gebhart/patrepeval huggingface dataset:
Furin-mediated Cleavage of Pseudomonas Exotoxin-derived Chimeric Toxins (1997)

Pseudomonas exotoxin (PE) requires proteolytic cleavage to generate a 37-kDa C-terminal fragment that translocates to the cytosol and ADP-ribosylates elongation factor 2. Cleavage within cells is mediated by furin, occurs between arginine 279 and glycine 280, and requires an arginine at both P1 and P4 residues. To study the proteolytic processing of PE-derived chimeric toxins, TGFalpha-PE38 (transforming growth factor fused to the domains II and III of PE) and a mutant form, TGFalpha-PE38gly279, were each produced in Escherichia coli. When assessed on various epidermal growth factor (EGF) receptor-positive cell lines, TGFalpha-PE38 was 100-500-fold more toxic than TGFalpha-PE38gly279. In contrast to PE, where cleavage by furin is only evident at pH 5.5, furin cleaved TGFalpha-PE38 over a broad pH range, while TGFalpha-PE38gly279 was resistant to cleavage. TGFalpha-PE38 was poorly toxic for furin-deficient LoVo cells, unless it was first pretreated in vitro with furin. Furin treatment produced a nicked protein that was 30-fold more toxic than its unnicked counterpart. Using the single chain immunotoxin HB21scFv-PE40 as a substrate, furin-mediated processing of an antibody-based immunotoxin was also evaluated. HB21scFv-PE40, which targets cells expressing the transferrin receptor, was cleaved in a similar fashion to that of TGFalpha-PE38 and nicked HB21scFv-PE40 exhibited increased toxicity for LoVo cells. In short-term experiments, the rate of reduction in protein synthesis by furin-nicked immunotoxins was increased compared with unnicked protein, indicating that cleavage by furin can be a rate-limiting step. We conclude that furin-mediated cleavage of PE-derived immunotoxins is important for their cytotoxic activity.
Optimizing exon skipping therapies for DMD. (2007)

Exon skipping is one of the more promising therapeutic options for Duchenne Muscular Dystrophy (DMD). The idea is to use antisense oligonucleotides to splice out selected exons from the pre-mRNA, at or next to the mutation site, so as to generate a translatable transcript from the mutant dystrophin gene. In principle, the majority of DMD mutations can be rescued by targeting selected exons. Recent developments of antisense oligonucleotides (AOs) such as 2O-methylated antisense oligonucleotides (2OMeAOs) or phosphorodiamidate morpholino oligomers (morpholinos, PMOs) have made it possible to restore dystrophin expression body-wide in dystrophic mice and dystrophic dogs by single or multi-exon skipping with no obvious side-effect. Since such treatment would, in many cases, require bespoke design of AOs, it is important to demonstrate treatment of a variety of mutations in dystrophic animals. In-frame deletion patterns usually result in a mix of Duchenne and milder Becker Muscular Dystrophy (BMD), but the ratio of Duchenne to Becker varies between patterns, and this provides useful information for selection of the exons that might most profitably be targeted. This review summarizes recent progress in exon skipping therapy and discusses future strategies.
Ultrafast photoconductors based on plasmonic gratings (2011)

We present an ultrafast photoconductor that offers significantly higher quantum efficiencies compared to conventional photoconductors. The ultrafast response is achieved by excitation of surface plasmon waves, localizing a major portion of the incident light near photoconductor contact electrodes.
Relations between Hepatotoxicity and Pharmacokinetics of Paracetamol in Rats and Mice (1978)

A dose-dependent increase of paracetamol serum half-life (t1/2) was found after oral and intravenous application in rats and oral application in mice. The hepatotoxic effects of paracetamol were not correlated with this prolongation of t1/2. Dithiocarb protected rats against paracetamol liver damage but did not change paracetamol t1/2. Paracetamol t1/2 was not influenced either by a hepatotoxic dose of carbon tetrachloride. In conclusion, the dose-dependent prolongation of paracetamol serum half-life is not due to paracetamol-induced liver damage but merely the consequence of saturated elimination processes.
Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. (1996)

According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (betaA) directly affects neurons, leading to neurodegeneration and tau phosphorylation. In rat hippocampal culture, betaA exposure activates tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK-3beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death. To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA in mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3beta in vitro and also in betaA-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death. In cholinergic neurons, betaA impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by betaA-induced TPKI/GSK-3beta. Thus, TPKI/GSK-3beta regulates PDH and participates in energy metabolism and acetylcholine synthesis. These results suggest that TPKI/GSK-3beta plays a key role in the pathogenesis of Alzheimer disease.
Death Induction by Recombinant Native TRAIL and Its Prevention by a Caspase 9 Inhibitor in Primary Human Esophageal Epithelial Cells (2004)

The cytotoxic death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a tumor-specific agent under development as a novel anticancer therapeutic agent. However, some reports have demonstrated toxicity of certain TRAIL preparations toward human hepatocytes and keratinocytes through a caspase-dependent mechanism that involves activation of the extrinsic death pathway and Type II signaling through the mitochondria. We have isolated and purified both His-tagged protein and three versions of native recombinant human TRAIL protein from Escherichia coli. We found that 5 mm dithiothreitol in the purification process enhanced oligomerization of TRAIL and resulted in the formation of hyper-oligomerized TRAILs, including hexamers and nonomers with an extremely high potency in apoptosis induction. Although death-inducing signaling complex formation was much more efficient in cells treated with hyper-oligomerized TRAILs, this did not convert TRAIL-sensitive Type II HCT116 colon tumor cells to a Type I death pattern as judged by their continued sensitivity to a caspase 9 inhibitor. Moreover, TRAIL-resistant Type II Bax-null colon carcinoma cells were not converted to a TRAIL-sensitive Type I state by hyper-oligomerized TRAIL. Primary human esophageal epithelial 2 cells were found to be sensitive to all TRAIL preparations used, including trimer TRAIL. TRAIL-induced death in esophageal epithelial 2 cells was prevented by caspase 9 inhibition for up to 4 h after TRAIL exposure. This result suggests a possible therapeutic application of caspase 9 inhibition as a strategy to reverse TRAIL toxicity. Hyper-oligomerized TRAIL may be considered as an alternative agent for testing in clinical trials.
Uric acid in chronic heart failure: a marker of chronic inflammation (1998)

Serum uric acid is strongly related to circulating markers of inflammation in patients with chronic heart failure. This is consistent with a role for increased xanthine oxidase activity in the inflammatory response in patients with chronic heart failure.
Scanning flow cytometry for individual particle analysis (2000)

With this work we review the development of theoretical and experimental aspects of the scanning flow cytometry (SFC). The optical and hydrodynamic systems of the SFC provide the measurement of fluorescence and light scattering of individual particles with a typical rate up to 500 particles/s. In addition the optical system of the SFC has the capability of individual particle analysis beyond that of an ordinary flow cytometry. The SFC measures an entire angular dependency of light scattering intensity (flying light scattering indicatrix, FLSI) over angles ranging from 5° to 120°. The fluorescence collection efficiency of the SFC approaches 1/3 of a sphere. Moreover, the optical system of the SFC provides the measurement of fluorescence in a time-resolved mode on a microsecond time scale. The processing of the output data in light scattering is based on a parametric solution of the inverse light-scattering problem, the FLSI method. The FLSI method allows the determination of size and refractive index of spherically modeled particles over a range of diameters from 0.9 to 15 μm and a range of refractive indexes from 1.37 to 1.60. The performance of the SFC in different applications has been demonstrated.
Genotypic Variation in Pathogenic Escherichia coli O157:H7 Isolated from Patients in Washington, 1984-1987 (1989)

Journal Article Genotypic Variation in Pathogenic Escherichia coli O157:H7 Isolated from Patients in Washington, 1984–1987 Get access Phillip I. Tarr, Phillip I. Tarr Please address requests for reprints to Dr. P. I. Tarr, Divisions of Gastroenterology and Infectious Diseases, Department of Pediatrics, RD-20, University of Washington, Seattle, Washington 98195. Search for other works by this author on: Oxford Academic PubMed Google Scholar Marguerite A. Neill, Marguerite A. Neill Search for other works by this author on: Oxford Academic PubMed Google Scholar Carla R. Clausen, Carla R. Clausen Search for other works by this author on: Oxford Academic PubMed Google Scholar John W. Newland, John W. Newland Search for other works by this author on: Oxford Academic PubMed Google Scholar Roger J. Neill, Roger J. Neill Search for other works by this author on: Oxford Academic PubMed Google Scholar Steve L. Moseley Steve L. Moseley Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 159, Issue 2, February 1989, Pages 344–347, https://doi.org/10.1093/infdis/159.2.344 Published: 01 February 1989 Article history Received: 05 May 1988 Revision received: 01 September 1988 Published: 01 February 1989
Josephson Current Flow in Pure Superconducting-Normal-Superconducting Junctions (1972)

It is shown that the Josephson current in a pure superconducting-normal-superconducting (SNS) sandwich with normal layer thickness large compared with the coherence distance can be calculated easily from the quasiparticle spectrum by use of Galilean invariance. The results agree with Ishii at $T=0\ifmmode^\circ\else\textdegree\fi{}$K and with an expression of Kulik for the bound-state contribution, but we do not find a larger contribution from states with $E$ near ${\ensuremath{\Delta}}_{0}$ as suggested by Kulik. The expected current decreases very rapidly with increase in temperature so that it would be necessary to go to very low temperatures to observe the effect.
Sag of Weight Materials in Oil Based Drilling Fluids (2002)

Abstract To be able to keep a well under control during drilling it is important to have the weight material suspended during the whole operation. Especially in oil based, or synthetic based drilling fluids, controlling sag is difficult. A large number of wells have experienced lost circulation or well control problems with the associated high costs relating to sag. There are limited field proven methods available to predict the potential for sag for a particular drilling fluid. Therefore, barite sag continues to be one of the most difficult tasks to handle for a drilling fluid engineer. It is well known that standard viscosity readings cannot be used to predict the sag potential of a drilling fluid. The current paper discusses in detail the mechanisms of sag in oil based drilling fluid and how to treat sag. It is shown that at ultra-low shear rates the oil based drilling fluid is shear thickening as opposed to the shear thinning effect observed at higher shear rates. It is described how this shear thickening behaviour leads to sag if the drilling fluid composition is incomplete. It is described how organophilic clay should be used to minimize sag and why different types of clay have different effect onto hindering sag although none of these differences have to be visible on standard viscometer readings. Furthermore, it is suggested that "modifiers" generally have little effect on preventing sag. Different methods to monitor or predict the sag potential of drilling fluids are also outlined. Dilution of the drilling fluid normally results in increased sag. Good practice is that the dilution with new drilling fluid should be minimized to control the sag properties of the oil based drilling fluid.
Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy (2016)

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the 'armor' agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.
Pharmacokinetic-Pharmacodynamic Relationships for the Heat Shock Protein 90 Molecular Chaperone Inhibitor 17-Allylamino, 17-Demethoxygeldanamycin in Human Ovarian Cancer Xenograft Models (2005)

Pharmacokinetic-pharmacodynamic relationships were established for 17-AAG. This information formed the basis of a pharmacokinetic-pharmacodynamic-driven phase I trial.
Paclitaxel, Estramustine Phosphate, and Carboplatin in Patients With Advanced Prostate Cancer (2001)

TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.
Conserved interaction of the papillomavirus E2 transcriptional activator proteins with human and yeast TFIIB proteins (1997)

Papillomavirus early gene expression is regulated by the virus gene-encoded E2 proteins. The best-characterized E2 protein, encoded by bovine papillomavirus type 1 (BPV-1), has been shown to interact with basal transcription factor IIB (TFIIB) and the TATA binding protein basal transcription factor (N. M. Rank and P. F. Lambert, J. Virol. 69:6323-6334, 1995). We demonstrate that the potent E2 transcriptional activator protein encoded by a gene of human PV type 16 also interacts with TFIIB in vitro. Moreover, a direct comparison of domains within human TFIIB (hTFIIB) required for VP16 and BPV-1 E2 indicates that these acidic activators interact with hTFIIB in a qualitatively similar manner. Our mapping experiments identify hTFIIB interaction domains within the amino-terminal activation domain of BPV-1 E2. Finally, we demonstrate in vitro interaction between Saccharomyces cerevisiae TFIIB and BPV-1 E2, an observation that is consistent with the importance of the E2-TFIIB interaction for BPV-1 E2 transactivation in both systems.
Identification of Mitogen-Activated Protein Kinase Signaling Pathways That Confer Resistance to Endoplasmic Reticulum Stress in Saccharomyces cerevisiae (2005)

Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor-independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress-inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, were also required for survival during ER stress. We further show that the SLT2 MAPK pathway was activated during ER stress, was responsible for increased resistance to ER stress, and functioned independently of the classic IRE1/HAC1 pathway. We propose that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress. This study shows the feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR.
Energy-selective reconstructions in X-ray computerised tomography (1976)

All X-ray computerized tomography systems that are available or proposed base their reconstructions on measurements that integrate over energy. X-ray tubes produce a broad spectrum of photon energies and a great deal of information can be derived by measuring changes in the transmitted spectrum. We show that for any material, complete energy spectral information may be summarized by a few constants which are independent of energy. A technique is presented which uses simple, low-resolution, energy spectrum measurements and conventional computerized tomography techniques to calculate these constants at every point within a cross-section of an object. For comparable accuracy, patient dose is shown to be approximately the same as that produced by conventional systems. Possible uses of energy spectral information for diagnosis are presented.
Effect of Seminal Extenders on Equine Fertility (1975)

Pregnancy rate, spermatozoan motility and spermatozoan agglutination were significantly lower in an extender containing .349% Tris than in an extender utilizing 2.4% Tris. First-cycle pregnancy rates of 22.2 and 11.1% were obtained with 500 and 100 × 106 motile spermatozoa in a 2.4% Tris extender, and a rate of 61.1% (P < .05) was obtained with 500 × 106 motile spermatozoa in raw semen. After four cycles there was no significant difference in fertility obtained with 2.4% Tris and the raw semen when 500 × 106 spermatozoa were utilized (72.2 vs 88.9%). First cycle pregnancy rates of 37.5, 75.0 and 75.0% were obtained in 1973 when mares were inseminated with 500 × 106 motile spermatozoa extended in 2.4% Tris, and cream-gel extenders and with raw semen, respectively. After three cycles, mares on the Tris-seminal treatment had a pregnancy rate of 75.0%, which was lower (P < .05) than the 95.8 and 91.7% for the cream-gel and raw-seminal treatments, respectively. The presence of glycerol in the Tris extenders may have been at least partially responsible for the depression of fertility. Pregnancy rates of 75.0 and 91.7% were obtained after one and three cycles, respectively, with a mean insemination volume of 1.5 ml of raw semen. Thus, a large insemination volume may not be necessary for maximum fertility in the mare.
Prednisolone interferes with neutrophil adhesion and neutrophil mediated endothelial injury (1999)

Adhesion of leukocytes to vascular endothelium is a crucial step in inflammation. This interaction may result in damage of the endothelial cells (EC). We evaluated the effects of prednisolone on adhesive interactions between human polymorphonuclear neutrophil granulocytes (PMN) and human umbilical vein endothelial cells (HUVEC) as well as PMN mediated cytotoxicity to HUVEC (as release of 51chromium), mediated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), lipoxin A4 (LXA4), and the calcium ionophore A23187 in vitro. Prednisolone dose-dependently interfered with adhesion and cytotoxicity induced by fMLP. Prednisolone (at 10 microM) led to a 39% reduction of adhesion and an almost complete inhibition of cytotoxicity, mainly by effects on the PMN. Prednisolone also interfered with cytotoxicity induced by LXA4 by effects on PMN as well as on HUVEC. Adhesion and cytotoxicity induced by the calcium ionophore A23187 was not affected in any way by prednisolone. Thus, in these in vitro models of vasculitis, prednisolone interferes with adhesive and cytotoxic interactions induced by receptor-dependent agonists. These protective effects of prednisolone might explain some of the beneficial effects of glucocorticoids in the treatment of vasculitis.
Structure of Influenza Virus Neuraminidase B/Lee/40 Complexed with Sialic Acid and a Dehydro Analog at 1.8-.ANG. Resolution: Implications for the Catalytic Mechanism (1994)

Neuraminidase is one of the two glycoprotein spikes protruding from the influenza virus membrane. We have determined by X-ray crystallography the native structure of B/Lee/40 neuraminidase (NA) and the structures of its crystals soaked with a substrate, N-acetylneuraminyllactose (NANL), and an inhibitor, 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) at 1.8-A resolution. NANL was hydrolyzed by the crystalline NA to generate the product N-acetylneuraminic acid (NANA, also known as sialic acid), which is still able to bind to NA. In the difference Fourier map of the presumed NA-NANA complex, the moiety bound in the active site had a distorted boat conformation of NANA, but there is no significant electron density for O2. The structure of the bound moiety is not identical to that of chemically synthesized DANA soaked into NA crystals. Prolonged incubation of NANA with NA in solution at room temperature produced only a trace amount of DANA as detected by NMR. On the basis of our studies, a mechanism is proposed for the enzymatic hydrolysis by influenza virus neuraminidase.
Parametric harmonic balance (2002)

Harmonic balance has established itself as an important technique for simulating high frequency circuits. However, this simulator struggles on strongly nonlinear circuits, particularly if there are several input signals at different frequencies. An important observation is that multi-tone nonlinear circuits usually react in a strongly nonlinear fashion in response to one signal, but in near-linear fashion in response to the others. In this paper we present an extension of harmonic balance that exploits these properties to reduce the time and memory required to perform accurate circuit-level frequency-domain simulation of mixers.