gebhart/patrepeval huggingface dataset:
High-performance liquid chromatography coupled to high-field proton nuclear magnetic resonance spectroscopy: application to the urinary metabolites of ibuprofen (1993)

The use of coupled reversed-phase high-performance liquid chromatography and high-field proton nuclear magnetic resonance spectroscopy (HPLC-NMR) for the detection and identification of the urinary metabolites of ibuprofen is described. Urine was obtained from a healthy human volunteer following a normal therapeutic dose of 400 mg of ibuprofen. Analysis was performed on both a freeze-dried urine concentrate and partially purified extracts obtained by solid-phase extraction onto C-18 bonded silica gel. Both continuous and stop-flow methods were used to obtain spectra enabling the major urinary metabolites of ibuprofen to be detected and identified.
Molecular Determinants of Ligand Binding to the Human Melanocortin-4 Receptor (2000)

To elucidate the molecular basis for the interaction of ligands with the human melanocortin-4 receptor (hMC4R), agonist structure-activity studies and receptor point mutagenesis were performed. Structure-activity studies of [Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone (NDP-MSH) identified D-Phe7-Arg8-Trp9 as the minimal NDP-MSH fragment that possesses full agonist efficacy at the hMC4R. In an effort to identify receptor residues that might interact with amino acids in this tripeptide sequence 24 hMC4R transmembrane (TM) residues were mutated (the rationale for choosing specific receptor residues for mutation is outlined in the Results section). Mutation of TM3 residues D122 and D126 and TM6 residues F261 and H264 decreased the binding affinity of NDP-MSH 5-fold or greater, thereby identifying these receptor residues as sites potentially involved in the sought after ligand-receptor interactions. By examination of the binding affinities and potencies of substituted NDP-MSH peptides at receptor mutants, evidence was found that core melanocortin peptide residue Arg8 interacts at a molecular level with hMC4R TM3 residue D122. TM3 mutations were also observed to decrease the binding of hMC4R antagonists. Notably, mutation of TM3 residue D126 to alanine decreased the binding affinity of AGRP (87-132), a C-terminal derivative of the endogenous melanocortin antagonist, 8-fold, and simultaneous mutations D122A/D126A completely abolished AGRP (87-132) binding. In addition, mutation of TM3 residue D122 or D126 decreased the binding affinity of hMC4R antagonist SHU 9119. These results provide further insight into the molecular determinants of hMC4R ligand binding.
Hydrogen Isotopic Profile in the Characterization of Sugars. Influence of the Metabolic Pathway (2002)

The site-specific natural hydrogen isotope ratios of plant metabolites determined by 2H nuclear magnetic resonance (SNIF-NMR method) can provide powerful criteria for inferring mechanistic and environmental effects on biosynthetic pathways. This work examines the potential of isotopic profiles for the main constituents of carbohydrates, glucose and fructose, to distinguish different photosynthetic pathways. An appropriate analytical strategy, involving three suitable isotopic probes, has been elaborated with a view to measuring simultaneously, in conditions devoid of isotopic perturbations, all (or nearly all) of the carbon-bound hydrogen isotope ratios. It is shown that the type of photosynthetic metabolism, either C3 (sugar beet, orange, and grape), C4 (maize and sugar cane), or CAM (pineapple), and the physiological status of the precursor plant exert strong influences on the deuterium distribution in the sugar molecules. Consequently, this isotopic fingerprint may be a rich source of information for the comparison of mechanisms in metabolic pathways. In addition, it can provide complementary criteria to ethanol as a probe for the origin of sugars.
Mitochondrial ATP-sensitive K+channels modulate cardiac mitochondrial function (1998)

Discovered in the cardiac sarcolemma, ATP-sensitive K+ (KATP) channels have more recently also been identified within the inner mitochondrial membrane. Yet the consequences of mitochondrial KATP channel activation on mitochondrial function remain partially documented. Therefore, we isolated mitochondria from rat hearts and used K+ channel openers to examine the effect of mitochondrial KATP channel opening on mitochondrial membrane potential, respiration, ATP generation, Ca2+ transport, and matrix volume. From a mitochondrial membrane potential of -180 +/- 15 mV, K+ channel openers, pinacidil (100 microM), cromakalim (25 microM), and levcromakalim (20 microM), induced membrane depolarization by 10 +/- 7, 25 +/- 9, and 24 +/- 10 mV, respectively. This effect was abolished by removal of extramitochondrial K+ or application of a KATP channel blocker. K+ channel opener-induced membrane depolarization was associated with an increase in the rate of mitochondrial respiration and a decrease in the rate of mitochondrial ATP synthesis. Furthermore, treatment with a K+ channel opener released Ca2+ from mitochondria preloaded with Ca2+, an effect also dependent on extramitochondrial K+ concentration and sensitive to KATP channel blockade. In addition, K+ channel openers, cromakalim and pinacidil, increased matrix volume and released mitochondrial proteins, cytochrome c and adenylate kinase. Thus, in isolated cardiac mitochondria, KATP channel openers depolarized the membrane, accelerated respiration, slowed ATP production, released accumulated Ca2+, produced swelling, and stimulated efflux of intermembrane proteins. These observations provide direct evidence for a role of mitochondrial KATP channels in regulating functions vital for the cardiac mitochondria.
Role of CD39 (NTPDase-1) in Thromboregulation, Cerebroprotection, and Cardioprotection (2005)

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to coronary, carotid, or peripheral arteries promotes excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently, inadequate therapeutic approaches to stroke and coronary artery disease (CAD) are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions among platelets and other blood cells. This led to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by different cell types that could not individually synthesize the metabolite(s). Endothelium controls platelet reactivity via at least three biochemical systems: autacoids leading to production of prostacyclin and nitric oxide (NO) and endothelial ecto-adenosine phosphatase (ADPase)/CD39/nucleoside triphosphate diphosphohydrolase (NTPDase-1). The autacoids are fluid phase reactants, not produced by tissues in the basal state, but are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, they exert fleeting actions in the immediate milieu and are rapidly inactivated. CD39 is an integral component of the endothelial cell (EC) surface and is substrate activated. It maintains vascular fluidity in the complete absence of prostacyclin and NO, indicating that the latter are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient and local action and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in animal models. It metabolically neutralizes a prothrombotic releasate via deletion of ADP-the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced adenosine triphosphate (ATP)- and ischemia-induced norepinephrine release in the heart. This action can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in cd39 null mice. Thus, CD39 represents the next generation of cardioprotective and cerebroprotective molecules. This article focuses on our interpretations of recent data and their implications for therapeutics.
Complex Formation by Human Cytomegalovirus Glycoproteins M (gpUL100) and N (gpUL73) (2000)

The envelope glycoproteins of human cytomegalovirus (HCMV) virions are incompletely characterized. We have analyzed complex formation between glycoprotein M (gM or gpUL100) and a second glycoprotein. gM-homologous proteins are conserved throughout the herpesvirus family and represent type III membrane proteins containing multiple hydrophobic sequences. In extracellular HCMV particles, gM was found to be complexed through disulfide bonds to a second protein with an apparent molecular mass of 50 to 60 kDa. The 50- to 60-kDa protein was found to be derived from reading frame UL73 of HCMV strain AD169. UL73-homologous genes are also conserved within herpesviruses. When transiently expressed by itself, the UL73 gene product consisted of a protein of 18 kDa. However, in the presence of gM, the UL73 gene product was posttranslationally modified to the 50- to 60-kDa species. Thus, gM and the UL73 gene product, which represents the gN homolog of herpesviruses, form a disulfide-linked complex in HCMV virions. Transient expression of gM and gN followed by fluorescence imaging with monoclonal antibodies against either protein demonstrated that complex formation was required for transport of the proteins from the endoplasmic reticulum to the Golgi and trans-Golgi compartments. Finally, we tested the gM-gN complex for reactivity with sera from HCMV-seropositive donors. Whereas most sera failed to react with either gM or gN when expressed alone, 62% of sera were positive for the gM-gN complex. Because a murine monoclonal antibody reactive with gN in the gM-gN complex efficiently neutralizes infectious virus, the gM-gN complex may represent a major antigenic target of antiviral antibody responses.
Surgical Wound Drainage: A Simple Device for Collection (1972)

No AccessJournal of Urology1 Aug 1972Surgical Wound Drainage: A Simple Device for Collection Casimir F. Firlit and John R. Canning Casimir F. FirlitCasimir F. Firlit More articles by this author and John R. CanningJohn R. Canning More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(17)60729-8AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Surgical Wound Drainage: A Simple Device for Collection." The Journal of Urology, 108(2), p. 327 © 1972 by The American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 108Issue 2August 1972Page: 327 Advertisement Copyright & Permissions© 1972 by The American Urological Association Education and Research, Inc.MetricsAuthor Information Casimir F. Firlit More articles by this author John R. Canning More articles by this author Expand All Advertisement PDF downloadLoading ...
A macrophage subpopulation recruited by CC chemokine ligand-2 clears apoptotic cells in noninfectious lung injury (2012)

CC chemokine ligand-2 (CCL2)/monocyte chemoattractant protein (MCP)-1 expression is upregulated during pulmonary inflammation, and the CCL2-CCR2 axis plays a critical role in leukocyte recruitment and promotion of host defense against infection. The role of CCL2 in mediating macrophage subpopulations in the pathobiology of noninfectious lung injury is unknown. The goal of this study was to examine the role of CCL2 in noninfectious acute lung injury. Our results show that lung-specific overexpression of CCL2 protected mice from bleomycin-induced lung injury, characterized by significantly reduced mortality, reduced neutrophil accumulation, and decreased accumulation of the inflammatory mediators IL-6, CXCL2 (macrophage inflammatory protein-2), and CXCL1 (keratinocyte-derived chemokine). There were dramatic increases in the recruitment of myosin heavy chain (MHC) II IA/IE(int)CD11c(int) cells, exudative macrophages, and dendritic cells in Ccl2 transgenic mouse lungs both at baseline and after bleomycin treatment compared with levels in wild-type mice. We further demonstrated that MHCII IA/IE(int)CD11c(int) cells engulfed apoptotic cells during acute lung injury. Our data suggested a previously undiscovered role for MHCII IA/IE(int)CD11c(int) cells in apoptotic cell clearance and inflammation resolution.
Balsalazide therapy in ulcerative colitis (2001)

Balsalazide is a 5-aminosalicylic acid (mesalazine) pro-drug which has an inert carrier molecule instead of the sulfapyridine moiety of sulfasalazine. It is designed to deliver 5-aminosalicylic acid to the colonic mucosa without the sulfapyridine-associated side-effects encountered with sulfasalazine. Several studies have confirmed the efficacy and patient tolerance of balsalazide. When compared to mesalazine at equivalent doses, it induced symptomatic and complete remission of acute ulcerative colitis in a greater proportion of patients. In particular, patients with resistant left-sided disease were shown to have a higher probability of achieving remission. Balsalazide was beneficial in patients with troublesome nocturnal symptoms. It has a similar efficacy in maintaining remission when compared to sulfasalazine and mesalazine. The advantage of balsalazide over other 5-aminosalicylic acid compounds is its superior patient tolerability with minimal side-effects.
Mapping the CD4 binding site for human immunodeficiency virus by alanine-scanning mutagenesis. (1990)

Infection of mononuclear cells by human immunodeficiency virus (HIV) begins with binding of the viral envelope glycoprotein, gp120, to its receptor, CD4. CD4 contains four extracellular immunoglobulin-like domains, the first of which (V1) is sufficient for HIV binding. V1 contains three sequences homologous to the antigen-complementarity-determining regions (CDR1 to -3) of immunoglobulin variable domains. While all three immunoglobulin CDRs are involved in antigen binding, only amino acids within and flanking the CDR2-like region of CD4 have been shown previously to be involved in gp120 binding. To investigate whether other regions in V1 take part in gp120 binding, we substituted alanine for each of 64 amino acids, including all of the hydrophilic residues in this domain. Mutations at four locations outside the CDR2-like sequence (amino acids 29, 59-64, 77-81, and 85) markedly affected gp120 binding, but not the overall structure of V1 as probed with eight conformationally sensitive monoclonal antibodies. Thus, the gp120-binding site of CD4 is not limited to the CDR2-like sequence and consists of several discontinuous segments. Several amino acids were identified that are critical for the conformation of V1; the importance of these residues suggests some differences in the folding of this domain compared to immunoglobulin variable domains. Three amino acid substitutions were found that increase the affinity for gp120 significantly (1.7- to 2-fold individually and 4.2-fold when combined), suggesting that it may be possible to improve the HIV-blocking ability of CD4-based molecules by increasing their gp120 binding affinity.
N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs (2018)

Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC<sub>0- t</sub> and a 1.7-fold improvement in brain AUC<sub>0- t</sub> with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC<sub>0- t</sub> with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.
Organophosphorus Chemistry. III. The Reactions of Triphenylphosphine with Secondary α-Bromo Ketones and with 2-Bromodimedone (1966)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOrganophosphorus Chemistry. III. The Reactions of Triphenylphosphine with Secondary α-Bromo Ketones and with 2-BromodimedoneIrving J. Borowitz, Kenneth C. Kirby Jr., and Rein VirkhausCite this: J. Org. Chem. 1966, 31, 12, 4031–4037Publication Date (Print):December 1, 1966Publication History Published online1 May 2002Published inissue 1 December 1966https://doi.org/10.1021/jo01350a034RIGHTS & PERMISSIONSArticle Views371Altmetric-Citations14LEARN 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 InReddit PDF (1018 KB) Get e-Alerts Get e-Alerts
Mutation profiling and treatment choosing of Chinese RET positive advanced lung cancer patients. (2018)

e21139 Background: RET is one of the rare driver genes in lung cancer, especially in NSCLC. In this study, we performed mutation profiling and treatment choice follow-up in Chinese advanced lung cancer patients. Methods: A total of 2755 advanced lung cancer patients were enrolled in this study, all samples were analyzed by next-generation sequencing across 59 genes based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations. Results: Mutation profiling was possible for all patients, RET rearrangements were detected in 36 patients (1.3%). Of these 36 RET+ patients, the median age was 53(range 27-86); 42% were female. The most common histologies were NSCLC (78%) and LMAC (6%). Interestingly, a SCLC patient has also been identified as RET+, which has not been reported before. RET rearrangement occured in all these patients, predominantly fused with KIF5B (67%) and CCDC6 (25%), with ANK, ERC1 and NCOA1 followed. ANK-RET and ERC1-RET were commonly founded in thyroid carcinoma or breast cancer, and rare in NSCLC. 4 patients coexist with EGFR mutations, were all resulting in EGFR-TKIs treatment. For treatments, 33% patients chose RET inhibitors, another 14% patients chose chemotherapy or chemoradiotherapy. Of the 13 patients never been treated, 31% (4/13) accepted RET inhibitors and received ORR 75%. Conclusions: RET fusion mutation has complex heterogeneity, target NGS profiling is a available tool that can detected rare fusion types, may provide insight into heterogeneity. There is still much room for growth for RET inhibitors in Chinese advanced lung cancer.
AN ALTERNATIVE METHOD FOR SCORING ADAPTIVE TESTS1 (1994)

ABSTRACT Modern applications of computerized adaptive testing (CAT) are typically grounded in Item Response Theory (IRT; Lord, 1980). While the IRT foundations of adaptive testing provide a number of approaches to adaptive test scoring that may seem natural and efficient to psychometricians, these approaches may be more demanding for test‐takers, test score users, interested regulatory institutions, and so forth, to comprehend. An alternative method, based on more familiar equated number‐correct scores and identical to that used to score and equate many conventional tests, is explored and compared with one that relies more directly on IRT. The conclusion is reached that scoring adaptive tests using the familiar number‐correct score, accompanied by the necessary equating to adjust for the intentional differences in adaptive test difficulty, is a statistically viable, although slightly less efficient, method of adaptive test scoring. To enhance the prospects for enlightened public debate about adaptive testing, it may be preferable to use this more familiar approach. Public attention would then likely be focussed on issues more central to adaptive testing, namely the adaptive nature of the test.
Brucella abortusand Its Closest Phylogenetic Relative,Ochrobactrumspp., Differ in Outer Membrane Permeability and Cationic Peptide Resistance (2000)

The outer membrane (OM) of the intracellular parasite Brucella abortus is permeable to hydrophobic probes and resistant to destabilization by polycationic peptides and EDTA. The significance of these unusual properties was investigated in a comparative study with the opportunistic pathogens of the genus Ochrobactrum, the closest known Brucella relative. Ochrobactrum spp. OMs were impermeable to hydrophobic probes and sensitive to polymyxin B but resistant to EDTA. These properties were traced to lipopolysaccharide (LPS) because (i) insertion of B. abortus LPS, but not of Escherichia coli LPS, into Ochrobactrum OM increased its permeability; (ii) permeability and polymyxin B binding measured with LPS aggregates paralleled the results with live bacteria; and (iii) the predicted intermediate results were obtained with B. abortus-Ochrobactrum anthropi and E. coli-O. anthropi LPS hybrid aggregates. Although Ochrobactrum was sensitive to polymyxin, self-promoted uptake and bacterial lysis occurred without OM morphological changes, suggesting an unusual OM structural rigidity. Ochrobactrum and B. abortus LPSs showed no differences in phosphate, qualitative fatty acid composition, or acyl chain fluidity. However, Ochrobactrum LPS, but not B. abortus LPS, contained galacturonic acid. B. abortus and Ochrobactrum smooth LPS aggregates had similar size and zeta potential (-12 to -15 mV). Upon saturation with polymyxin, zeta potential became positive (1 mV) for Ochrobactrum smooth LPS while remaining negative (-5 mV) for B. abortus smooth LPS, suggesting hindered access to inner targets. These results show that although Ochrobactrum and Brucella share a basic OM pattern, subtle modifications in LPS core cause markedly different OM properties, possibly reflecting the adaptive evolution of B. abortus to pathogenicity.
Microscale and nanoscale hierarchical structured mesh films with superhydrophobic and superoleophilic properties induced by long-chain fatty acids (2006)

Inspired by the lotus effect, we fabricate new microscale and nanoscale hierarchical structured copper mesh films by a simple electrochemical deposition. After modification of the long-chain fatty acid monolayer, these films show superhydrophobic and superoleophilic properties, which could be used for the effective separation of oil and water. The length of the fatty acid chain strongly influences the surface wettability of as-prepared films. It is confirmed that the cooperative effect of the hierarchical structure of the copper film and the nature of the long-chain fatty acid contribute to this unique surface wettability.
Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) (2015)

ClinicalTrials.gov NCT01014052.