gebhart/patrepeval huggingface dataset:
Synthesis, Fluorine-18 Radiolabeling, and Biological Evaluation ofN-((E)-4-Fluorobut-2-en-1-yl)-2β-carbomethoxy-3β-(4′-halophenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Brain Dopamine Transporter with Positron Emission Tomography (2010)

The N-(E)-fluorobutenyl-3beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as (18)F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [(18)F]9-[(18)F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [(18)F]9. PET imaging with [(18)F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [(18)F]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was > or = 4.
Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. (2013)

3 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
The plasminogen system and cell surfaces: evidence for plasminogen and urokinase receptors on the same cell type. (1986)

The capacity of cells to interact with the plasminogen activator, urokinase, and the zymogen, plasminogen, was assessed using the promyeloid leukemic U937 cell line and the diploid fetal lung GM1380 fibroblast cell line. Urokinase bound to both cell lines in a time-dependent, specific, and saturable manner (Kd = 0.8-2.0 nM). An active catalytic site was not required for urokinase binding to the cells, and 55,000-mol-wt urokinase was selectively recognized. Plasminogen also bound to the two cell lines in a specific and saturable manner. This interaction occurred with a Kd of 0.8-0.9 microM and was of very high capacity (1.6-3.1 X 10(7) molecules bound/cell). The interaction of plasminogen with both cell types was partially sensitive to trypsinization of the cells and required an unoccupied high affinity lysine-binding site in the ligand. When plasminogen was added to the GM1380 cells, a line with high intrinsic plasminogen activator activity, the bound ligand was comprised of both plasminogen and plasmin. Urokinase, in catalytically active or inactive form, enhanced plasminogen binding to the two cell lines by 1.4-3.3-fold. Plasmin was the predominant form of the bound ligand when active urokinase was added, and preformed plasmin can also bind directly to the cells. Plasmin on the cell surface was also protected from its primary inhibitor, alpha 2-antiplasmin. These results indicate that the two cell lines possess specific binding sites for plasminogen and urokinase, and a family of widely distributed cellular receptors for these components may be considered. Endogenous or exogenous plasminogen activators can generate plasmin on cell surfaces, and such activation may provide a mechanism for arming cell surfaces with the broad proteolytic activity of this enzyme.
Dynamic Distribution of Linker Histone H1.5 in Cellular Differentiation (2012)

Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells.
Chlorocarbon emission scenarios: Potential impact on stratospheric ozone (1983)

Prior analyses of chlorocarbons and their effects on stratospheric ozone have primarily concentrated on examining potential perturbations from two chlorofluorocarbons, CFC ℓ 3 (CFC‐11) and CF 2 C ℓ 2 (CFC‐12). The purpose of this study is to provide an updated theoretical analysis of the potential effect on ozone due to past and future chlorocarbon emissions. To assess the overall impact from chlorinated emissions on the ozone layer, all chlorocarbons presently thought to be of likely concern are examined. A broad spectrum of scenarios is evaluated in order to provide an envelope including conceivable changes in future chlorocarbon emissions. Results indicate that CFC ℓ 2 CF 2 C ℓ (CFC‐113), CH 3 CC ℓ 3 , and CC ℓ 4 could contribute significantly to predicted changes in total ozone based on their current emission rates.
Mucosal vaccines to prevent porcine reproductive and respiratory syndrome: a new perspective (2012)

Porcine reproductive and respiratory syndrome (PRRS) is an economically important infectious disease of swine. Constant emergence of variant strains of PRRS virus (PPRSV) and virus-mediated immune evasion followed by viral persistence result in increased incidence and recurrence of PRRS in swine herds. Current live and killed PRRSV vaccines administered by a parenteral route are ineffective in inducing complete protection. Thus, new approaches in design and delivery of PRRSV vaccines are needed to reduce the disease burden of the swine industry. Induction of an effective mucosal immunity to several respiratory pathogens by direct delivery of a vaccine to mucosal sites has proven to be effective in a mouse model. However, there are challenges in eliciting mucosal immunity to PRRS due to our limited understanding of safe and potent mucosal adjuvants, which could potentiate the mucosal immune response to PRRSV. The purpose of this review is to discuss methods for induction of protective mucosal immune responses in the respiratory tract of pigs. The manuscript also discusses how PRRSV modulates innate, adaptive and immunoregulatory responses at both mucosal and systemic sites of infected and/or vaccinated pigs. This information may help in the design of innovative mucosal vaccines to elicit superior cross-protective immunity against divergent field strains of PRRSV.
Pharmaceutical approval update. (2013)

Albiglutide (Tanzeum) for type-2 diabetes, ramucirumab (Cyramza) for advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma, and ceritinib (Zykadia) for metastatic non-small-cell lung cancer.
Regulatory T Cells and Human Disease (2020)

Naturally occurring CD4<sup>+</sup> regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.
11Beta-hydroxysteroid dehydrogenase responsible for carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes. (1998)

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals and is most likely involved in the etiology of tobacco smoke-induced lung cancer. To exert its carcinogenic potential, NNK must be metabolically activated by alpha-hydroxylation at either the methyl or methylene carbons adjacent to the N-nitroso group. The main detoxification pathway of NNK involves carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol followed by glucuronosylation at the hydroxy moiety produced by carbonyl reduction. Whereas there has been great success in the identification of cytochrome P450 species catalyzing NNK activation, the enzyme responsible for NNK carbonyl reduction has been searched for since 1980. In previous investigations, we succeeded in identifying the NNK carbonyl reducing enzyme in mouse liver microsomes as being 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD 1; EC 1.1.1.146), an enzyme that is physiologically involved in glucocorticoid oxidoreduction. In this study, the expression of 11beta-HSD 1 was established on the mRNA (reverse transcription-PCR) and protein (immunoblot) levels. Kinetics of glucocorticoid oxidoreduction were determined with corticosterone and dehydrocorticosterone as substrates for oxidation and reduction, respectively. The apparent Vmax (135.8 versus 48.1 pmol/min/mg of protein) and Km (6.8 versus 35.8 microM) values were much in favor for corticosterone oxidation compared to dehydrocorticosterone reduction. NNK carbonyl reduction displayed an apparent Vmax of 655 pmol/min/mg of protein and a Km of 629 microM. Interestingly, the intrinsic clearance (Vmax/Km ratio) of NNK carbonyl reduction (1.04) corresponds roughly to that of glucocorticoid reduction (1.34). The physiological glucocorticoid substrates of 11beta-HSD 1 (corticosterone and dehydrocorticosterone) and the selective 11beta-HSD 1 inhibitor glycyrrhetinic acid turned out to be strong inhibitors of NNK carbonyl reduction, displaying Ki values of 37.8, 21.3, and 10.9 microM, respectively. Affinity-purified antibodies specific for mouse liver 11beta-HSD 1 inhibited NNK carbonyl reduction in a concentration-dependent manner. For example, at the highest antibody concentration (5 microg of protein), 11beta-HSD 1 activity was decreased to a residual 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formation of only 7.9% compared to the uninhibited control, thus conclusively demonstrating NNK carbonyl reduction to be mediated by 11beta-HSD 1 in mouse lung microsomes. Evidence is provided in the present study that 11beta-HSD 1 is expressed in mouse lung and that it functions as NNK carbonyl reductase in mouse lung microsomes. These findings may have potentially important implications for smokers who express low levels of 11beta-HSD 1/NNK carbonyl reductase and/or are concurrently being exposed to 11beta-HSD 1 modulators.
Hepatic Differentiation of Human Embryonic Stem Cells Is Promoted by Three-Dimensional Dynamic Perfusion Culture Conditions (2011)

The developmental potential of human embryonic stem cells (hESCs) holds great promise to provide a source of human hepatocytes for use in drug discovery, toxicology, hepatitis research, and extracorporeal bioartificial liver support. There are, however, limitations to induce fully functional hepatocytes on conventional two-dimensional (2D) static culture. It had been shown that dynamic three-dimensional (3D) perfusion culture is superior to induce maturation in fetal hepatocytes and prolong hepatic functions of primary adult hepatocytes. We investigated the potential of using a four-compartment 3D perfusion culture to induce hepatic differentiation in hESC. Undifferentiated hESC were inoculated into hollow fiber-based 3D perfusion bioreactors with integral oxygenation. Hepatic differentiation was induced with a multistep growth factor cocktail protocol. Parallel controls were operated under equal perfusion conditions without the growth factor supplementations to allow for spontaneous differentiation, as well as in conventional 2D static conditions using growth factors. Metabolism, hepatocyte-specific gene expression, protein expression, and hepatic function were evaluated after 20 days. Significantly upregulated hepatic gene expression was observed in the hepatic differentiation 3D culture group. Ammonia metabolism activity and albumin production was observed in the 3D directed differentiation culture. Drug-induced cytochrome P450 gene expression was increased with rifampicin induction. Using flow cytometry analysis the mature hepatocyte marker asialoglycoprotein receptor was found on up to 30% of the cells in the 3D system with directed hepatic differentiation. Histological and immunohistochemical analysis revealed structural formation of hepatic and biliary marker-positive cells. In contrast to 2D culture, the 3D perfusion culture induced more functional maturation in hESC-derived hepatic cells. 3D perfusion bioreactor technologies may be useful for further studies on generating hESC-derived hepatic cells.
Pyrrolidines. IX. 3-Aryl-3-pyrrolidinols (1964)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPyrrolidines. IX. 3-Aryl-3-pyrrolidinolsWilliam A. Gould, Paul M. Lish, Yao-Hua Wu, Herbert R. Roth, Walter G. Lobeck Jr., James M. Berdahl, and Rolland F. FeldkampCite this: J. Med. Chem. 1964, 7, 1, 60–67Publication Date (Print):January 1, 1964Publication History Published online1 May 2002Published inissue 1 January 1964https://pubs.acs.org/doi/10.1021/jm00331a014https://doi.org/10.1021/jm00331a014research-articleACS PublicationsRequest reuse permissionsArticle Views181Altmetric-Citations4LEARN 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
Oxygen Sensing in Nonaqueous Media Using Porous Glass with Covalently Bound Luminescent Ru(II) Complexes (1998)

A comparative study of the oxygen-quenching features of novel luminescent Ru(II) complexes, covalently attached to controlled porous glass (CPG), has been performed in methanol, chloroform, toluene, cyclohexane, and n-hexane. The investigated dyes contain 1,10-phenanthroline-4,7-bis(phenylsulfonate) (s2d), 5-acetamide-1,10-phenanthroline (acap), and 5-tetradecanamide-1,10-phenanthroline (tdap) coordinated to the Ru(s2d)2 moiety. The immobilization procedure involves stable sulfonamide linkages to amino-derivatized CPG-Glycophase, the loading being a function of indicator molecular size (i.e., highest for the [Ru(s2d)2(acap)]2- dye). Steady-state and time-resolved emission analysis have revealed that oxygen quenching is purely dynamic and occurs on the glass bead surface. Using a continuous-flow system and a conventional spectrofluorometer, a detection limit of 6.2 μM (200 ppb) oxygen in methanol has been achieved and a 2−4-fold one in the other organic solvents tested, with dynamic ranges over two decades. The analytical figures of merit make the fabricated sensing phases suitable for fiber-optic industrial monitors and oxygen transducers for optical biosensing in nonaqueous media.
Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network (2003)

The Myc/Max/Mad transcription factor network is critically involved in cell behavior; however, there is relatively little information on its genomic binding sites. We have employed the DamID method to carry out global genomic mapping of the Drosophila Myc, Max, and Mad/Mnt proteins. Each protein was tethered to Escherichia coli DNA adenine-methyltransferase (Dam) permitting methylation proximal to in vivo binding sites in Kc cells. Microarray analyses of methylated DNA fragments reveals binding to multiple loci on all major Drosophila chromosomes. This approach also reveals dynamic interactions among network members as we find that increased levels of dMax influence the extent of dMyc, but not dMnt, binding. Computer analysis using the REDUCE algorithm demonstrates that binding regions correlate with the presence of E-boxes, CG repeats, and other sequence motifs. The surprisingly large number of directly bound loci ( approximately 15% of coding regions) suggests that the network interacts widely with the genome. Furthermore, we employ microarray expression analysis to demonstrate that hundreds of DamID-binding loci correspond to genes whose expression is directly regulated by dMyc in larvae. These results suggest that a fundamental aspect of Max network function involves widespread binding and regulation of gene expression.
The impact of state physical education requirements on youth physical activity and overweight (2007)

To combat childhood overweight in the US, which has risen dramatically in the past three decades, many medical and public health organizations have called for students to spend more time in physical education (PE) classes. This paper is the first to examine the impact of state PE requirements on student PE exercise time. It also exploits variation in state laws as quasi-natural experiments in order to estimate the causal impact of PE on overall student physical activity and weight. We study nationwide data from the Youth Risk Behavior Surveillance System for 1999, 2001, and 2003 merged with data on state minimum PE requirements from the 2001 Shape of the Nation Report. We find that high school students with a binding PE requirement report an average of 31 additional minutes per week spent physically active in PE class. Our results also indicate that additional PE time raises the number of days per week that girls report having exercised vigorously or having engaged in strength-building activity. We find no evidence that PE lowers BMI or the probability that a student is overweight. We conclude that raising PE credit requirements may make girls more physically active overall but there is not yet the scientific base to declare raising PE requirements an anti-obesity initiative for either boys or girls.
Analysis of an engineered plasma kallikrein inhibitor and its effect on contact activation (2010)

Engineering of protein-protein interactions is used to enhance the affinity or specificity of proteins, such as antibodies or protease inhibitors, for their targets. However, fully diversifying all residues in a protein-protein interface is often unfeasible. Therefore, we limited our phage library for the serine protease inhibitor ecotin by restricting it to only tetranomial diversity and then targeted all 20 amino acid residues involved in protein recognition. This resulted in a high-affinity and highly specific plasma kallikrein inhibitor, ecotin-Pkal. To validate this approach we dissected the energetic contributions of each wild type (wt) or mutated surface loop to the binding of either plasma kallikrein (PKal) or membrane-type serine protease 1. The analysis demonstrated that a mutation in one loop has opposing effects depending on the sequence of surrounding loops. This finding stresses the cooperative nature of loop-loop interactions and justifies targeting multiple loops with a limited diversity. In contrast to ecotin wt, the specific loop combination of ecotin-Pkal discriminates the subtle structural differences between the active enzymes, PKal and Factor XIIa, and their respective zymogen forms. We used ecotin-Pkal to specifically inhibit contact activation of human plasma at the level mediated by plasma kallikrein.
X‐ray scattering in full‐field digital mammography (2003)

Effects of x-ray scattering on full-field digital mammography are analyzed with the scattering model of Seibert and Boone [Med. Phys. 15, 567-575 (1988)]. A new method is introduced for the estimation of model parameters from measurements. It is shown that with breasts thinner than a certain threshold, removing the anti-scatter grid leads to an improved contrast-to-noise ratio with a smaller patient dose. A fast approximate algorithm is presented for determining the scattered field in a gridless digital mammogram.
Regulation of macrophage Ia expression in mice with severe combined immunodeficiency: induction of Ia expression by a T cell-independent mechanism. (1986)

We have studied the expression of Ia molecules by macrophages from mice with severe combined immunodeficiency (CB-17 scid) that lack demonstrable T cell and B cell functions. CB-17 scid mice had approximately normal numbers of Ia-bearing macrophages in the peritoneal cavity, spleen, and liver. Peritoneal macrophages responded in culture to T cell-derived lymphokines with enhanced expression of Ia molecules. However, unlike immunocompetent controls, SCID mice could not enhance Ia expression in an antigen-specific T cell-dependent manner after secondary challenge in vivo with a conventional protein antigen such as hemocyanin. Further demonstration of their T cell deficiency was the failure of CB-17 scid spleen cells to proliferate and produce IL 2 in response to the T cell mitogen, concanavalin A. Upon infection with Listeria monocytogenes, CB-17 scid mice developed chronically high loads of bacteria, whereas CB-17 control mice eliminated all viable bacteria and became resistant to secondary infection. However, Listeria-infected CB-17 scid mice did show, in parallel with the CB-17 controls, an unexpected and striking increase of Ia-positive macrophages. These data indicate that induction of Ia expression in macrophages can occur via a mechanism that is independent of mature T cells.
A Thermodynamic Scale for the Helix-Forming Tendencies of the Commonly Occurring Amino Acids (1990)

Amino acids have distinct conformational preferences that influence the stabilities of protein secondary and tertiary structures. The relative thermodynamic stabilities of each of the 20 commonly occurring amino acids in the alpha-helical versus random coil states have been determined through the design of a peptide that forms a noncovalent alpha-helical dimer, which is in equilibrium with a randomly coiled monomeric state. The alpha helices in the dimer contain a single solvent-exposed site that is surrounded by small, neutral amino acid side chains. Each of the commonly occurring amino acids was substituted into this guest site, and the resulting equilibrium constants for the monomer-dimer equilibrium were determined to provide a list of free energy difference (delta delta G degree) values.