gebhart/patrepeval huggingface dataset:
Controlling False Discoveries During Interactive Data Exploration (2017)

Recent tools for interactive data exploration significantly increase the chance that users make false discoveries. They allow users to (visually) examine many hypotheses and make inference with simple interactions, and thus incur the issue commonly known in statistics as the "multiple hypothesis testing error." In this work, we propose a solution to integrate the control of multiple hypothesis testing into interactive data exploration systems. A key insight is that existing methods for controlling the false discovery rate (such as FDR) are not directly applicable to interactive data exploration. We therefore discuss a set of new control procedures that are better suited for this task and integrate them in our system, QUDE. Via extensive experiments on both real-world and synthetic data sets we demonstrate how QUDE can help experts and novice users alike to efficiently control false discoveries.
Intracellular ribozyme-catalyzed trans-cleavage of RNA monitored by fluorescence resonance energy transfer (2000)

Small catalytic RNAs like the hairpin ribozyme are proving to be useful intracellular tools; however, most attempts to demonstrate trans-cleavage of RNA by ribozymes in cells have been frustrated by rapid cellular degradation of the cleavage products. Here, we describe a fluorescence resonance energy transfer (FRET) assay that directly monitors cleavage of target RNA in tissue-culture cells. An oligoribonucleotide substrate was modified to inhibit cellular ribonuclease degradation without interfering with ribozyme cleavage, and donor (fluorescein) and acceptor (tetramethylrhodamine) fluorophores were introduced at positions flanking the cleavage site. In simple buffers, the intact substrate produces a strong FRET signal that is lost upon cleavage, resulting in a red-to-green shift in dominant fluorescence emission. Hairpin ribozyme and fluorescent substrate were microinjected into murine fibroblasts under conditions in which substrate cleavage can occur only inside the cell. A strong FRET signal was observed by fluorescence microscopy when substrate was injected, but rapid decay of the FRET signal occurred when an active, cognate ribozyme was introduced with the substrate. No acceleration in cleavage rates was observed in control experiments utilizing a noncleavable substrate, inactive ribozyme, or an active ribozyme with altered substrate specificity. Subsequently, the fluorescent substrates were injected into clonal cell lines that expressed cognate or noncognate ribozymes. A decrease in FRET signal was observed only when substrate was microinjected into cells expressing its cognate ribozyme. These results demonstrate trans-cleavage of RNA within mammalian cells, and provide an experimental basis for quantitative analysis of ribozyme activity and specificity within the cell.
Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. (1996)

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.
A Taxonomic Revision of Echinacea (Asteraceae: Heliantheae) (2002)

Abstract A morphometric analysis was conducted of Echinacea Moench (Asteraceae) to measure variation between native populations for taxonomic purposes. Data were collected from living and herbarium specimens. From a matrix of 321 specimens by 74 characters, a pair-wise distance matrix was computed using Gower's coefficient. Cluster strategies were explored from the distance matrix. MODECLUS clustering separated the data into two clusters, and a flexible agglomerative clustering method separated the data into the same two clusters, which were broken into four sub-clusters. Canonical discriminant analysis gave significant support for the two- and the four-cluster solutions. Canonical discriminant analysis also showed support for eight smaller clusters identified using McGregor's 1968 classification. We recognize two subgenera and four species: Echinacea subg. Echinacea contains only E. purpurea; Echinacea subg. Pallida contains E. atrorubens, E. laevigata, and E. pallida. The revised varieties are as follows: E. atrorubens var. atrorubens, E. atrorubens var. neglecta, E. atrorubens var. paradoxa, E. pallida var. angustifolia, E. pallida var. pallida, E. pallida var. sanguinea, E. pallida var. simulata, and E. pallida var. tennesseensis. A cladistic analysis was done on the four species. In the most parsimonious solution, E. purpurea was basally divergent to a clade of the other three species (70% bootstrap value), and all four were distinguishable by at least one apomorphy. A key to Echinacea taxa is provided, which should be valuable given the pharmaceutical and horticultural importance of Echinacea. Communicating Editor: Paul Wilson
Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. (1988)

The amino-terminal amino acid sequence and several internal peptide sequences of angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A, kininase II; EC 3.4.15.1) purified from human kidney were used to design oligonucleotide probes. The nucleotide sequence of ACE mRNA was determined by molecular cloning of the DNA complementary to the human vascular endothelial cell ACE mRNA. The complete amino acid sequence deduced from the cDNA contains 1306 residues, beginning with a signal peptide of 29 amino acids. A highly hydrophobic sequence located near the carboxyl-terminal extremity of the molecule most likely constitutes the anchor to the plasma membrane. The sequence of ACE reveals a high degree of internal homology between two large domains, suggesting that the molecule resulted from a gene duplication. Each of these two domains contains short amino acid sequences identical to those located around critical residues of the active site of other metallopeptidases (thermolysin, neutral endopeptidase, and collagenase) and therefore bears a putative active site. Since earlier experiments suggested that a single Zn atom was bound per molecule of ACE, only one of the two domains should be catalytically active. The results of genomic DNA analysis with the cDNA probe are consistent with the presence of a single gene for ACE in the haploid human genome. Whereas the ACE gene is transcribed as a 4.3-kilobase mRNA in vascular endothelial cells, a 3.0-kilobase transcript was detected in the testis, where a shorter form of ACE is synthesized.
Immune checkpoint inhibitors for nonsmall cell lung cancer treatment (2016)

Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 (PD-1) pathway [PD-1/programmed death-ligand 1 (PD-L1)] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.
Diversity of folds in animal toxins acting on ion channels (2004)

Animal toxins acting on ion channels of excitable cells are principally highly potent short peptides that are present in limited amounts in the venoms of various unrelated species, such as scorpions, snakes, sea anemones, spiders, insects, marine cone snails and worms. These toxins have been used extensively as invaluable biochemical and pharmacological tools to characterize and discriminate between the various ion channel types that differ in ionic selectivity, structure and/or cell function. Alongside the huge molecular and functional diversity of ion channels, a no less impressive structural diversity of animal toxins has been indicated by the discovery of an increasing number of polypeptide folds that are able to target these ion channels. Indeed, it appears that these peptide toxins have evolved over time on the basis of clearly distinct architectural motifs, in order to adapt to different ion channel modulating strategies (pore blockers compared with gating modifiers). Herein, we provide an up-to-date overview of the various types of fold from animal toxins that act on ion channels selective for K+, Na+, Ca2+ or Cl- ions, with special emphasis on disulphide bridge frameworks and structural motifs associated with these peptide folds.
Heat Shock Protein 90 Inhibition Depletes TrkA Levels and Signaling in Human Acute Leukemia Cells (2010)

Nerve growth factor (NGF) induces autophosphorylation and downstream progrowth and prosurvival signaling from the receptor tyrosine kinase TrkA. Overexpression or activating mutation of TrkA has been described in human acute myeloid leukemia cells. In the present study, we show the chaperone association of TrkA with heat shock protein 90 (hsp90) and the inhibitory effect of the hsp90 inhibitor, 17-DMAG, on TrkA levels and signaling in cultured and primary myeloid leukemia cells. Treatment with 17-DMAG disrupted the binding of TrkA with hsp90 and the cochaperone cdc37, resulting in polyubiquitylation, proteasomal degradation, and depletion of TrkA. Exposure to 17-DMAG inhibited NGF-induced p-TrkA, p-AKT, and p-ERK1/2 levels, as well as induced apoptosis of K562, 32D cells with ectopic expression of wild-type TrkA or the constitutively active mutant Delta TrkA, and of primary myeloid leukemia cells. Additionally, 17-DMAG treatment inhibited NGF-induced neurite formation in the rat pheochromocytoma PC-12 cells. Cotreatment with 17-DMAG and K-252a, an inhibitor of TrkA-mediated signaling, induced synergistic loss of viability of cultured and primary myeloid leukemia cells. These findings show that TrkA is an hsp90 client protein, and inhibition of hsp90 depletes TrkA and its progrowth and prosurvival signaling in myeloid leukemia cells. These findings also support further evaluation of the combined activity of an hsp90 inhibitor and TrkA antagonist against myeloid leukemia cells.
Pharmacokinetic Analysis of Neoplasms Using Contrast- enhance^ Dynamic Magnetic Resonance Imaging (1999)

Pharmacokinetic analysis using dynamic magnetic resonance imaging provides insight into various physiological aspects of tumors, including capillary wall permeability and the volume of the interstitial space. This physiology may be investigated in either a heuristic or model-based fashion using various methods presented in the literature. This review describes many of these approaches and provides some guidelines for those intending to use dynamic magnetic resonance imaging in the investigation of neoplasms.
Production of Recombinant Human Monoclonal Antibody Usingras-Amplified BHK-21 Cells in a Protein-free Medium (1996)

A ras oncogene-amplified recombinant BHK-21 cell line (ras-rBHK-IgG) has been established, and was shown to hyperproduce the recombinant IgG chimeric human monoclonal antibody (hMAb) AE6F4, which recognizes lung cancer cells. We found that the ras-rBHK-IgG cell could be easily cultured in a protein-free ERDF medium supplemented with iron(III) nitrate, hydroxyethyliminodiacetic acid, and non-protein synthetic attachment factor as well as in a serum-free ERDF medium supplemented with insulin, transferrin, ethanolamine, and sodium selenite. The productivity of recombinant hMAb from the cells cultured in dishes at high cell densities was higher in protein-free medium than in serum-containing medium. True high density culture of the ras-rBHK-IgG cells was done in protein-free medium using the Tecnomouse, which is a novel hollow fiber bioreactor system. After culture for 30 days in protein-free culture, a total amount of about 14 mg of the recombinant hMAb AE6F4 was obtained, and was shown to be reactive against lung cancer cells in tissues.
Expression of ets-1 and ets-2 in colonic neoplasms. (2002)

These results suggest that ets-1 and ets-2 may act as transcription regulators of the genes related to colonic carcinogenesis and the progression of colonic adenocarcinoma.
Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells (2013)

FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells.
Genetic determinants of p53-induced apoptosis and growth arrest. (1996)

Previous studies have suggested that expression of p53 in cancer cells can result in either growth arrest or apoptosis. Accordingly, expression of p53 in a series of colorectal cancer cell lines yielded growth arrest in some lines (A-lines) and apoptosis in others (D-lines). To investigate the basis of this difference, we evaluated the role of p21WAF1/Cip1, a known mediator of p53-induced growth arrest. Inactivation of p21 by homologous recombination converted an A-line to a D-line, suggesting that p21 could protect cells from apoptosis. However, examination of p53-induced p21 expression in naturally occurring D-lines and A-lines demonstrated that the induction of p21 could not account for the differential response to p53. Moreover, when a D-line was fused to an A-line, the resulting hybrid cells underwent apoptosis in response to p53, indicating that the apoptosis pathway was dominant over the growth arrest pathway. Therefore, the apoptotic response to p53 in colorectal cancer cells is modulated by at least two factors: p21-mediated growth arrest that can protect cells from apoptosis in A-cells, and trans-acting factors in D-cells that can overcome this protection, resulting in cell death.
Surface Characterization and Electrochemical Properties of Alkyl, Fluorinated Alkyl, and Alkoxy Monolayers on Silicon (2001)

Alkyl and fluorinated alkyl monolayers covalently bonded to the silicon (111) surface have been prepared by UV illumination of the H−Si(111) surface while immersed in a solution of olefin precursor under high vacuum. An alkoxy monolayer covalently bonded to the silicon (111) surface is formed by the reaction of the H−Si(111) surface with a heated solution of primary alcohol precursors under high vacuum. Ellipsometry, X-ray photoelectron spectroscopy, and atomic force microscopy are used to characterize the three monolayers. The alkyl monolayer is measured to have the largest number of organic adsorbates per surface silicon atom. Properties of the monolayers on the silicon surface are probed by cyclic voltammetry. The hydrophobic alkyl monolayer slows the oxidation of the silicon surface by water. The three monolayers also slow the rate of electron transfer across the silicon−electrolyte interface by acting as a tunneling barrier. The alkyl monolayer in tetrahydrofuran exhibits a large and reproducible blocking of the electron transfer.
[ 18 F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node staging of prostate cancer: a prospective study of 210 patients (2012)

• Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer. • However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases.
Comparisons of the Intraocular Tissue Distribution, Pharmacokinetics, and Safety of 125I-Labeled Full-Length and Fab Antibodies in Rhesus Monkeys Following Intravitreal Administration (1999)

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.
An acyl-CoA:cholesterol acyltransferase (ACAT)-related gene is involved in the accumulation of triacylglycerols in Sacchoromyces cerevisiae (2000)

The major route for the synthesis of triacylglycerol (TAG) in yeast as well as in all TAG-accumulating organisms has been suggested to occur via the acylation of diacylglycerol (DAG) by acyl-CoA:diacylglycerol acyltransferase (DAGAT). Genes encoding DAGAT have been identified in both plant and animal tissues. These genes show strong sequence similarities to genes encoding acyl-CoA:cholesterol acyltransferase (ACAT). So far no Saccharomyces cerevisiae DAGAT gene has been published; however, two ACAT-like genes, ARE1 and ARE2, are present in the yeast genome. Both these genes have been suggested to be involved in the synthesis of sterol esters. We have now shown that the ARE1 gene in yeast also is involved in the synthesis of TAG, whereas the ARE2 gene is more specifically involved in the synthesis of sterol esters.
Third-generation database system manifesto (1990)

We call the older hierarchical and network systems first generation datftha~ systems and refer to the current collection of relmional systems as the second generation. In this paper we consider the characteristics that must be ~ri~fied by the next generation of data managexs, which we call third generation database systems.
Scientific rationale for inhaled combination therapy with long-acting β2-agonists and corticosteroids (2002)

The addition of an inhaled long-acting beta2-agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients and two fixed combination inhalers (salmeterol/fluticasone and formoterol/budesonide) are increasingly used as a convenient controller in patients with persistent asthma. There is a strong scientific rationale for the combination of these two drug classes. ICS suppress the chronic inflammation of asthma and reduce airway hyperresponsiveness and this is achieved at low doses in most patients. LABA act on different aspects of the pathophysiology of asthma. In addition to their bronchodilator action, LABA also inhibit mast cell mediator release, plasma exudation and may reduce sensory nerve activation. Thus these two classes of drug address complementary aspects of the pathophysiology of asthma that neither drug class is able to achieve alone. There are several positive interactions between LABA and ICS. Corticosteroids increase the expression of beta2-receptors by increasing gene transcription. Experimentally this protects against the loss of beta2-receptors in response to long-term exposure to beta2-agonists. While this is unlikely to be important in bronchodilator responses to beta2-agonists, in view of the large beta-receptor reserve, it is probably important in preventing loss of beta-agonist effects on the nonbronchodilator actions of LABA discussed earlier. beta2-Agonists may potentiate the molecular mechanism of corticosteroid actions, with increased nuclear localization of glucocorticoid receptors and additive or sometimes synergistic suppression of inflammatory mediator release. Thus LABA and ICS may optimize each others beneficial actions in the airways, but the low systemic effects of these drugs do not result in any increase in adverse effects. Long-acting beta2-agonists corticosteroid inhaler therapy is therefore a logical advance and results in effective control of asthma in the majority of patients without significant adverse effects. This simplified approach to long-term asthma therapy has a strong scientific rationale.
Dissecting OFDM: the independent roles of the cyclic prefix and the IDFT operation (2001)

An orthogonal frequency-division multiplex (OFDM) system encodes each block of data by first performing an inverse discrete Fourier transform operation and then adding a cyclic prefix. This letter uses the Cramer-Rao bound (CRB) to study the roles of these two operations. The main result is that a cyclic prefix allows almost all channels, including channels with otherwise unstable inverses, to be inverted accurately and moreover, it is the most efficient way of achieving this stability.
SNOMAD (Standardization and NOrmalization of MicroArrayData): web-accessible gene expression data analysis (2002)

SNOMAD is a collection of algorithms for the normalization and standardization of gene expression datasets derived from diverse biological and technological sources. In addition to conventional transformations and visualization tools, SNOMAD includes two non-linear transformations which correct for bias and variance which are non-uniformly distributed across the range of microarray element signal intensities: (1). Local mean normalization; and (2). Local variance correction (Z-score generation using a locally calculated standard deviation).