gebhart/patrepeval huggingface dataset:
Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus (2015)

Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4'-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2'-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC-3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2'-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing.
An update on cytokines in the pathogenesis of insulin‐dependent diabetes mellitus (1998)

Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that -cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF, and IFN) and type 1 cytokines (IFN, TNF, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF). Cytokines (IL-1, TNF, TNF and IFN) may be directly cytotoxic to -cells by inducing nitric oxide and oxygen free radicals in the -cells. In addition, cytokines may sensitize -cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the -cells (an action of IFN), and inducing Fas (CD95) expression on -cells (actions of IL-1, and possibly TNF and IFN). Transgenic expression of cytokines in -cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN, IFN, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4 + T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN-producing), but other islet-specific Th1 clones that produce TGF can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN, also IL-1, TNF, IL-2, and IL-6-by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs-significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF, and IL-6) and type 1 cytokines (IFN, IL-2 and IL-12) in IDDM development.
A chloroplast gene encoding a protein with one zinc finger (1989)

We have sequenced a pea chloroplast gene encoding a protein with a zinc finger (zfp A). The putative protein is conserved in chloroplast DNA and shows sequence homology to the E. coli protein controlling fol C expression. Exposure of etiolated pea leaves to light leads to the accumulation of zfp A transcripts. The accumulation of these transcripts does not require de novo protein synthesis in the chloroplast, although the expression of highly inducible genes such as rbc L requires it. These properties suggest that zfp A encodes a protein involved in the regulation of chloroplast gene expression.
Optoacoustic sources: a practical Green function-based model for thin film laser-ultrasound generation (2001)

The theory of optoacoustic generation of ultrasound in fluids through the thermoelastic effect has been addressed, considering the case of a thin absorbing film used as a target for the laser light. A novel theoretical method, based on the use of the Green function and of the image theorem, has been developed and discussed. The model is mainly carried out in time and space domains, and connects the sound field directly to the laser pulse intensity through equations that show the relevant underlying phenomena. With respect to standard double transform (Laplace + Hankel) techniques, it ensures a simpler physical understanding and appears to be more robust from the computational point of view. Moreover it allows us to identify the approximations that may simplify many practical problems. Many approximate formulae are deduced, in addition to the most significant ultrasonic pressure field parameters, such as amplitude and bandwidth, which are explicitly evaluated in terms of laser excitation and of the materials characteristics.
Selection against expression of the Escherichia coli gene gpt in hprt+ mouse teratocarcinoma and hybrid cells. (1987)

Thioxanthine is toxic for mammalian cells transformed by the dominant selectable marker gpt. It allowed us to select, in the presence of the endogenous hypoxanthine-guanine phosphoribosyltransferase gene, mutants that did not express gpt any more and also hybrid cells that had lost the chromosome carrying it. The gpt marker is thus dominant in negative as well as in positive selection, which makes it potentially very useful for genetic studies of mammalian cells.
Long-term caloric restriction delays age-related decline in proliferation capacity of murine lens epithelial cells in vitro and in vivo. (1997)

A significantly reduced proliferative capacity of LE cells is associated with increased age of mice and is delayed by long-term caloric restriction as measured in vitro and in vivo. How caloric restriction mediates its effects on LE cell proliferation remains to be investigated further.
Preferential binding of the xeroderma pigmentosum group A complementing protein to damaged DNA (1993)

The xeroderma pigmentosum group A complementing protein (XPAC) is involved in an early step of nucleotide excision repair, the main process that removes UV damage and many chemical lesions from DNA. To explore the properties and function of XPAC, recombinant protein encoded by the human XPAC cDNA was expressed with an N-terminal polyhistidine tag in Escherichia coli and purified to homogeneity. The soluble fusion protein could correct the repair defect in vitro of XP-A cell extracts. XPAC protein bound to DNA with a preference for UV-irradiated over nonirradiated DNA, as determined by a gel electrophoresis mobility shift assay with a 258 base pair DNA fragment (the association constant was approximately 3 x 10(6) M-1 for the fragment irradiated with 6 kJ/m2 UV light). Removal of cyclobutane pyrimidine dimers from UV-irradiated DNA by enzymatic photoreactivation did not significantly reduce binding of XPAC to the irradiated fragment, indicating that binding was mostly due to (6-4) photoproducts, with a preference for a (6-4) photoproduct over an undamaged base pair up to 300-fold. Undamaged single-stranded DNA competed about 4-fold more effectively than undamaged double-stranded DNA for binding of XPAC to a UV-irradiated fragment. In addition, XPAC bound to DNA treated with the chemotherapeutic agent cis-diamminedichloroplatinum(II). The results suggest that XPAC functions as a key component in recognition of DNA damage during repair.
The effect of anti-Z-DNA antibodies on the B-DNA-Z-DNA equilibrium. (1986)

Four different preparations of rabbit and goat anti-Z-DNA antibodies were examined to determine the effects of antibody binding on the B-DNA-Z-DNA equilibrium. One of the four antibodies, a goat IgG, caused a marked lowering in the ionic strength required for the B-DNA to Z-DNA transition in poly(dG-dC) X poly(dG-dC), shifting the midpoint from 2.25 to 2.0 M NaCl. This IgG had a more prominent high affinity antibody population than did the other goat IgG, which caused little change in the midpoint of this transition. The presence of anti-Z-DNA antibodies also reduced the degree of negative supercoiling required for the formation of Z-DNA in (dG-dC)n sequences inserted into closed circular plasmid DNA. The goat IgG with the more marked effect on the salt-induced transition also had a greater effect in favoring Z-DNA formation in negatively supercoiled plasmids. A shift toward Z-DNA formation was observed in circular dichroism measurements upon antibody binding to poly(dG-dC) X poly(dG-dC) in very low ionic strength solution as well. We propose that the stabilization of Z-DNA by antibody binding in poly(dG-dC) X poly(dG-dC) occurs cooperatively, several antibody molecules binding to a single polymer molecule and stabilizing the entire molecule in Z-DNA through their combined binding energies. The stabilization of Z-DNA by antibody binding in a supercoiled plasmid can be significant, and failure to consider this effect and to choose appropriate conditions for measurement can lead to errors in estimating when Z-DNA will form in response to negative supercoiling.
High Prognostic Impact of Flow Cytometric Minimal Residual Disease Detection in Acute Myeloid Leukemia: Data From the HOVON/SAKK AML 42A Study (2013)

In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.
Phenotypic heterogeneity in breast fibroblasts: Functional anomaly in fibroblasts from histologically normal tissue adjacent to carcinoma (1994)

Histologically normal breast tissue was obtained from women undergoing surgery for benign breast lesions (n = 12) and mammary carcinomas (n = 15). Four fibroblast subpopulations (FI, FII, FIII and FIV) were isolated from these specimens by differential digestion and centrifugation. FI cells were the first to be released from the tissue digest and consequently assumed to be derived from the interlobular stroma; FIV fibroblasts were tightly associated with the epithelial organoids and are therefore believed to be of intralobular origin. These cells were characterised in terms of their migratory phenotype (classified as either foetal- or adult-like) and the production of motility factors according to previously described techniques. FI fibroblasts obtained from patients with benign breast lesions displayed a foetal migratory phenotype (10/11) and secreted detectable quantities of motility factors (11/11). In contrast, none of the FIV fibroblasts (0/10) obtained from these same patients displayed a foetal-like migratory phenotype or secreted motility factors. In the case of fibroblasts obtained from cancer patients, both FI (13/13) and FIV (13/13) fibroblasts displayed a foetal-like migratory phenotype and secreted motility factors. Fibroblasts were also derived from skin (n = 12) and breast fat tissue (n = 4) of certain patients. In agreement with our previously published observations, skin fibroblasts obtained from non-cancer and cancer patients also differed in terms of their migratory behaviour: none of the skin fibroblast lines (0/5) obtained from non-cancer patients were foetal-like, compared to 3/7 lines from cancer patients. All fat-derived fibroblasts (1 non-cancer and 3 cancer patients) were also foetal-like. Our results indicate (i) functional heterogeneity between FI and FIV fibroblasts of normal breast, and (ii) the presence of functionally aberrant (i.e., foetal-like) FIV fibroblasts in histologically normal breast tissue adjacent to a carcinoma.
Quality assessment of buccal versus blood genomic DNA using the Affymetrix 500 K GeneChip (2007)

Buccal cytobrushes stored long-term result in sufficient dsDNA concentrations to achieve high genotyping call rates and concordance with stored blood samples in the context of Affymetrix 500 K SNP genotyping. Thus, given high-quality collection and storage protocols, it is possible to use stored buccal cytobrush samples for genome-wide association studies.
High incidence of anti‐FVIII antibodies against non‐coagulant epitopes in haemophilia A patients: a possible role for the half‐life of transfused FVIII (1996)

The occurrence of antibodies (Abs) capable of inhibiting factor VIII (FVIII) coagulant activity is a severe complication in haemophilia A, leading to the inhibition of transfused FVIII activity. It is not known whether, or to what extent, post-transfusion antibodies may also arise against non-coagulant epitopes. Therefore we set up a system capable, in theory, to detect all the FVIII-induced antibodies by use of an enzyme-linked immunoassorbent assay (ELISA) based on coating human recombinant FVIII onto polystyrene microtitre plates. Serum samples from 23 patients affected by haemophilia A of different gravity (22 referred to our Centre and one to the Bari Centre) were analysed. Although only one patient was positive at Bethesda assay, the presence of antibodies in ELISA was detected in 39% of patients in variable degrees; transfusion with FVIII was found to induce a raise in antibody titre, arguing in favour of the specificity of the phenomenon. The clinical relevance of these non-inhibitory antibodies was evaluated in three patients; although half-life did not show any change in the patients without or with low amount of antibodies, FVIII clearance was found enhanced in the patient displaying high titre antibodies. We propose detection of anti-FVIII antibodies by ELISA when routinely assessing haemophilia A patients.
The immunopathogenesis of allergic skin diseases in dogs and cats. (2009)

Hypersensitivity in veterinary medicine has been recently redefi ned as “Objectively reproducible clinical signs initiated by exposure to a defi ned stimulus at a dose tolerated by normal dogs” [1]. A number of different types exist, broadly mediated by antibody or immunocompetent lymphoid cells. However this represents an oversimplifi cation, and, as exemplifi ed especially by atopic dermatitis (AD), a complex interplay between various arms of the innate and acquired immune systems is involved. SUMMARY
Advances in the management of hyperlipidemia-induced atherosclerosis (2008)

Although hyperlipidemia clearly plays a role in developing cardiovascular disease, the 10% of the population with the highest LDL levels account for only 20% of cardiovascular disease events. Thus, in order to significantly reduce the burden of cardiovascular disease, subjects with only modest dyslipidemia need to be treated with lipid-lowering therapy. Current guidelines have recommended aggressive lipid-lowering therapy in subjects at high risk of cardiovascular disease. The rationale behind this and treatment options to achieve target lipid goals are discussed.
Neurotrophins in lung health and disease (2010)

Neurotrophins (NTs) are a family of growth factors that are well-known in the nervous system. There is increasing recognition that NTs (nerve growth factor, brain-derived neurotrophic factor and NT3) and their receptors (high-affinity TrkA, TrkB and TrkC, and low-affinity p75NTR) are expressed in lung components including the nasal and bronchial epithelium, smooth muscle, nerves and immune cells. NT signaling may be important in normal lung development, developmental lung disease, allergy and inflammation (e.g., rhinitis, asthma), lung fibrosis and even lung cancer. In this review, we describe the current status of our understanding of NT signaling in the lung, with hopes of using aspects of the NT signaling pathway in the diagnosis and therapy of lung diseases.
The MIPS M2000 system (2003)

The M2000 represents an attempt to design a system optimized to support a RISC (reduced-instruction-set computer) processor. While RISC processors in general have a high memory-bandwidth requirement, the R3000 through the use of data block refill, instruction streaming, and write streaming has been tuned to require yet more bandwidth. This tuning is reflected in its 1.25 average cycles per instruction. The M2000 attacks the memory-bandwidth problem by extensive use of page-mode DRAMs (dynamic random-access memory) for all memory accesses: processor reads, processor writes, I/O reads, and I/O writes, using page-mode access. Where a bandwidth mismatch is present, i.e. between the I/O bus and the memory array. FIFO (first-in, first out) buffering is provided to prevent memory tieup.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Cloning and Characterization ofCAD1/AAF1, a Gene fromCandida albicansThat Induces Adherence to Endothelial Cells after Expression inSaccharomyces cerevisiae (1998)

Adherence to the endothelial cell lining of the vasculature is probably a critical step in the egress of Candida albicans from the intravascular compartment. To identify potential adhesins that mediate the attachment of this organism to endothelial cells, a genomic library from C. albicans was used to transform a nonadherent strain of Saccharomyces cerevisiae. The population of transformed yeasts was enriched for highly adherent clones by repeated passages over endothelial cells. One clone which exhibited a fivefold increase in endothelial cell adherence, compared with S. cerevisiae transformed with vector alone, was identified. This organism also flocculated. The candidal DNA fragment within this adherent/flocculent organism was found to contain a single 1.8-kb open reading frame, which was designated CAD1. It was found to be identical to AAF1. The predicted protein encoded by CAD1/AAF1 contained features suggestive of a regulatory factor. Consistent with this finding, immunoelectron microscopy revealed that CAD1/AAF1 localized to the cytoplasm and nucleus but not the cell wall or plasma membrane of the transformed yeasts. Because yeasts transformed with CAD1/AAF1 both flocculated and exhibited increased endothelial cell adherence, the relationship between adherence and flocculation was examined. S. cerevisiae expressing either of two flocculation phenotypes, Flo1 or NewFlo, adhered to endothelial cells as avidly as did yeasts expressing CAD1/AAF1. Inhibition studies revealed that the flocculation phenotype induced by CAD1/AAF1 was similar to Flo1. Thus, CAD1/AAF1 probably encodes a regulatory protein that stimulates endothelial cell adherence in S. cerevisiae by inducing a flocculation phenotype. Whether CAD1/AAF1 contributes to the adherence of C. albicans to endothelial cells remains to be determined.
Properly Folded Bacterially Expressed H1N1 Hemagglutinin Globular Head and Ectodomain Vaccines Protect Ferrets against H1N1 Pandemic Influenza Virus (2010)

This is the first study that describes production in bacterial system of properly folded functional globular HA1 domain trimers, lacking the HA2 transmembrane protein, that elicit potent neutralizing antibody responses following vaccination and protect ferrets from in vivo challenge. The combination of bacterial expression system with established quality control methods could provide a mechanism for rapid large scale production of influenza vaccines in the face of influenza pandemic threat.
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis (2010)

Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element-binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate-binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid-antisense oligonucleotides results in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.
Amniotic Membrane Transplantation With or Without Limbal Allografts for Corneal Surface Reconstruction in Patients With Limbal Stem Cell Deficiency (1998)

For partial limbal deficiency with superficial involvement, AMT alone is sufficient and hence superior to ALT because there is no need to administer cyclosporine. For total limbal deficiency, additional ALT is needed, and AMT helps reconstruct the perilimbal stroma, with reduced inflammation and vascularization, which collectively may enhance the success of ALT.
The Constitutents of Ecballium elaterium L. VI. The Functions of Elatericin A1,2 (1959)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Constitutents of Ecballium elaterium L. VI. The Functions of Elatericin A1,2David Lavie and Youval ShvoCite this: J. Am. Chem. Soc. 1959, 81, 12, 3058–3061Publication Date (Print):June 1, 1959Publication History Published online1 May 2002Published inissue 1 June 1959https://pubs.acs.org/doi/10.1021/ja01521a037https://doi.org/10.1021/ja01521a037research-articleACS PublicationsRequest reuse permissionsArticle Views52Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts