gebhart/patrepeval huggingface dataset:
Evaluation of Cholesterol Reduction Activity of Methyl-β-cyclodextrin Using Differentiated Human Neurons and Astrocytes (2012)

Recent advances in stem cell technology have enabled large-scale production of human cells such as cardiomyocytes, hepatocytes, and neurons for evaluation of pharmacologic effect and toxicity of drug candidates. The assessment of compound efficacy and toxicity using human cells should lower the high clinical attrition rates of drug candidates by reducing the impact of species differences on drug efficacy and toxicity from animal studies. Methyl-β-cyclodextrin (MBCD) has been shown to reduce lysosomal cholesterol accumulation in skin fibroblasts derived from patients with Niemann Pick type C disease and in the NPC1-/- mouse model. However, the compound has never been tested in human differentiated neurons. We have determined the cholesterol reduction effect of MBCD in neurons differentiated from human neural stem cells (NSCs) and commercially available astrocytes. The use of NSCs for producing differentiated neurons in large quantities can significantly reduce the production time and enhance the reproducibility of screening results. The EC(50) values of MBCD on cholesterol reduction in human neurons and astrocytes were 66.9 and 110.7 µM, respectively. The results indicate that human neurons differentiated from the NSCs and human astrocytes are useful tools for evaluating pharmacologic activity and toxicity of drug candidates to predict their clinical efficacy.
Recovery of Drugs of Abuse from the Immunalysis Quantisal Oral Fluid Collection Device (2006)

Drug recovery from a new oral fluid collection device was assessed. The evaluation was performed in vitro at three physiologically relevant concentrations for the following substances: amphetamine, methamphetamine, morphine, codeine, cocaine, benzoylecgonine, methadone, oxazepam, and Delta(9)-tetrahydrocannabinol (THC). Drug-free and drug-fortified controls were prepared and their concentration verified by liquid chromatography-tandem mass spectrometry. Aliquots of the controls were then "collected" with the device (n=3) using the manufacturer's recommended procedure. Collected samples were stored for 12 h to simulate shipping before analysis. Fresh, non-"collected" aliquots of each pool (n=3) were concurrently analyzed. The drug recoveries from the Quantisal were expressed as a mean percentage of the concurrently analyzed aliquots that were not subjected to device collection. Recoveries for oxazepam exceeded 97%, for amphetamine and methamphetamine exceeded 93%, and for opioids all exceeded 91%. The recoveries of cocaine were >91% and >82% for its polar metabolite, benzoylecgonine. Especially noteworthy was the recovery of THC from the Quantisal collector (81.3-91.4%). When compared with recoveries reported from other collection devices, the Quantisal was clearly superior.
Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors (2016)

Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S,4S)-4,4-difluoroproline substituted analogue 34a demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.
Mast Cell-Dependent B and T Lymphocyte Activation Is Mediated by the Secretion of Immunologically Active Exosomes (2001)

Mitogenic activity of bone marrow-derived mouse mast cells and mast cell lines P815 and MC/9 on B and T lymphocytes is present in their culture supernatants. To identify this activity, mast cells were incubated in serum-free medium and the supernatant was subjected to differential centrifugation, which resulted in two fractions, the hypodense and dense fraction (pellet). When analyzed for their mitogenic activity on spleen cells, all activity was found to be associated with the dense fraction. Electron microscopy studies revealed the presence in this fraction of small vesicles called exosomes with a heterogeneous size from 60 to 100 nm of diameter. When cocultured with spleen cells, purified exosomes induced blast formation, proliferation, as well as IL-2 and IFN-gamma production, but no detectable IL-4. Similar data were obtained by injecting exosomes into naive mice. In contrast to mast cell lines, a pretreatment with IL-4 is required for bone marrow-derived mast cells to secrete active exosomes. Structurally, exosomes were found to harbor immunologically relevant molecules such as MHC class II, CD86, LFA-1, and ICAM-1. These findings indicate that mast cells can represent a critical component of the immunoregulatory network through secreted exosomes that display mitogenic activity on B and T lymphocytes both in vitro and in vivo.
Role of Spinal Afferents and Calcitonin Gene-Related Peptide in the Postoperative Gastric Ileus in Anesthetized Rats (1994)

These data indicate that spinal sensory neurons and CGRP partly mediate postoperative gastric ileus. CGRP may be released from spinal sensory neuron terminals in the celiac and superior mesenteric ganglia as part of an extraspinal intestinogastric inhibitory reflex activated by abdominal surgery.
The Gabor wave front set (2012)

We define the Gabor wave front set $WF_G(u)$ of a tempered distribution $u$ in terms of rapid decay of its Gabor coefficients in a conic subset of the phase space. We show the inclusion $$WF_G(a^w(x,D) u) \subseteq WF_G(u), u \in \mathscr S'(\mathbb R^d), a \in S_{0,0}^0,$$ where $S_{0,0}^0$ denotes the Hörmander symbol class of order zero and parameter values zero. We compare our definition with other definitions in the literature, namely the classical and the global wave front sets of Hörmander, and the $\cS$-wave front set of Coriasco and Maniccia. In particular, we prove that the Gabor wave front set and the global wave front set of Hörmander coincide.
Involvement of the Cytoplasmic C-Terminal Domain of Connexin43 in Neuronal Migration (2009)

During brain development, young neurons closely associate with radial glial while migrating from the ventricular zone (VZ) to the cortical plate (CP) of the neocortex. It has been shown previously that gap junctions are needed for this migration to occur properly, but the precise mechanism responsible is still in question. Here, we used Cre recombinase, driven by the nestin promoter, to conditionally knock-out a floxed coding DNA of the connexin43 (Cx43) gene in mice. Radial glia in the VZ normally express connexin43. They undergo divisions that produce neurons and astrocytes and serve as migratory guides for the daughter cells that they produce. Based on histological analysis, we suggest that removing Cx43 from radial glia alters the normal lamination of the mouse neocortex. To monitor newborn neurons during development, we introduced a plasmid containing green fluorescent protein driven by a neuronal (Talpha1 tubulin) promoter into the embryonic neocortex using in utero electroporation. The transfected migrating neurons remain in the VZ/intermediate zone (IZ) of the Cx43 conditional knock-out (Cx43cKO) animals, whereas in Cx43(fl/fl) mice, neurons migrate through the IZ into the CP, indicating that deletion of Cx43 from nestin-positive cells disrupts neuronal migration. We were able to rescue migration of Cx43cKO neurons by electroporating a cytomegalovirus-Cx43 expression plasmid into the embryonic cortex. In contrast, a C-terminal truncated form of Cx43 failed to rescue neuronal migration. In addition, Cx43(K258stop) mice, in which Cx43 lacks the last 125 amino acid residues of the cytoplasmic C-terminal domain, gave results similar to those seen with the Cx43cKO mice. This study illustrates that deletion of the C-terminal domain of Cx43 alters neuronal migration in the neocortex.
Guanine polynucleotides are self‐antigens for human natural autoantibodies and are significantly reduced in the human genome (2015)

In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome.
Polyethylene Glycol Modified FGF21 Engineered to Maximize Potency and Minimize Vacuole Formation (2013)

Fibroblast growth factor 21 (FGF21) is involved in regulating energy metabolism, and it has shown significant promise as a treatment for type II diabetes; however, the native protein has a very short circulating half-life necessitating frequent injections to maintain a physiological effect. Polyethylene glycol (PEG) conjugation to proteins has been used as a method for extending the circulating half-life of many pharmaceutical proteins; however, PEG does carry the risk of vacuole formation, particularly in the renal tubular epithelium. Since renal vacuole formation may be particularly problematic for diabetic patients, we engineered site-directed PEGylated variants of FGF21 with sustained potency and minimized vacuole formation. This was accomplished both by probing the site of PEGylation on FGF21 as well as by examining various PEG configurations. While the site of PEGylation has a significant impact on the bioactivity of FGF21, it has only a marginal impact on vacuole formation; however, the configuration and number of PEGs conjugated to the protein has a much more profound effect on vacuologenesis.
Palladium-Catalyzed Synthesis of Aryl Sulfides from Aryl Triflates (1998)

ADVERTISEMENT RETURN TO ISSUECommunicationNEXTPalladium-Catalyzed Synthesis of Aryl Sulfides from Aryl TriflatesNan Zheng, J. Christopher McWilliams, Fred J. Fleitz, Joseph D. Armstrong, and R. P. VolanteView Author Information Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Mail Drop R80Y-360, Rahway, New Jersey 07065 Cite this: J. Org. Chem. 1998, 63, 26, 9606–9607Publication Date (Web):December 5, 1998Publication History Received27 July 1998Published online5 December 1998Published inissue 1 December 1998https://pubs.acs.org/doi/10.1021/jo9814703https://doi.org/10.1021/jo9814703rapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views2189Altmetric-Citations151LEARN 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 SUBJECTS:Aromatic compounds,Catalysts,Ligands,Phenyls,Sulfides Get e-Alerts
Antibodies to a defined region of pp60src neutralize the tyrosine-specific kinase activity. (1983)

Site-specific antibodies to pp60src, the transforming protein of Rous sarcoma virus (RSV), have been prepared by immunizing rabbits with a chemically synthesized pentadecapeptide corresponding to residues 498-512 (Cys-Trp-Arg-Lys-Asp-Pro-Glu-Glu-Arg-Pro-Thr-Phe-Lys-Tyr-Leu) as deduced from the nucleotide sequence of the Prague C src gene. Antibodies specific for the synthetic peptide were purified from immune sera by affinity chromatography on peptide-bound Sepharose and characterized by a number of immunocytochemical techniques. Immunoprecipitation and Western blot analyses of normal and RSV-transformed cell lines revealed that this peptide antibody identified the authentic viral src gene product. This finding was further supported by indirect immunofluorescence on RSV-transformed rat kidney cells. The anti-peptide antibodies produced dramatic intracellular staining patterns characteristic of the src protein. Although able to immunoprecipitate pp60src, in vitro kinase reactions indicated that, unlike sera from RSV-induced tumor-bearing rabbits, the peptide antibody did not serve as a phosphate acceptor in the immunocomplex. Moreover, immunoprecipitates of pp60src prepared from this site-specific immune reagent were unable to phosphorylate exogenously added casein or the synthetic peptide substrate, Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly. In contrast, pp60src-containing immunoprecipitates made from an anti-peptide serum specific for the COOH-terminal six amino acids (residues 521-526), a region only eight amino acids removed, readily phosphorylated both substrates. This evidence indicates that an antibody directed against residues 498-512 neutralizes the kinase activity of pp60src and suggests that this region may be functionally necessary for the tyrosine-specific kinase activity of this transforming protein.
Photolytic technique for producing microlenses in photosensitive glass (1985)

A process is described whereby 2-D arrays of small diameter spherical lenses are produced in a homogeneous photosensitive glass by a photothermal technique. The mechanism of the lens formation is explained on the basis of the density change of the photonucleated microcrystalline phase developed relative to the unexposed glass. The lens formation is related to such variables as optical exposure, thermal schedule, glass thickness, and lens diameter. Optical characterization of the lenses produced by this technique was carried out by interferometric and MTF measurements. One-to-one conjugate erect imaging lens arrays were fabricated and tested.
Cardiovascular and respiratory effects of spermidine and spermine: an experimental study. (1984)

Spermidine (SPD) and spermine (SPM) produced in anaesthetized dogs significant cardiovascular changes at higher doses than other transmitters, i.e. l-noradrenaline, l-adrenaline, histamine, acetylcholine, which produce cardiovascular effects at doses of 0.01-0.05 micrograms/kg given intravenously. SPD was shown to be more active than SPM. The hypotensive response observed after i.v. injection is due to histamine release. The hypotensive and bradycardic effects observed after microinjection of SPD into III cerebral ventricle or into the vertebral artery and of SPM into the vertebral artery are due to an increase in parasympathetic output. Spermidine increased and spermine decreased the baroreceptor reactivity. SPD and SPM did not change the vascular beta- and alpha-adrenergic, cholinergic and histaminergic receptor reactivity.
Observation of discrete electronic states in a zero-dimensional semiconductor nanostructure (1988)

Electronic transport through a three-dimensionally confined semiconductor quantum well (``quantum dot'') has been investigated. Fine structure observed in resonant tunneling through the quantum dot corresponds to the discrete density of states of a zero-dimensional system.
Life prediction of advanced materials for gas turbine application (1995)

Emphasis is placed on life characterization based on low cycle fatigue under isothermal conditions and thermomechanical fatigue. Microstructure of failed coated and uncoated specimens is being analyzed. IN 738 LC is the material; the coating is either overlay (NiCoCrAly) or NiAl-based aluminide.
A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients (2006)

This preliminary study showed that patients with marked cartilage loss (JSN>or=0.6 mm) receiving RIS 15 mg/day retained vertical trabecular structure, and those receiving RIS 50 mg/week increased vertical trabecular number, thereby preserving the structural integrity of subchondral bone in knee OA.
Use of nondegenerate resonant leaky modes to fashion diverse optical spectra (2004)

In this paper, we show that bandstop and bandpass filters with versatile spectral attributes can be implemented with modulated films possessing asymmetric grating profiles. The profile asymmetry breaks the resonant leaky mode degeneracy at normal incidence thereby permitting precise spectral spacing of interacting leaky modes with interesting implications in optical filter design. Several example filters, containing only a single grating layer, are designed with this methodology to demonstrate the concept.
Polymerase structures and function: variations on a theme? (1995)

Free access1 November 1995 Share on Polymerase structures and function: variations on a theme?Authors: C M Joyce, T A SteitzAuthors Info & AffiliationsDOI: https://doi.org/10.1128/jb.177.22.6321-6329.1995 PDF/EPUB
Polar Residues in the Transmembrane Domains of the Type 1 Angiotensin II Receptor Are Required for Binding and Coupling (1996)

Type 1 angiotensin receptors (AT1) are G-protein coupled receptors, mediating the physiological actions of the vasoactive peptide angiotensin II. In this study, the roles of 7 amino acids of the rat AT1A receptor in ligand binding and signaling were investigated by performing functional assays of individual receptor mutants expressed in COS and Chinese hamster ovary cells. Substitutions of polar residues in the third transmembrane domain with Ala indicate that Ser105, Ser107, and Ser109 are not essential for maintenance of the angiotensin II binding site. Replacement of Asn111 or Ser115 does not alter the binding affinity for peptidic analogs, but modifies the ability of the receptor to interact with AT1 (DuP753)- or AT2 (CGP42112A)-specific ligands. These 2 residues are probably involved in determining the binding specificity for these analogs. The absence of G-protein coupling to the Ser115 mutant suggests that this residue, in addition to previously identified residues, Asp74 and Tyr292, participates in the receptor activation mechanism. Finally, Lys102 (third helix) and Lys199 (fifth helix) mutants do not bind angiotensin II or different analogs. Co-expression of these two deficient receptors permitted the restoration of a normal binding site. This effect was not due to homologous recombination of the cDNAs but to protein trans-complementation.
Multi-parent recombination with simplex crossover in real coded genetic algorithms (1999)

In this paper, we proposed simplex crossover (SPX), a multi-parent recombination operator for real-coded genetic algorithms. SPX generates offspring vector values by uniformly sampling values from simplex formed by m (2 ≤ m ≤ number of parameters + 1) parent vectors. The SPX features an independence from of coordinate systems. Experimental results using test functions, which are commonly used in studies of evolutionary algorithms, showed SPX works well on functions having multimodality and/or epistasis with a medium number of parents: 3-parent on a low dimensional function or 4 parents on high dimensional functions.
A Review of α1-Antitrypsin Deficiency (2011)

α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.
Breath‐hold water and fat imaging using a dual‐echo two‐point dixon technique with an efficient and robust phase‐correction algorithm (2004)

A two-point Dixon technique using a novel phase-correction algorithm and commercially available dual-echo fast gradient-echo pulse sequence is presented. The phase-correction algorithm determines the directional rather than phase distribution of signals due to field inhomogeneities. Specifically, a region-growing scheme uses precalculated spatial gradients of the signal phase to guide the growth sequence, so there is no need to manually select the seeds or use an empirical angular threshold. Further, the determination of the signal direction of a given pixel is based on both the amplitude and phase of the surrounding pixels, the direction of which has already been determined. The advantages of this algorithm include its easy implementation, computational efficiency, and robustness in the presence of pixels with large phase uncertainty. The feasibility and usefulness of the technique are demonstrated in vivo with artifact-free water and fat images of an entire abdomen in a single breath-hold.