gebhart/patrepeval huggingface dataset:
Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited (2002)

Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca(2+)- and protein kinase C-alpha-dependent mechanisms and/or activation of p38(MAPK) and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.
Invited: New Developments in Materials and Processing Aspects of Silicon Device Technology (1977)

Recent developments in materials and processing aspects of silicon device technology are reviewed. Important advances in silicon materials, passivation, CVD processing, ion implantation and diffusion, metallization, device lithography, and packaging/assembly are discussed in relationship to the overall goals of semiconductor manufacturers. It is concluded that the most important developments include more highly controlled and better understood processes, simpler and more efficient processing equipment, and greatly advanced techniques in device lithography.
Modulation of the hyperpolarization‐activated current (Ih) by cyclic nucleotides in guinea‐pig primary afferent neurons. (1996)

1. Whole-cell patch-clamp recordings were made from dissociated guinea-pig nodose and trigeminal ganglion neurons in culture to study second messenger mechanisms of the hyperpolarization-activated current (Ih) modulation. 2. Prostaglandin E2 (PGE2) and forskolin modulate Ih in primary afferents by shifting the activation curve in the depolarizing direction and increasing the maximum amplitude. 3. The cAMP analogues, RP-cAMP-S (an inhibitor of protein kinase A (PKA)) and SP-cAMP-S (an activator of PKA), both shifted the activation curve of Ih to more depolarized potentials and occluded the effects of forskolin. These results suggest that Ih is modulated by a direct action of the cAMP analogues. 4. Superfusion of other cyclic nucleotide analogues (8-Br-cAMP, 8-(4-chlorophenylthio)-cAMP and 8-Br-cGMP) mimicked the actions of forskolin and PGE2, but dibutyryl cGMP, 5'-AMP and adenosine had no effect on Ih. 8-Br-cAMP and 8-Br-cGMP had similar concentration response profiles, suggesting that Ih has little nucleotide selectivity. 5. The inhibitor peptide (PKI), the catalytic subunit of PKA (C subunit) and phosphatase inhibitors (microcystin and okadaic acid) had no effect on forskolin modulation of Ih. 6. These results indicate that Ih is regulated by cyclic nucleotides in sensory neurons. Positive regulation of Ih by prostaglandins produced during inflammation may lead to depolarization and facilitation of repetitive activity, and thus contribute to sensitization to painful stimuli.
The Effect of Inhibitor Transport on Leveling in Electrodeposition (1991)

The electrodeposition of nickel into an angular trench in the presence of coumarin, a widely used inhibitor, is simulated using boundary layer approximations representative of flow parallel and transverse to the groove. Based on the diffusion‐adsorption mechanism of leveling action, the dependence of the developing contours on variations in the Langmuir coefficient and inhibitor/metal‐ion flux ratio are investigated. Leveling efficiency is shown to be highest for thin, planar boundary layers, and lowest for contour following boundary layers. The model successfully predicts the leveling‐off of the inhibitor effect with increasing inhibitor vs. metal‐ion flux, and that there is an optimal mass transfer boundary layer thickness, or flux of additive which results in superior leveling performance. Satisfactory agreement is found between the predicted contours, obtained by solving the model equations using the boundary element method, and the experimental leveling efficiencies determined by previous investigators.
Porting the galaxy system to Mandarin Chinese (1997)

GALAXY is a human-computer conversational system that provides a spoken lan-guage interface for accessing on-line information. It was initially implemented for En-glish in travel-related domains, including air travel, local city navigation, and weather. Efforts were started to develop multilingual systems within the framework of GALAXY several years ago. This thesis focuses on developing the Mandarin Chinese version of the GALAXY system, including speech recognition, language understanding and lan-guage generation components. Large amounts of Mandarin speech data have been collected from native speakers to derive linguistic rules, acoustic models, language models and vocabularies for Chinese. Comparisons between the Chinese and English languages have been made in the context of system implementation. Some issues that are specific for Chinese have been addressed, to make the system core more language independent. Overall, the system produced reasonable responses nearly 70 % of the time for spontaneous Mandarin test data collected in a &amp;quot;wizard &amp;quot; mode, a performance that
Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone. (1987)

Transcription of the rat growth hormone (rGH) gene in pituitary cells is increased by addition of thyroid hormone (T3). This induction is dependent on the presence of specific sequences just upstream of the rGH promoter. We have partially purified T3 receptor from rat liver and examined its interaction with these rGH sequences. We show here that T3 receptor binds specifically to a site just upstream of the basal rGH promoter. This binding site includes two copies of a 7-base-pair direct repeat, the centers of which are separated by 10 base pairs. Deletions that specifically remove the T3 receptor binding site drastically reduce response to T3 in transient transfection experiments. These results demonstrate that T3 receptor can recognize specific DNA sequences and suggest that it can act directly as a positive transcriptional regulatory factor.
mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. (1998)

mu-Opioid receptors are the pharmacological targets of endogenous opioid peptides and morphine-like alkaloid drugs. Previous studies of transfected cells and peripheral neurons indicate that opioid receptors are rapidly internalized after activation by the alkaloid agonist etorphine but not after activation by morphine. To determine whether opioid receptors in the central nervous system are regulated by a similar process of agonist-selective internalization, mu-opioid receptors were examined in rat brain neurons after treatment of animals with opioid drugs. Internalized mu receptors were observed within 30 min after intraperitoneal injection of the alkaloid agonist etorphine, and this process was blocked by the antagonist naloxone. Colocalization of internalized opioid receptors with transferrin receptors in confocal optical sections indicated that receptor internalization observed in vivo is mediated by a membrane trafficking pathway similar to that observed previously in vitro using transfected human embryonic kidney 293 cells. Morphine failed to induce detectable rapid internalization of receptors, even when administered to animals at doses far in excess of those required to induce analgesia. To quantify these agonist-selective differences and to analyze an array of opioid ligands for their ability to trigger internalization, we used flow cytometry on stably transfected 293 cells. These studies indicated that the different effects of individual agonists are not correlated with their potencies for receptor activation and that a variety of clinically important agonists differ significantly in their relative abilities to stimulate the rapid internalization of opioid receptors.
Classifying mutagens as to their specificity in causing the six possible transitions and transversions: A simple analysis using the salmonella mutagenicity assay (1986)

The standard Salmonella tester strains used to detect base substitution mutations carry the hisG428 ochre mutation (TA102 and TA104) and the hisG46 missense mutation (TA100). These mutations can be reverted by base changes at their mutant his loci or at extragenic suppressor loci. The base changes resulting in each class of revertants of these mutations have been identified, and simple phenotypic screens have been developed to distinguish among them. Revertants at extragenic suppressor loci are distinguished from those at the his loci by their sensitivity to inhibitory histidine analogs. The four ochre suppressor loci of hisG428 are distinguished by their ability to support growth of nonsense mutants of phage P22. These screens are the basis for a rapid and simple system for determining the base substitution specificity of mutagens using hisG428- and hisG46-containing tester strains. Diagnostic mutagens specific for each of the six possible base changes (transitions and transversions) have been identified. Using these diagnostic mutagens, two additional strains, each specifically reverted by a single base substitution mutation, have been developed to provide a minimum of two loci at which to detect each type of base change. The ability of this system to provide detailed information about mutational specificity in a variety of DNA repair backgrounds will allow further elucidation of the mechanisms of mutagenesis and DNA repair.
CARBON SUBOXIDE AND PROTEINS (1941)

In Paper I of this series (1) there was reported the reaction of carbon suboxide, C302, with an aqueous solution of glycine to give malonyldiglycine.The present communication describes further studies of the behavior of this reagent with amino acids in the presence of water.Like glycine, lysine adds to C302 through its a-amino group if the e-amino is protected.Thus there was obtained from c-benzoyldl-lysine the expected malonyldi-(E-benzoyl-dl-lysine)cu-amide.This behavior can be accepted as typical of all primary a-amino groups, and indicates that the free terminal amino groups in proteins react similarly.The e-amino group of lysine also gives well defined crystalline products if the a! group is protected.From or-benzoyl-Z-lysine there was obtained malonyldi-(a-benzoyl-Z-lysine)e-amide, which formed equally well in solutions of pH 8.0 or 6.0.The loss of amino nitrogen by proteins on exposure to GO2 has already been attributed to the reaction of this group in the lysine residue.There is, however, in malonyl proteins more combined malonic acid than can be accounted for by amide formation alone (1).This led to the investigation of the behavior of C&O2 with suitable derivatives of tyrosine, an amino acid which is known to be acetylated at its phenolic hydroxyl by ketene (2).Both the diester, di-(N-carbobenzoxy-I-tyrosyl) malonate and the monoester, mono-(N-carbobenzoxy-Z-tyrosyl) malonate were found to be present after the addition of 1.5 molar equivalents of C302 to a slightly alkaline solution of carbobenzoxytyrosine.The yields,
Expression of RIG-I, IRF3, IFN-β and IRF7 determines resistance or susceptibility of cells to infection by Newcastle Disease Virus (2009)

Newcastle Disease Virus (NDV) is an avian paramyxovirus with anti-neoplastic and immune-stimulatory properties which has raised considerable interest for cancer therapy. To better understand the molecular nature of the tumor selective replication of NDV, we investigated the cellular responses of murine normal and tumor cells after infection by NDV. To this end, we compared the basal expression of different antiviral proteins as well as the expression induced by the addition of NDV to the cells in vitro and in vivo. Primary macrophages were found to be resistant to NDV infection and exhibited a high basal and induced expression of various antiviral genes. In contrast, macrophage-derived RAW tumor cells were highly susceptible to NDV infection and displayed a low expression of several antiviral genes. Macrophage-derived J774 tumor cells were intermediate with regard to NDV replication and antiviral gene expression. The responsiveness to exogenously added IFN-alpha was found highest in normal macrophages, lowest in the RAW cells, and intermediate in the J774 cells. We also analysed dendritic cells as well as additional normal and tumor cell types. A strong inverse correlation was obeserved between the susceptibility to infection and the basal expression of the antiviral genes RIG-I, IRF3, IRF7 and IFN-beta. A strong expression of these genes can explain the resistance of normal cells to NDV infection and a weak antiviral gene expression the broad susceptibility of tumor cells.
Solution Structure of an Intramolecular DNA Triplex Containing an N7-Glycosylated Guanine Which Mimics a Protonated Cytosine, (1997)

The three-dimensional structure of a pyrimidine-purine-pyrimidine DNA triplex containing an N7-glycosylated guanine (7G) in the third strand has been determined by NMR spectroscopy, restrained molecular dynamics calculations, and complete relaxation matrix refinement. Glycosylation of the guanine at the N7 position permits it to adopt a conformation such that the Hoogsteen face of the base mimics the arrangement of hydrogen bond donors seen in protonated cytosine. The NMR data confirm the previously proposed hydrogen bonding scheme of the 7G x G x C triplet. The three-dimensional structure of the triplex accommodates the 7G with less distortion of the phosphodiester backbone than would be required for an N9-glycosylated guanine in the same sequence position, but some changes in the positions of the phosphodiester backbone are present compared to a C+ x G x C triplet. The structure provides a rationale for the observations that 7G binds to Watson-Crick G x C base pairs with higher specificity and affinity than guanine, but with a lower stability at pH 5.2 than would be provided by a canonical C+ x G x C triplet.
Stochastic Cost-Volume-Profit Analysis and Decision Theory (1986)

William Lehman Timber Ltd (WLT) are importers and distributors of wood and forest products. WLT have extensive yards at the port of Goole, and are contemplating the installation (on currently unused space within the Goole yards) of plant for the distillation of fusel oil. Considerations of cash flow make it strongly in WLT’s interests to lease this plant rather than purchase it outright. Two types of fusel oil distillation plant are available for leasing; direct distillation (DD) plant is being quoted with lease payments of £320000 per annum, while the more sophisticated catalysis-assisted (CA) plant is being quoted with lease payments of £490000 per annum. Because these plants are based on quite distinct technologies, they carry out the process of distillation with widely differing efficiencies. CA plant is capable of producing fusel oil at a variable cost of £0.17 per litre, while DD plant is capable of producing only at a variable cost of £0.28 per litre. WLT is part of a vertically-integrated forest products group, and sells solely through 250 ‘captive’ wholesalers belonging to this group. These wholesalers do not currently stock fusel oil, but will all be required to do so when WLT makes it available to them. The price to the wholesaler is determined by competitive considerations, and will be 55p per litre irrespective of whether the fusel oil is produced by CA plant or DD plant.
The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. (1982)

Purified brush border fractions prepared from rat kidneys were solubilized in detergent, iodinated, and subjected to immunoprecipitation to identify the pathogenic antigen present in brush border membranes that is responsible for the production of Heymann nephritis (HN). Purified IgG prepared from the sera of rabbits or rats immunized with a crude cortical preparation, known as Fx1A, precipitated multiple peptides, whereas IgG eluted from glomeruli of rats with active or passive HN specifically immunoprecipitated a single large glycoprotein (Mr = 330,000). This protein (gp330) was subsequently purified by gel filtration and lentil lectin affinity chromatography from detergent-solubilized brush border membranes. When rats were immunized with purified gp330, they developed anti-brush border antibodies and active HN. IgG prepared from the serum of rats with active HN caused passive HN when injected into normal recipients. Rats immunized against brush border membrane proteins depleted of gp330 developed anti-brush border antibodies but did not develop HN. Further analysis of gp330 indicated that it is solubilized by detergent treatment of isolated brush border microvilli, and its antigenic component is released from intact microvilli by trypsin. By immunoperoxidase staining it was localized to the luminal side of the brush border membranes. These results indicate that (i) gp330 is the pathogenic antigen of HN; (ii) the antigen is a glycoprotein of the brush border membrane; and (iii) it is disposed with its pathogenic domain(s) facing the tubule lumen.
Acoustic Markov models used in the Tangora speech recognition system (2003)

The Speech Recognition Group at IBM Research has developed a real-time, isolated-word speech recognizer called Tangora, which accepts natural English sentences drawn from a vocabulary of 20000 words. Despite its large vocabulary, the Tangora recognizer requires only about 20 minutes of speech from each new user for training purposes. The accuracy of the system and its ease of training are largely attributable to the use of hidden Markov models in its acoustic match component. An automatic technique for constructing Markov word models is described and results are included of experiments with speaker-dependent and speaker-independent models on several isolated-word recognition tasks.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells (2002)

Anergic/suppressive CD4+CD25+ T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4+CD25+ T cells display a broad usage of the T cell receptor Vbeta repertoire,suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4+CD45RO+CD45RB(low) subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4+ T cells that have experienced repeated episodes of antigen-specific stimulation in vivo. This suggests that anergic/suppressive CD4+CD25+ T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4+T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non-professional antigen-presenting cells. We suggest that besides being generated in the thymus, CD4+CD25+ regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.
WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors (1998)

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.
Purification and partial characterization of small proteoglycans I and II, bone sialoproteins I and II, and osteonectin from the mineral compartment of developing human bone. (1987)

Using nondegradative isolation procedures we purified and characterized five major noncollagenous proteins from developing human bone. Small bone proteoglycan I, Mr approximately 350,000 on sodium dodecyl sulfate (SDS), 4-20% gradient polyacrylamide gels has a different amino-terminal sequence of NH2-Asp-Glu-Glu-()-Gly-Ala-Asp-Thr and is not cross-reactive with the small bone proteoglycan II, Mr approximately 200,000 on SDS-gradient polyacrylamide gels. Bone proteoglycan II is 95% N terminally blocked and the small amount that can be sequenced has an amino-terminal sequence (NH2-Asp-Glu-Ala-()-Gly-Ile. . .) that is apparently similar but not identical to a small proteoglycan isolated by Brennan, M.J., Oldberg, A., Pierschbacher, M.D., and Ruoslahti, E. (1984) J. Biol. Chem. 259, 13742-13750 from human fetal placenta membrane. Two bone sialoproteins, each of which migrates at a Mr approximately 80,000 on SDS gels, have also been isolated. Bone sialoprotein I has an amino-terminal sequence of NH2-Ile-Pro-Val-Lys-Gln-Ala. . . which is different from that of bone sialoprotein II with an amino-terminal sequence of NH2-Phe-Ser-Met-Lys-Asn-Leu. . . The two bone sialoproteins do not cross-react on Western blot analysis. Human bone osteonectin contains a large number of cysteines, more than 90% of which appear to be in disulfide bonds. The N-terminal amino acid sequence of human bone osteonectin was nearly identical to bovine bone osteonectin and had many similarities to a protein found in mouse parietal endoderm (Mason, I.J., Taylor, A., Williams, J.G., Sage, H., and Hogan, B.L.M. (1986) EMBO J. 5, 1831-1837.