gebhart/patrepeval huggingface dataset:
Keeping Secrets Secret (2000)

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beta-Glucuronidase from Escherichia coli as a gene-fusion marker. (1986)

We have developed a gene-fusion system based on the Escherichia coli beta-glucuronidase gene (uidA). The uidA gene has been cloned from E. coli K-12 and its entire nucleotide sequence has been determined. beta-Glucuronidase has been purified to homogeneity and characterized. The enzyme has a subunit molecular weight of 68,200, is very stable, and is easily and sensitively assayed using commercially available substrates. We have constructed gene fusions of the E. coli lacZ promoter and coding region with the coding region of the uidA gene that show beta-glucuronidase activity under lac control. Plasmid vectors have been constructed to facilitate the transfer of the beta-glucuronidase coding region to heterologous control regions, using many different restriction endonuclease cleavage sites. There are several biological systems in which uidA-encoded beta-glucuronidase may be an attractive alternative or complement to previously described gene-fusion markers such as beta-galactosidase or chloramphenicol acetyltransferase.
A novel method to analyze 5‐hydroxymethylcytosine in CpG sequences using maintenance DNA methyltransferase, DNMT1 (2015)

Hydroxymethylcytosine has been shown to be involved in DNA demethylation and gene expression. Although methods to determine the position of hydroxymethylcytosine at single-base resolution have been reported, these methods involve some difficulties. Here, we report a simple method to analyze hydroxymethylcytosine in the CpG sequence utilizing the maintenance DNA methylation activity of DNMT1, which selectively methylates hemi-methylated but not hemi-hydroxymethylated CpG sequences. The method enables monitoring of the dynamics of the hydroxymethylation state of a specific genome site.
Molecular Cloning of the Gene for a Conserved Major Immunoreactive 28-Kilodalton Protein ofEhrlichia canis: a Potential Serodiagnostic Antigen (1999)

A gene encoding a 28-kDa protein of Ehrlichia canis was cloned, sequenced, and expressed, and a comparative molecular analysis with homologous genes of E. canis, Cowdria ruminantium, and Ehrlichia chaffeensis was performed. The complete gene has an 834-bp open reading frame encoding a protein of 278 amino acids with a predicted molecular mass of 30.5 kDa. An N-terminal signal sequence was identified, suggesting that the protein undergoes posttranslational modification to a mature 27.7-kDa protein (P28). The E. canis p28 gene has significant nucleic acid and amino acid sequence homologies with the E. chaffeensis outer membrane protein-1 (omp-1) gene family, with the Cowdria ruminantium map-1 gene, and with other E. canis 28-kDa-protein genes. Southern blotting revealed the presence of at least two additional homologous p28 gene copies in the E. canis genome, confirming that p28 is a member of a polymorphic multiple-gene family. Amino acid sequence analysis revealed that E. canis P28 has four variable regions, and it shares similar surface-exposed regions, antigenicity, and T-cell motifs with E. chaffeensis P28. The p28 genes from seven different E. canis isolates were identical, indicating that the gene for this major immunoreactive protein is highly conserved. In addition, reactivity of sera from clinical cases of canine ehrlichiosis with the recombinant P28 demonstrated that the recombinant protein may be a reliable serodiagnostic antigen.
Measurement and Analysis of Spyware in a University Environment. (2004)

Abstract Over the past few years, a relatively new computingphenomenon has gained momentum: the spread of &amp;amp;quot;spyware. &amp;amp;quot; Though most people are aware of spyware, theresearch community has spent little effort to understand its nature, how widespread it is, and the risks it presents.This paper is a first attempt to do so. We first discuss background material on spyware, in-cluding the various types of spyware programs, their methods of transmission, and their run-time behavior.By examining four widespread programs (Gator, Cydoor, SaveNow, and eZula), we present a detailed analysis oftheir behavior, from which we derive signatures that can be used to detect their presence on remote computersthrough passive network monitoring. Using these signatures, we quantify the spread of these programs amonghosts within the University of Washington by analyzing a week-long trace of network activity. This trace was gath-ered from August 26th to September 1st, 2003. From this trace, we show that: (1) these four pro-grams affect approximately 5.1 % of active hosts on campus, (2) many computers that contain spyware have morethan one spyware program running on them concurrently, and (3) 69 % of organizations within the universitycontain at least one host running spyware. We conclude by discussing security implications of spyware and spe-cific vulnerabilities we found within versions of two of these spyware programs. 1
Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors (2005)

Understanding the complex histological, genetic and molecular changes that lead to malignant transformation of squamous epithelia of the head and neck will likely guide the development of methods for improved diagnosis, monitoring and treatment of head and neck squamous cell carcinoma (HNSCC). The development and use of animal models that closely mimic the histopathology and molecular pathogenesis of HNSCC in humans would greatly expand the research possibilities and provide a means of testing potential therapeutic agents. However, many available animal models of HNSCC fall short of this objective. In order for investigators to select the appropriate model to answer scientific questions, it is important to understand the benefits and limitations of available animal models for the study of HNSCC. The purpose of this work is to give an overview of the most pertinent animal models of HNSCC, and to discuss future directions of research in this field.
Effects of ear-canal standing waves on measurements of distortion-product otoacoustic emissions (1995)

At frequencies above 3 kHz, standing waves in the ear canal complicate calibration of stimulus sound-pressure levels (SPLs) for measurements of distortion-product otoacoustic emissions (DPOAEs). In the literature, two stimulus-presentation strategies have been used for DPOAE measurements. In the "in-the-ear adjustment" strategy, the voltage command to the speakers is adjusted to maintain a constant stimulus SPL across frequency at the DPOAE-measurement microphone. In the "iso-voltage" strategy, the voltage presented to the speakers is held constant across frequency, on the basis of the assumption that the frequency response of the speakers is approximately flat at the eardrum in the average human ear canal. Because of standing-wave effects, there are large, systematic but idiosyncratic differences of stimulus SPL between the two strategies. DPOAE-versus-frequency functions ("DPOAE audiograms") obtained using both stimulus-presentation strategies in the same ears are presented. The differences of stimulus SPL between the two strategies, and the associated differences of DPOAE amplitude, are described and quantified. Around frequencies of standing-wave minima at the DPOAE probe, the in-the-ear adjustment strategy resulted in smaller DPOAEs at high L1 = L2, but much larger DPOAEs at low L1 = L2, than did the iso-voltage strategy. For any L1, the DPOAE-amplitude differences between the two strategies varied systematically with L1-L2. At the stimulus levels used to construct previously published population norms for clinical applications (i.e., L1 > or = 65 dB SPL), there are only small differences of mean DPOAE amplitudes, and of the standard deviations of these means, between the two strategies.
Implantable Penile Venous Compression Device: Initial Experience in the Acute Canine Model (1992)

We have designed a venous compression device implantable at the base of the penis outside the tunica albuginea. Because it does not require exposure of individual veins for ligation, the risk to the cavernous nerve is practically nil. It occludes the venous return only temporarily, and thus collaterals are less likely to occur. In this preliminary acute study in dogs (N = 13), the penile venous compression device was shown to be effective and safe in controlling penile venous drainage and maintaining rigid erection.
The development of mitochondrial medicine. (1994)

Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.
NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8–11 (2008)

NetMHC-3.0 is trained on a large number of quantitative peptide data using both affinity data from the Immune Epitope Database and Analysis Resource (IEDB) and elution data from SYFPEITHI. The method generates high-accuracy predictions of major histocompatibility complex (MHC): peptide binding. The predictions are based on artificial neural networks trained on data from 55 MHC alleles (43 Human and 12 non-human), and position-specific scoring matrices (PSSMs) for additional 67 HLA alleles. As only the MHC class I prediction server is available, predictions are possible for peptides of length 8-11 for all 122 alleles. artificial neural network predictions are given as actual IC(50) values whereas PSSM predictions are given as a log-odds likelihood scores. The output is optionally available as download for easy post-processing. The training method underlying the server is the best available, and has been used to predict possible MHC-binding peptides in a series of pathogen viral proteomes including SARS, Influenza and HIV, resulting in an average of 75-80% confirmed MHC binders. Here, the performance is further validated and benchmarked using a large set of newly published affinity data, non-redundant to the training set. The server is free of use and available at: http://www.cbs.dtu.dk/services/NetMHC.
Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634 (2014)

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).
1-Deoxy-d-xylulose-5-phosphate Synthase, a Limiting Enzyme for Plastidic Isoprenoid Biosynthesis in Plants (2001)

The initial step of the plastidic 2C-methyl-D-erythritol 4-phosphate (MEP) pathway that produces isopentenyl diphosphate is catalyzed by 1-deoxy-d-xylulose-5-phosphate synthase. To investigate whether or not 1-deoxy-d-xylulose-5-phosphate synthase catalyzes a limiting step in the MEP pathway in plants, we produced transgenic Arabidopsis plants that over- or underexpress this enzyme. Compared with non-transgenic wild-type plants, the transgenic plants accumulate different levels of various isoprenoids such as chlorophylls, tocopherols, carotenoids, abscisic acid, and gibberellins. Phenotypically, the transgenic plants had slight alterations in growth and germination rates. Because the levels of several plastidic isoprenoids correlate with changes in 1-deoxy-D-xylulose-5-phosphate synthase levels, we conclude that this enzyme catalyzes one of the rate-limiting steps of the MEP biosynthetic pathway. Furthermore, since the product of the MEP pathway is isopentenyl diphosphate, our results suggest that in plastids the pool of isopentenyl diphosphate is limiting to isprenoid production.
Class II MHC Molecules Are Specific Receptors for Staphylococcus Enterotoxin A (1989)

T cell proliferation in response to stimulation with Staphylococcus enterotoxin A (SEA) requires accessory cells that express class II major histocompatibility complex (MHC) molecules. Murine fibroblasts transfected with genes encoding the alpha and beta subunits of HLA-DR, DQ, or DP were used to show that the proliferative response of purified human T cells to SEA is dependent on class II molecules but is not restricted by the haplotype of the responder. Binding of fluoresceinated SEA to class II transfectants and precipitation of class II heterodimers with SEA-Sepharose show that the proliferative response is a result of SEA binding to class II molecules. The binding is specific for class II molecules and is independent of class II allotype or isotype. The ability of SEA to bind class II molecules may be a general characteristic of this class of antigens, now called "superantigens".
Recovery of active medium-chain-length-poly-3-hydroxyalkanoate polymerase from inactive inclusion bodies using ion-exchange resin (2000)

A novel process for the purification of active medium-chain-length-polyhydroxyalkanoate (mcl-PHA) polymerase was developed. This process is based on solubilization and activation of inactive polymerase inclusion bodies by incubation with ion-exchange resin. The mcl-PHA polymerase 1 from Pseudomonas oleovorans was overproduced from the Palk promoter. Most of the polymerase produced was sequestered in the cytoplasm as an inactive form in insoluble aggregates. By incubating the protein aggregates with S-Sepharose ion-exchange resin in the presence of dithiothreitol and glycerol, the mcl-PHA polymerase could be extracted in an active and soluble form with a final yield of about 5.2 mg/g of cell dry weight. The solubilized polymerase was able to catalyse the in vitro synthesis of mcl-PHA without any additional cell components, suggesting its potential application for production of biopolymer. The procedure used here may be of general value in solubilizing and activating purified inactive labile enzymes.
A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer. (2014)

3007 Background: 4-1BB agonists markedly enhance cytotoxic T-cell responses, resulting in anti-tumor activity in several models. PF-05082566 is a fully humanized IgG2 agonist monoclonal antibody targeting 4-1BB.This portion of the first-in-human phase I study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PF-0508256 monotherapy in patients with advanced cancer. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancies for which no curative therapy was available. Cohorts of 3-6 patients were enrolled initially using a 3+3 design (0.006 to 0.3 mg/kg), then a Time-To-Event CRM design for higher doses (0.6 to 5 mg/kg). Patients received PF-05082566 via intravenous infusion every 4 weeks (one cycle) with an 8 week period for assessment of dose-limiting toxicity (DLT). Radiographic assessments were conducted every 8 weeks, using RECIST 1.1. Results: 27 patients have been treated with PF-05082566 up to the 0.3 mg/kg dose level, including colorectal cancer (n=11), Merkel cell carcinoma (n=6), pancreatic adenocarcinoma (n=2), and one each of nasopharyngeal cancer, ampullary cancer, squamous cell lung cancer, carcinoma of unknown primary, melanoma, sarcoma, follicular lymphoma, and lymphocytic lymphoma (SLL). 25 patients completed the DLT assessment period and 7 patients remain on therapy. All discontinuations from treatment were due to disease progression. Median number of cycles ranged from 2 (at 0.006 mg/kg) to 7 (at 0.24 mg/kg). There was no apparent relationship between increasing doses and the frequency or severity of treatment emergent adverse events, which were mostly Grade 1. One patient treated at 0.06 mg/kg had Grade 3 elevation in alkaline phosphatase. No additional significant elevations in liver enzymes and no DLTs have occurred to date. Preliminary PK data suggests a linear increase in drug exposure with increasing dose, and a half life of ~10 days. A best overall response of stable disease was observed in 22% (6/27) patients. Conclusions: PF-05082566 was well tolerated, with evidence of disease stabilization in multiple patients. Enrollment continues at higher dose levels to obtain additional safety, PK, PD, and efficacy data. Clinical trial information: NCT01307267.
The Use of Granulocyte Colony-Stimulating Factor During Retroviral Transduction on Fibronectin Fragment CH-296 Enhances Gene Transfer Into Hematopoietic Repopulating Cells in Dogs (1999)

A competitive repopulation assay in the dog was used to develop improved gene transfer protocols for hematopoietic stem cell gene therapy. Using this assay, we previously showed improved gene transfer into canine hematopoietic repopulating cells when CD34-enriched marrow cells were cocultivated on gibbon ape leukemia virus (GALV)-based retrovirus vector-producing cells. In the present study, we have investigated the use of fibronectin fragment CH-296 and 2 growth factor combinations to further improve gene transfer efficiency. CD34-enriched marrow cells from each dog were prestimulated for 24 hours and then divided into 3 equal fractions. Two fractions were placed into flasks coated with either CH-296 or bovine serum albumin (BSA) and virus-containing medium supplemented with growth factors, and protamine sulfate was replaced 4 times over a 48-hour period. One fraction was cocultivated on irradiated PG13 (GALV-pseudotype) packaging cells for 48 hours. In 2 animals, cells of the different fractions were transduced in the presence of human FLT-3 ligand (FLT3L), canine stem cell factor (cSCF), and human megakaryocyte growth and development factor (MGDF), and in 2 other dogs, transduction was performed in the presence of FLT3L, cSCF, and canine granulocyte-colony stimulating factor (cG-CSF). The vectors used contained small sequence differences, allowing differentiation of cells genetically marked by the different vectors. After transduction, nonadherent and adherent cells from all 3 fractions were pooled and infused into lethally irradiated dogs. Polymerase chain reaction and Southern blot analysis were used to determine the persistence of the transferred vectors in the peripheral blood and marrow cells after transplantation. The highest levels of gene transfer were obtained when cells were transduced in the presence of FLT3L, cSCF, and cG-CSF (gene transfer levels of more than 10% for more than 8 months so far). Compared with the 2 animals that received cells transduced with FLT3L, cSCF, and MGDF, gene transfer levels were significantly higher when dogs received cells that were transduced in the presence of cG-CSF. Transduction on CH-296 resulted in gene transfer levels that were at least as high as transduction by cocultivation. In summary, the overall levels of gene transfer obtained with these conditions should be sufficiently high to allow stem cell gene therapy studies aimed at correcting genetic diseases in dogs as a model for human gene therapy.