gebhart/patrepeval huggingface dataset:
Characterization of Cationic Liposome-Mediated Gene Transfer In Vivo by Intravenous Administration (1997)

Physicochemical properties of the cationic liposomes, including structure of the cationic lipid-to-DNA ratio, liposome particle size, and inclusion of the helper lipids, were studied for their effect on the level, site, and duration time of gene expression in vivo by intravenous administration. Using a cytomegalovirus (CMV)-driven gene expression system containing either the luciferase or green fluorescence protein gene as a reporter and two cationic lipids [N-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA) and 1,2-dioleoyloxy-3-trimethylammonium propane (DOTAP)], we demonstrated in vivo by a single intravenous injection of DNA/liposome complexes into mice, that cationic liposomes are capable of transfecting cells in organs such as the lung, heart, liver, spleen, and kidney. Transfection efficiency is determined mainly by the structure of the cationic lipid and the ratio of cationic lipid to DNA. Although the presence of cholesterol in DOTAP liposomes did not affect transfection activity, inclusion of dioleoylphosphatidylethanolamine (DOPE) into either DOTAP or DOTMA liposomes significantly decreases liposome transfection activity in vivo. Results form time course show that gene expression in different organs is transient, with a peak level between 4 and 24 hr, dropping to less than 1% of the peak level by day 4. Experiments with repeated injections showed that the peak level of gene expression could be regained by subsequent injection.
Inactive Type II and Type I Receptors for TGFβ Are Dominant Inhibitors of TGFβ-dependent Transcription (1995)

Although transforming growth factor-beta (TGF beta) is implicated in differentiation and disease, proof of in vivo function requires specific inhibitors of the TGF beta cascade. TGF beta binds a family of type I and type II receptors (T beta RI, T beta RII), containing a cytoplasmic serine/threonine kinase domain. We previously reported that kinase-deficient T beta RII (delta kT beta RII) blocks TGF beta-dependent transcription in cardiac myocytes. It is controversial whether both receptors are needed in all cells for gene regulation by TGF beta or whether they mediate distinct subsets of TGF beta-dependent events. To resolve this uncertainty, TGF beta-dependent transcription was investigated in cardiac myocytes versus mink lung epithelial cells. 1) delta kT beta RII inhibits induction of a TGF beta-responsive reporter gene, in both cell backgrounds. 2) Charged-to-alanine mutations of key residues of the T beta RII kinase, including consensus ATP binding and amino acid recognition motifs, are competent for binding but not transcriptional activation. Each inactive receptor inhibits TGF beta-dependent transcription in both cell types. 3) Kinase-deficient T beta RI (delta kT beta RI) likewise impairs TGF beta-dependent transcription, less completely than delta kT beta RII; kinase-deficient activin type I receptor has no effect. 4) TGF beta-binding proteins in cardiac cells and Mv1Lu cells are comparable by affinity labeling and immunoprecipitation; however, Mv1Lu cells express up to 3-fold higher levels of T beta RII and T beta RI. Thus, the model inferred from TGF beta-resistant cell lines (that T beta RII and T beta RI are necessary in tandem for the TGF beta-signaling complex to regulate transcription) is valid for cardiac myocytes, the cell type most prominently affected in TGF beta-deficient animals.
Speciation and Mobility of Arsenic in Agricultural Lime (2009)

Agricultural liming materials are used to correct soil acidity and to improve plant growth and microbial functionality. A relatively low-grade agricultural lime was found to contain up to 125 mg kg(-1) arsenic (As), which is above any fertilizing materials code threshold. The color of the milled material is brown due to ample oxide dendrites. Microprobe elemental maps confirmed that these accessory oxide mineral phases are responsible for the elevated As concentrations in the limestone. The black Mn-bearing dendrites contain minor amounts of As, whereas the brown Fe-bearing dendrites contain the major part of the As inventory, with an Fe/As molar ratio around 100. Because the elemental maps represent only a few sample regions of interest (ROI), the results are corroborated by a bulk five-step sequential extraction of the lime, which suggests that a majority of the As is bound to acid-reducible phases. Because repartitioning of the As oxyanion during extraction cannot be ruled out, X-ray absorption spectroscopy with micrometer resolution (micro-XAS) was used as a solid-state speciation analysis approach. The micro-XAS results at the Fe K-edge for the selected ROIs revealed the brown dendrites to consist of ferrihydrite and goethite, whereas those at the As K-edge revealed that the pentavalent As species arsenate predominates, with As-Fe distance and coordination indicating binding as a mononuclear inner-spheric adsorbate complex. Batch experiments with soil exposed to submerged conditions of up to 41 d revealed a negligible As release rate from the lime (approximately 40 ng kg(-1) d(-1)). The results of this study corroborate regulatory codes that set the permissible As content in agricultural lime relative to the respective Fe content.
Molecular analysis of stimulatory anti-thyrotropin receptor antibodies (TSAbs) involved in Graves' disease. Isolation and reconstruction of antibody genes, and production of monoclonal TSAbs (1996)

Anti-thyrotropin (TSH) receptor autoantibodies (TRAbs) have been known to be involved in Graves' disease. To understand the molecular mechanism for pathogenesis of TSAbs in Graves' disease, we isolated and reconstituted the Ig genes of EBV-transformed B cell clones producing monoclonal thyroid stimulating Ab (TSAb) obtained from patients with Graves' disease. The V region genes of Ig heavy (H) and light (L) chains of two TSAb clones, IgG clone B6B7 and IgM clone 101-2, were isolated by the PCR. Nucleotide sequencing analysis revealed that germ-line VH and VK segments widely used for autoantibodies including the previously isolated TRAbs were utilized in the two clones. A significant number of somatic mutations were found in V regions of both clones, indicating the involvement of somatic mutations for the TSAb specificity. Reconstituted Ig H and L chain genes of the two clones were stably introduced into myeloma cells for IgG1 production. IgGs purified from cultured supernatants of both transfectants exhibited significant TSAb activities, while they did not inhibit TSH binding to the receptor. The successful expression of recombinant TSAbs in eukaryotic cells will provide opportunities to apply them to various pathophysiologic, diagnostic and therapeutic investigations in autoimmune thyroid diseases.
Dipeptidyl Peptidase IV-Resistant [d-Ala2]Glucose-Dependent Insulinotropic Polypeptide (GIP) Improves Glucose Tolerance in Normal and Obese Diabetic Rats (2002)

The therapeutic potential of glucose-dependent insulinotropic polypeptide (GIP) for improving glycemic control has largely gone unstudied. A series of synthetic GIP peptides modified at the NH2-terminus were screened in vitro for resistance to dipeptidyl peptidase IV (DP IV) degradation and potency to stimulate cyclic AMP and affinity for the transfected rat GIP receptor. In vitro experiments indicated that [d-Ala2]GIP possessed the greatest resistance to enzymatic degradation, combined with minimal effects on efficacy at the receptor. Thus, [d-Ala2]GIP1–42 was selected for further testing in the perfused rat pancreas and bioassay in conscious Wistar and Zucker rats. When injected subcutaneously in normal Wistar, Fa/?, or fa/fa Vancouver Diabetic Fatty (VDF) Zucker rats, both GIP and [d-Ala2]GIP significantly reduced glycemic excursions during a concurrent oral glucose tolerance test via stimulation of insulin release. The latter peptide displayed greater in vivo effectiveness, likely because of resistance to enzymatic degradation. Hence, despite reduced bioactivity in diabetic models at physiological concentrations, GIP and analogs with improved plasma stability still improve glucose tolerance when given in supraphysiological doses, and thus may prove useful in the treatment of diabetic states.
Mouse Rt6.1 is a thiol‐dependent arginine‐specific ADP‐ribosyltransferase (1999)

Mouse T-cell antigens Rt6.1 and Rt6.2 are glycosylphosphatidylinositol-anchored arginine-specific adenosine diphosphate (ADP)-ribosyltransferases. In the present study, we obtained evidence that an arginine-specific ADP-ribosyltransferase activity liberated from BALB/c mouse splenocytes by phosphatidylinositol-specific phospholipase C increased fivefold in the presence of dithiothreitol and that the activity was immunoprecipitated by polyclonal antibodies generated against recombinant rat RT6.1. When mouse Rt6.1 was expressed as a recombinant protein, the transferase activity of Rt6.1 was stimulated by dithiothreitol, and inhibited by N-ethylmaleimide, while activities of recombinant mouse Rt6.2 and the Glu-207 mutant of rat RT6.1 [Hara, N., Tsuchiya, M., and Shimoyama, M. (1996) J. Biol. Chem. 271, 29552-29555] were unaffected by either agent. In addition to four cysteine residues conserved among mouse Rt6 and rat RT6 antigens, Rt6.1 has two extra cysteine residues at positions 80 and 201. To investigate a contribution of these extra cysteines in mouse Rt6.1 to thiol dependency of Rt6.1 transferase activity, Cys-80 and Cys-201 of Rt6.1 were replaced with serine and phenylalanine, respectively, the corresponding residues of mouse Rt6. 2 and rat RT6.1. Transferase activity of the Phe-201 mutant of Rt6.1 lost thiol dependency while that of the Ser-80 mutant remained thiol-dependent. Thus, we conclude that mouse Rt6.1 is a thiol-dependent arginine-specific ADP-ribosyltransferase, and that Cys-201 confers thiol dependency on Rt6.1 transferase. Our study indicates that arginine-specific ADP-ribosyltransferase activity detected on BALB/c mouse splenocytes is attributed to Rt6.1 and that Rt6.1 differs from Rt6.2 in enzymatic property of the transferase and perhaps in immunoregulatory functions.
A Facile Reduction of Sulfones to Sulfides (1973)

Diisobutylaluminum hydride is shown to be an effective reagent for the reduction of sulfones to sulfides. Yields as high as 70% are obtained in this normally difficult reduction. A technique for the easy isolation from the reaction mixture of volatile sulfides is described.
Urinary Excretion of Free and Conjugated 3′,5′-Diiodothyronine and 3,3′-Diiodothyronine* (1981)

RIAs for the estimation of 3',5'-diiodothyronine (3',5'-T2) and 3,3'-diiodothyronine (3,3'-T2) in human urine have been established. The urinary excretion of both glucuronide and sulfate conjugates of T2 and of T4, T3, and rT3 were estimated by means of enzymatic deconjugation. In healthy controls, the mean excretion (picomoles per 24 h) of free T4 was 1820, that of free T3 was 813, that of free rT3 was 77, that of free 3',5'-T2 was 13, and that of free 3,3'-T2 was 674. The total excretion of free and conjugated T4 was 2941, that of T3 was 1283, that of rT3 was 791, that of 3',5'-T2 was 709, and that of 3,3'-T2 was 2688. Significant amounts of sulfated T4 and T3 could not be demonstrated, amounts of sulfated T4 and T3 could not be demonstrated, whereas the excretion of sulfated rT3 was higher than that of glucuronidated rT3 (P less than 0.001). In contrast, glucuronidated and sulfated 3',5'-T2 as well as glucuronidated and sulfated 3,3'-T2 were found in the urine in equal amounts. In hyperthyroidism, the excretions of free and glucuronidated iodothyronines were increased, whereas the increase of the excretions of sulfated iodothyronines were less pronounced, only reaching statistical significance for 3,3'-T2 (P less than 0.02). In hypothyroidism, the excretions of both free, glucuronidated and sulfated iodothyronines were reduced. Significant amounts of sulfated T4 and T3 could not be demonstrated in urine from hyperthyroid or hypothyroid patients. Our data demonstrate that the amounts of free iodothyronines excreted in the urine vary considerably, suggesting active renal handling. The amounts of urinary glucuronidated and sulfated conjugates of the different iodothyronines studied vary considerably and are affected by thyroid function.
Invited review: Myoblast transfer: A possible therapy for inherited myopathies? (1991)

A potential therapeutic strategy for genetic diseases is to alter the genetic constitution of the affected tissues by means of grafts of normal precursor or stem cells. Over several years, evidence has accumulated to suggest that primary diseases of skeletal muscle, such as Duchenne muscular dystrophy, may be susceptible to this approach. This review makes a critical examination of such background evidence, and also of more recent data directly addressing the concept of therapy by means of grafts of normal myogenic cells. It is concluded that the data establish the principle that such grafts effect an alteration of the genetic constitution and phenotype of skeletal muscle and, therefore, might be used to alleviate recessively inherited myopathies. Several obstacles to the therapeutic application of this method to human disease are also identified; these seem to be problems of a technical nature rather than of basic principle, and none appears insuperable.
Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes (2010)

Intestinal health requires the coexistence of eukaryotic self with the gut microbiota and dysregulated host-microbial interactions can result in intestinal inflammation. Here, we show that colitis improved in T-bet(-/-)Rag2(-/-) mice that consumed a fermented milk product containing Bifidobacterium animalis subsp. lactis DN-173 010 strain. A decrease in cecal pH and alterations in short chain fatty acid profiles occurred with consumption, and there were concomitant increases in the abundance of select lactate-consuming and butyrate-producing bacteria. These metabolic shifts created a nonpermissive environment for the Enterobacteriaceae recently identified as colitogenic in a T-bet(-/-)Rag2(-/-) ulcerative colitis mouse model. In addition, 16S rRNA-based analysis of the T-bet(-/-)Rag2(-/-) fecal microbiota suggest that the structure of the endogenous gut microbiota played a key role in shaping the host response to the bacterial strains studied herein. We have identified features of the gut microbiota, at the membership and functional level, associated with response to this B. lactis-containing fermented milk product, and therefore this model provides a framework for evaluating and optimizing probiotic-based functional foods.
Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control (2011)

Cyclin-dependent kinase 5 (Cdk5) is an atypical but essential member of the Cdk kinase family, and its dysregulation or deletion has been implicated in inflammation-related disorders by an undefined mechanism. Here we show that Cdk5 is an indispensable activator of the GAIT (IFN-γ-activated inhibitor of translation) pathway, which suppresses expression of a posttranscriptional regulon of proinflammatory genes in myeloid cells. Through induction of its regulatory protein, Cdk5R1 (p35), IFN-γ activates Cdk5 to phosphorylate Ser(886) in the linker domain of glutamyl-prolyl tRNA synthetase (EPRS), the initial event in assembly of the GAIT complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of Ser(999), the second essential event in GAIT pathway activation. Diphosphorylated EPRS is released from its residence in the tRNA multisynthetase complex for immediate binding to NS1-associated protein and subsequent binding to ribosomal protein L13a and GAPDH. The mature heterotetrameric GAIT complex binds the 3' UTR GAIT element of VEGF-A and other target mRNAs and suppresses their translation in myeloid cells. Inhibition of Cdk5/p35 inhibits both EPRS phosphorylation events, prevents EPRS release from the tRNA multisynthetase complex, and blocks translational suppression of GAIT element-bearing mRNAs, resulting in increased expression of inflammatory proteins. Our study reveals a unique role of Cdk5/p35 in activation of the major noncanonical function of EPRS, namely translational control of macrophage inflammatory gene expression.
Continuous profiling (1997)

This article describes the Digital Continuous Profiling Infrastructure, a sampling-based profiling system designed to run continuously on production systems. The system supports multiprocessors, works on unmodified executables, and collects profiles for entire systems, including user programs, shared libraries, and the operating system kernel. Samples are collected at a high rate (over 5200 samples/sec. per 333MHz processor), yet with low overhead (1–3% slowdown for most workloads). Analysis tools supplied with the profiling system use the sample data to produce a precise and accurate accounting, down to the level of pipeline stalls incurred by individual instructions, of where time is bring spent. When instructions incur stalls, the tools identify possible reasons, such as cache misses, branch mispredictions, and functional unit contention. The fine-grained instruction-level analysis guides users and automated optimizers to the causes of performance problems and provides important insights for fixing them.
Eco Cyc: Encyclopedia of Escherichia coli genes and metabolism (1999)

The EcoCyc database describes the genome and gene products of Escherichia coli, its metabolic and signaltransduction pathways, and its tRNAs. The database describes 4391 genes of E.coli, 695 enzymes encoded by a subset of these genes, 904 metabolic reactions that occur in E.coli, and the organization of these reactions into 129 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc has many references to the primary literature, and is a (qualitative) computational model of E.coli metabolism. EcoCyc is available at
VirulentSalmonella typhimuriumhas two periplasmic Cu, Zn-superoxide dismutases (1999)

Periplasmic Cu, Zn-cofactored superoxide dismutase (SodC) protects Gram-negative bacteria from exogenous oxidative damage. The virulent Salmonella typhimurium strain ATCC 14028s has been found to contain two discrete periplasmic Cu, Zn-SOD enzymes that are only 57% identical at the amino acid level. SodCI is carried by a cryptic bacteriophage, and SodCII is closely related to the Cu, Zn-superoxide dismutase of Escherichia coli. All Salmonella serotypes appear to carry the sodCII locus, but the phage-associated sodCI gene is found only in certain strains belonging to the most highly pathogenic serotypes. Expression of either sodC locus appears to be enhanced during stationary phase, but only sodCII is regulated by the alternative sigma factor sigmas (RpoS). Mutants lacking both sodC genes are less lethal for mice than mutants possessing either sodC locus alone, indicating that both Cu, Zn-SOD enzymes contribute to Salmonella pathogenicity. The evolutionary acquisition of an additional sodC gene has contributed to the enhanced virulence of selected Salmonella strains.
Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies (2005)

The antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) in patients with thromboembolic complications. In APS, most aPL are autoantibodies to beta2-glycoprotein I and prothrombin, which play a major role in the APS pathogenesis. Nevertheless, antibodies with the same antigen specificity are also found in aPL patients with leprosy, in whom thromboembolic complications are uncommon. The in vivo upregulation of the tissue factor (TF) pathway and the imbalance of cytokines have been proposed as potential mechanisms of thrombosis in the APS. We measured the circulating levels of TF, interleukin 6 (IL-6), IL-6 receptor (sIL-6R), tumor necrosis factor (TNF-alpha) and interferon gamma (IFN-gamma) in 83 patients with autoimmune aPL (42 with and 41 without clinical features of definite primary APS), 48 leprosy patients (33 with aPL) and 48 normal controls. There was a trend (P = 0.06) to higher median sTF in patients with autoimmune aPL (139 pg/mL) compared with leprosy patients (103.5 pg/mL) and controls (123 pg/mL). In addition, the frequency of raised sTF levels (> 187 pg/mL) was significantly higher in the group with autoimmune aPL [22.9% (APS 21.4%, non-APS 24.4%)] but not in leprosy (10.4%) compared with controls (4.2%). Elevated levels of IL-6 and TNF-alpha and a trend to lower IFN-gamma were found in patients with definite APS. Leprosy patients with aPL, however, had increased TNF-alpha and IFN-gamma but normal IL-6 levels. Levels of sIL-6R did not differ between controls and either patients with autoimmune aPL or leprosy. The different cytokine profiles as well as differences in circulating levels of TF might contribute to the high thrombotic risk found in patients with autoimmune aPL but not in leprosy related aPL patients.
New Unexpected Products During Heteroannulation of 1,4‐Naphthoquinone Derivatives. (2003)

Abstract For Abstract see ChemInform Abstract in Full Text.
Inhibition of Benzo[a]pyrene‐Induced Forestomach Neoplasia in Mice by Citrus Limonoids (1989)

The limonoids, limonin and nomilin, are bitter principles found in common edible citrus fruits. Nomilin, when given three times (at 5 and 10 mg per animal) every two days, induced increased glutathione S-transferase activity 2.48 and 3.44 times over the control, respectively, in the liver of female ICR/Ha mice. The increases of GST activity in the small intestinal mucosa were 3.00 and 4.17, respectively, over the control. Limonin, when given at the same dose levels, was not active in the liver. However, marginal activity was obtained in the small intestinal mucosa. Nomilin, which is the more active enzyme inducer, was found to inhibit benzo[a]pyrene (BP)-induced neoplasia in the forestomach of ICR/Ha mice. The number of mice with tumors was reduced from 100 to 72%, and the number of tumors per mouse was significantly decreased as a result of nomilin treatment. Limonin, which is a weak enzyme inducer, was less potent as an inhibitor of BP-induced neoplasia. These findings suggest limonoids as a class of regularly consumed natural products may be effective chemopreventive agents.
Genome of Human Hepatitis C Virus (HCV): Gene Organization, Sequence Diversity, and Variation (2000)

Hepatitis C virus (HCV) is the major etiologic agent of non-A, non-B hepatitis. HCV infection frequently causes chronic hepatitis, which progresses to liver cirrhosis and hepatocellular carcinoma. Since the discovery of HCV in 1989, a large number of genetic analyses of HCV have been reported, and the viral genome structure has been elucidated. An enveloped virus, HCV belongs to the family Flaviviridae, whose genome consists of a positive-stranded RNA molecule of about 9.6 kilobases and encodes a large polyprotein precursor (about 3000 amino acids). This precursor protein is cleaved by the host and viral proteinase to generate at least 10 proteins: the core, envelope 1 (E1), E2, p7, nonstructural (NS) 2, NS3, NS4A, NS4B, NS5A, and NS5B. These HCV proteins not only function in viral replication but also affect a variety of cellular functions. HCV has been found to have remarkable genetic heterogeneity. To date, more than 30 HCV genotypes have been identified worldwide. Furthermore, HCV may show quasispecies distribution in an infected individual. These findings may have important implications in diagnosis, pathogenesis, treatment, and vaccine development. The hypervariable region 1 found within the envelope E2 protein was shown to be a major site for the genetic evolution of HCV after the onset of hepatitis, and might be involved in escape from the host immunesurveillance system.