we found that glucose-induced thermogenesis was reduced in association with loss of the early phase of insulin release (control 102 +/- 21.3 vs. SRIF 72 +/- 27.8 J/5 h, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free‐Energy Calculations, and Biological Testing (2008)

NAD+-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.
THE DEPENDENCE OF THE CONFORMATIONS OF SYNTHETIC POLYPEPTIDES ON AMINO ACID COMPOSITION1,2 (1960)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTHE DEPENDENCE OF THE CONFORMATIONS OF SYNTHETIC POLYPEPTIDES ON AMINO ACID COMPOSITION1,2E. R. Blout, C. de Lozé, S. M. Bloom, and G. D. FasmanCite this: J. Am. Chem. Soc. 1960, 82, 14, 3787–3789Publication Date (Print):July 1, 1960Publication History Published online1 May 2002Published inissue 1 July 1960https://pubs.acs.org/doi/10.1021/ja01499a080https://doi.org/10.1021/ja01499a080research-articleACS PublicationsRequest reuse permissionsArticle Views206Altmetric-Citations160LEARN 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
Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation (2008)

We have previously shown that intratumor administration of HSV-1716 (an ICP34.5 null mutant) resulted in significant reduction of tumor growth and a significant survival advantage in a murine model of ovarian cancer. Herewith we report that oncolytic HSV-1716 generates vaccination effects in the same model. Upon HSV-1716 infection, mouse ovarian tumor cells showed high levels of expression viral glycoproteins B and D and were highly phagocyted by dendritic cells (DCs). Interestingly, increased phagocytosis of tumor-infected cells by DCs was impaired by heparin, and anti-HSV glycoproteins B and D, indicating that viral infection enhances adhesive interactions between DCs and tumor apoptotic bodies. Moreover, HSV-1716 infected cells expressed high levels of heat shock proteins 70 and GRP94, molecules that have been reported to induce maturation of DCs, increase cross-presentation of antigens and promote antitumor immune response. After phagocytosis of tumor-infected cells, DCs acquired a mature status in vitro and in vivo, upregulated the expression of costimulatory molecule and increased migration towards MIP-3beta. Furthermore, HSV-1716 oncolytic treatment markedly reduced vascular endothelial growth factor (VEGF) levels in tumor-bearing animals thus abrogating tumor immunosuppressive milieu. These mechanisms may account for the highly enhanced antitumoral immune responses observed in HSV-1716 treated animals. Oncolytic treatment induced a significantly higher frequency of tumor-reactive IFNgamma producing cells, and induced a robust tumor infiltration by T cells. These results indicate that oncolytic therapy with HSV-1716 facilitates antitumor immune responses.
Glycosylation profiling of immunoglobulin G (IgG) subclasses from human serum (2007)

All four subclasses of human serum IgG contain a single N-glycosylation site in the constant region of their heavy chain, which is occupied by biantennary, largely core-fucosylated and partially truncated oligosaccharides, that may carry a bisecting N-acetylglucosamine and sialic acid residues. IgG glycosylation has been shown to be altered under various physiological and pathological circumstances. IgG N-glycan profiles vary with age, and galactosylation for example is enhanced during pregnancy. Several diseases including rheumatoid arthritis are associated with a reduction in galactosylation of the IgG N-glycans. Here, we describe a robust method for the isolation of IgG subclasses using protein A (binds IgG1, IgG2, and IgG4) and protein G (binds additionally IgG3) at the 96-well plate level, which is suitable for automation. Isolated IgGs were digested with trypsin, and obtained glycopeptides were analyzed by nano-LC-MS. Glycopeptides were characterized by CID as well as electron transfer dissociation (ETD). The method provided glycosylation profiles for IgG1, IgG2, IgG3, and IgG4 and revealed distinct differences in N-glycosylation between the four IgG subclasses. The changes in galactosylation associated with rheumatoid arthritis could readily be monitored. This method is suitable for the subclass-specific analysis of IgG glycosylation from clinical samples.
Future Advances in COPD Therapy (2001)

There is a pressing need for more effective drug treatments for COPD. New bronchodilators include a long-acting anticholinergic tiotropium bromide and a dual beta2-dopamine2-receptor agonist. But no treatments prevent the progression of COPD. Mediator antagonists in development include leukotriene B4 antagonists, chemokine receptor antagonists and more potent antioxidants. The inflammation of COPD is resistant to corticosteroids, so new anti-inflammatory drugs need to be developed. These include phosphodiesterase-4 inhibitors, nuclear factor-kappaB inhibitors and p38 MAP kinase inhibitors. Small molecule protease inhibitors, including neutrophil elastase inhibitors and selective matrix metalloproteinase inhibitors are also in development. Future drug targets may be identified by gene array and proteomics.
Shape reconstruction from images: Pixel fields and Fourier transform (2014)

We discuss shape reconstruction methods for data presented in various image spaces. We demonstrate the usefulness of the Fourier transform in transferring image data and shape model projections to a domain more suitable for shape inversion. Using boundary contours in images to represent minimal information, we present uniqueness results for shapes recoverable from interferometric and range-Doppler data. We present applications of our methods to adaptive optics, interferometry, and range-Doppler images.
Inactivation of Lassa, Marburg, and Ebola viruses by gamma irradiation (1982)

Because of the cumbersome conditions experienced in a maximum containment laboratory, methods for inactivating highly pathogenic viruses were investigated. The infectivity of Lassa, Marburg, and Ebola viruses was inactivated without altering the immunological activity after radiation with Co60 gamma rays. At 4 degrees C, Lassa virus was the most difficult to inactivate with a rate of 5.3 X 10(-6) log 50% tissue culture infective dose per rad of CO60 radiation, as compared with 6.8 X 10(-6) log 50% tissue culture infective dose per rad for Ebola virus and 8.4 X 10(-6) log 50% tissue culture infective dose per rad for Marburg virus. Experimental inactivation curves, as well as curves giving the total radiation needed to inactivate a given concentration of any of the three viruses, are presented. We found this method of inactivation to be superior to UV light or beta-propiolactone inactivation and now routinely use it for preparation of material for protein-chemistry studies or for preparation of immunological reagents.
Dominance of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization and internalization on human Th2 cells (2003)

Chemokines and their receptors play a pivotal role in controlling T cell trafficking in immunity and inflammation. Two chemokines, CCL17 and CCL22, activate the chemokine receptor CCR4, expressed on functionally distinct subsets of T cells: cutaneous leukocyte-associated antigen (CLA)+ skin-homing, T helper (Th) 2, and CD25+ T suppressor cells. Here, we compared the ability of CCL17 and CCL22 to promote CCR4 internalization as a mechanism of regulation of receptor function on human Th2 cells. We report that CCL22 is a potent and rapid inducer of CCR4 internalization, while CCL17 is not. CCR4 internalization does not require G protein coupling, while being dependent on lipid rafts integrity and clathrin-coated pits functionality. Cell surface disappearance of CCR4 is rapidly reversed upon removal of exogenous ligand by virtue of receptor recycling. CCR4 internalization leads to a loss of functional responsiveness, while recovery of surface expression leads to re-acquisition of chemotactic sensitivity of Th2 cells. The differential CCR4 desensitization and internalization reported here and the distinct expression patterns of CCL17 and CCL22 observed in vivo suggest that while CCL17 may act first on CCR4 at the endothelial surface to promote vascular recognition, CCL22 could subsequently engage the receptor within the tissue microenvironment to guide cellular localization.
Specific interaction of vitronectin with the cell‐secreted protease inhibitor glia‐derived nexin and its thrombin complex (1990)

Interaction of vitronectin with glia-derived nexin (GDN), thrombin, and the complex GDN-thrombin was demonstrated in direct binding assays that indicated the formation of binary and ternary complexes. The concentration of vitronectin necessary to obtain 50% saturation of the immobilized GDN-thrombin complex binding sites (EC50) was about 1 nM. Under similar experimental conditions, the EC50 of vitronectin for the immobilized antithrombin-III-thrombin complex was about fivefold higher. A tight complex was also formed between vitronectin and immobilized GDN (EC50 approximately 1.5 nM) but when vitronectin was immobilized, GDN displayed a reduced affinity for vitronectin (EC50 approximately 10 nM). These results suggest differences between the immobilized and free conformations of GDN and/or vitronectin. In contrast, vitronectin displayed negligible affinity for antithrombin III. Biotinylated GDN was used to characterize further the binding of GDN or the GDN-thrombin complex to vitronectin. The interaction of the biotinylated GDN-thrombin complex with immobilized vitronectin (EC50 approximately 2 nM) was completely blocked by nonbiotinylated complexes of thrombin with either GDN or antithrombin III, whereas free GDN, free thrombin and the GDN-trypsin complex were only weak competitors. Active-site-blocked urokinase and the complex GDN-urokinase also strongly competed for binding of the biotinylated GDN-thrombin complex to vitronectin. Binding of biotinylated GDN to immobilized vitronectin was specific, saturable and was competed with decreasing efficiency by the GDN-thrombin complex, free GDN and free antithrombin III. These interactions between the adhesive component vitronectin and the serine protease inhibitor GDN may relate to localized control of thrombin and/or urokinase action at certain extravascular sites. These results are discussed in terms of binding sites for vitronectin on GDN, thrombin, and the GDN-thrombin complex.
Analysis of the causes of high rates of carcase rejection at a poultry processing plant (1995)

A poultry processing plant received approximately 33.65 million birds from 87 commercial broiler growing units in 1992. Carcase rejection rates of 3 per cent or more were recorded in birds received from 13.2 per cent of the rearing houses distributed among 48 per cent of the growing units. The higher rates of carcase rejection were found on the units with an average flock size of over 100,000 birds and from rearing houses with a population of more than 30,000 birds. The main causes of rejection were birds dead on arrival, disease and miscellaneous conditions. The average rates of carcase rejection for birds dead on arrival and disease were higher on the units with a high rejection rate than on the others. The commonest cause of carcase rejection due to disease was colisepticaemia.
Prevention of coronary heart disease by raising high-density lipoprotein cholesterol? (2000)

Consistent with several potentially anti-atherogenic activities of high-density lipoproteins in vitro, low plasma levels of high-density lipoprotein cholesterol are associated with an increased risk of coronary heart disease. In addition to genes, lifestyle factors (e.g. smoking, being overweight and physical inactivity) strongly affect plasma high-density lipoprotein cholesterol levels. Moreover, a low level of high-density lipoprotein cholesterol interacts with other risk factors. Raising of high-density lipoprotein cholesterol by either adjustments of lifestyle or drug intervention as well as elimination of additional risk factors are thus thought to affect coronary risk. Here, we summarize the outcomes of observational and interventional studies as well as genetic and experimental research which have recently much advanced our understanding of the function and regulation of high-density lipoprotein metabolism. We conclude from the data that changes in the kinetics and functionality of high-density lipoprotein rather than changes in plasma high-density lipoprotein cholesterol levels per se will affect the anti-atherogenicity of therapeutic interference with high-density lipoprotein metabolism.
Site-Specific Thermodynamics:  Understanding Cooperativity in Molecular Recognition (1998)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSite-Specific Thermodynamics: Understanding Cooperativity in Molecular RecognitionEnrico Di CeraView Author Information Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St. Louis, Missouri 63110 Cite this: Chem. Rev. 1998, 98, 4, 1563–1592Publication Date (Web):May 9, 1998Publication History Received16 December 1997Revised8 April 1998Published online9 May 1998Published inissue 1 June 1998https://pubs.acs.org/doi/10.1021/cr960135ghttps://doi.org/10.1021/cr960135gresearch-articleACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views917Altmetric-Citations76LEARN 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 SUBJECTS:Chemical specificity,Electron correlation,Free energy,Genetics,Peptides and proteins Get e-Alerts
Antagonists of the Platelet P2T Receptor:  A Novel Approach to Antithrombotic Therapy (1999)

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.
IκB Kinase (IKK)-Associated Protein 1, a Common Component of the Heterogeneous IKK Complex (1999)

Activation of the transcription factor NF-kappaB is controlled by the sequential phosphorylation, ubiquitination, and degradation of its inhibitory subunit, IkappaB. We recently purified a large multiprotein complex, the IkappaB kinase (IKK) signalsome, which contains two regulated IkappaB kinases, IKK1 and IKK2, that can each phosphorylate IkappaBalpha and IkappaBbeta. The IKK signalsome contains several additional proteins presumably required for the regulation of the NFkappaB signal transduction cascade in vivo. In this report, we demonstrate reconstitution of IkappaB kinase activity in vitro by using purified recombinant IKK1 and IKK2. Recombinant IKK1 or IKK2 forms homo- or heterodimers, suggesting the possibility that similar IKK complexes exist in vivo. Indeed, in HeLa cells we identified two distinct IKK complexes, one containing IKK1-IKK2 heterodimers and the other containing IKK2 homodimers, which display differing levels of activation following tumor necrosis factor alpha stimulation. To better elucidate the nature of the IKK signalsome, we set out to identify IKK-associated proteins. To this end, we purified and cloned a novel component common to both complexes, named IKK-associated protein 1 (IKKAP1). In vitro, IKKAP1 associated specifically with IKK2 but not IKK1. Functional analyses revealed that binding to IKK2 requires sequences contained within the N-terminal domain of IKKAP1. Mutant versions of IKKAP1, which either lack the N-terminal IKK2-binding domain or contain only the IKK2-binding domain, disrupt the NF-kappaB signal transduction pathway. IKKAP1 therefore appears to mediate an essential step of the NF-kappaB signal transduction cascade. Heterogeneity of IKK complexes in vivo may provide a mechanism for differential regulation of NF-kappaB activation.
Cytoplasmic tail deletion of T cell receptor (TCR) beta-chain results in its surface expression as glycosylphosphatidylinositol-anchored polypeptide on mature T cells in the absence of TCR-alpha. (1994)

Surface expression of the T cell antigen receptor (TCR) in mature T cells requires the association of a variable heterodimer (alpha.beta or gamma.delta) with six invariant CD3 polypeptides (gamma, delta, epsilon-epsilon, zeta-zeta, or zeta-eta). We described here that deletion of the cytoplasmic tail polypeptide sequence (Lys-Lys-Lys-Asn-Ser) of TCR beta-chain (beta CT) results in expression of the truncated beta-chain on the surface of a mature T cell hybridoma line, in the absence of TCR-alpha, as a glycophosphatidylinositol (GPI)-anchored monomeric polypeptide. The GPI-anchored TCR-beta CT is not associated with CD3-epsilon and is incapable of conventional signal transduction. Association with TCR-alpha prevents beta CT from GPI-linkage formation. The alpha beta CT heterodimer binds the CD3 polypeptides, and the resultant TCR alpha beta CT/CD3 complex is capable of signal transduction. Our data show that a signal sequence for GPI-linkage formation is present in TCR-beta, and this alternative membrane anchoring mechanism can be utilized by beta-chain polypeptide lacking the CT sequence. We conclude therefore that in the absence of TCR-alpha expression, the beta-chain CT sequence plays an essential function in hindering GPI-linkage formation, thereby preventing escape of incompletely assembled TCR beta-chain to the cell surface of mature T cells.
Methods for the freeze-fracturing of nerve tissue cultures and cell monolayers. (1975)

Two methods for freeze-cleaving of thin tissue layers are presented. Whereas a simple technique can be employed to fracture continuous, relatively firm tissue layers, a more sophisticated technique employing special carriers is needed to fracture very thin and incomplete layers, e.g., the fiber outgrowth of cultured nerve tissue or sparsely seeded isolated cells. Both methods basically consist of freezing the specimens sandwiched between two small metal carriers which are then fractured apart so that the cleavage plane runs through the tissue. In the resulting replicas of such thin specimens, large membrane areas are exposed, and new information is provided on the topography of membrane properties in entire cells or cell processes. The technique should also be useful for studies on the interactions of cells grown in culture.