gebhart/patrepeval huggingface dataset:
Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpesvirus guanosine analogs related to buciclovir (1986)

9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine (3HM-HBG), (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([+/-]2HM-HBG), and cis-9-(4-hydroxy-2-butenyl)guanine (2EN-HBG), new acyclic guanosine analogs structurally related to buciclovir (BCV [(R)-9-(3,4-dihydroxybutyl)guanine]), were evaluated in parallel with buciclovir as anti-herpes simplex virus (HSV) agents. In cell cultures, replication of different strains of HSV type 1 (HSV-1) and HSV-2 was inhibited at nontoxic drug concentrations. The concentrations giving 50% inhibition of plaque formation were, however, dependent on virus strain and cell type. In most cell types, the order of activity against HSV-1 strains was 3HM-HBG greater than (+/-)2HM-HBG greater than BCV greater than 2EN-HBG, whereas the drugs showed an approximately equivalent activity against HSV-2 strains in different cells. The cytotoxic effects of the drugs were also cell type dependent, the order of activity being BCV greater than 3HM-HBG = (+/-)2HM-HBG greater than 2EN-HBG. At growth-inhibitory concentrations, the guanosine analogs BCV, 3HM-HBG, and (+/-)2HM-HBG showed clastogenic effects in human lymphocytes, mainly because of the induction of chromatid breaks. When evaluated for their anti-HSV effects in systemic HSV-1 infections in mice, the order of activity was BCV = 3HM-HBG greater than (+/-)2HM-HBG greater than 2EN-HBG, and in mice infected systemically with HSV-2, only BCV and 3HM-HBG showed efficacy. The differences between efficacy in vitro and in vivo could be explained in part by differences in kinetics of the drugs in mouse plasma, as the more efficacious drugs, BCV and 3HM-HBG, showed lower clearances and longer half-lives than the less efficacious ones, (+/-)2HM-HBG and 2EN-HBG. When used topically against a cutaneous HSV-1 infection in guinea pigs, 3HM-HBG showed an effect equivalent to that of BCV, whereas (+/-)2HM-HBG and 2EN-HBG were inactive. Mechanistically, the guanosine analogs were characterized by a high affinity for the viral thymidine kinase and a low affinity fo a cellular thymidine kinase and by their inhibition of viral DNA synthesis in infected cells.
Implementation techniques for main memory database systems (1984)

With the availability of very large, relatively inexpensive main memories, it is becoming possible keep large databases resident in main memory In this paper we consider the changes necessary to permit a relational database system to take advantage of large amounts of main memory We evaluate AVL vs B+-tree access methods for main memory databases, hash-based query processing strategies vs sort-merge, and study recovery issues when most or all of the database fits in main memory As expected, B+-trees are the preferred storage mechanism unless more than 80--90% of the database fits in main memory A somewhat surprising result is that hash based query processing strategies are advantageous for large memory situations
Culture prior to transplantation preserves the ultrastructural integrity of monkey pancreatic islets (2003)

Transplantation of pancreatic islets represents a promising way of curing type I diabetes (insulin-dependent diabetes mellitus). Culture enables the survival of endocrine tissue awaiting islet transplantation and reduces islet immunogenicity prior to xenografting. In this study, attempts were made to preserve the monkey islets in culture for 7 days and to study the ultrastructure by electron microscopy. The islets were isolated from monkey pancreas by the collagenase digestion method and were separated from acinar cells by dextran density gradient centrifugation. These islets were preserved in a humidified atmosphere of 5% carbon dioxide and 95% air for 7 days. The culture medium used was CMRL-1066. After 7 days of culture the islets were processed for light and electron microscopic studies, which revealed that the cultured islets were intact and maintained their structural integrity. Semi-thin sections of the cultured islets showed morphology with occasional structural alterations at the periphery. Dithizone staining of the cultured islets showed crimson red colour, proving that the islets were pure and without any exocrine contamination. Electron microscopy showed that the cultured islets had well-preserved alpha-, beta- and delta-cells. Different cell types of the monkey pancreatic islets were identified by the presence of their characteristic secretory granules. The ultrastructural characteristics present in hormone-synthesizing cells, i.e. rough-endoplasmic reticulum, Golgi apparatus, mitochondria and secretory granules, were observed as in native islets.
Extracellular Isoforms of CD6 Generated by Alternative Splicing Regulate Targeting of CD6 to the Immunological Synapse (2007)

The great majority of mammalian genes yield multiple transcripts arising from differential mRNA processing, but in very few instances have alternative forms been assigned distinct functional properties. We have cloned and characterized a new isoform of the accessory molecule CD6 that lacks the CD166 binding domain and is expressed in rat and human primary cells. The novel isoform, CD6Deltad3, results from exon 5 skipping and consequently lacks the third scavenger receptor cysteine-rich (SRCR) domain of CD6. Differential expression of the SRCR domain 3 resulted in a remarkable functional difference: whereas full-length CD6 targeted to the immunological synapse, CD6Deltad3 was unable to localize at the T cell:APC interface during Ag presentation. Analysis of expression of CD6 variants showed that, while being more frequent in coexpression with full-length CD6, the CD6Deltad3 isoform constituted the sole species in a small percentage of T cells. In the rat thymus, CD6Deltad3 is less represented in double-positive thymocytes but is detectable in nearly 50% of single-positive CD4 or CD8 thymocytes, suggesting that CD6 switching between full-length and Deltad3 isoforms may be involved in thymic selection. Strikingly, CD6Deltad3 is markedly up-regulated upon activation of T lymphocytes, partially substituting full-length CD6, as evaluated by RT-PCR analysis at the single-cell level, by immunoblotting, and by flow cytometry using Abs recognizing SRCR domains 1 and 3 of human CD6. This elegant mechanism controlling the expression of the CD166 binding domain may help regulate signaling delivered by CD6, through different types of extracellular engagement.
PTGS2 (Cyclooxygenase-2) Expression and Survival among Colorectal Cancer Patients: A Systematic Review (2013)

There is insufficient evidence to recommend PTGS2 expression as a prognostic marker in patients with colorectal cancer. Furthermore, studies providing adjusted results are required.
Sustained Expression of Therapeutic Level of Factor IX in Hemophilia B Dogs by AAV-Mediated Gene Therapy in Liver (2000)

We demonstrate that a single intraportal vein injection of a recombinant adeno-associated virus (rAAV) vector encoding canine factor IX (cFIX) cDNA under the control of a liver-specific enhancer/promoter leads to a long-term correction of the bleeding disorder in hemophilia B dogs. Stable expression of the therapeutic level of cFIX (5% of normal level) was detected in the plasma of a dog injected with an AAV vector at a dose of 4.6 x 10(12) particles/kg for over 7 months. Both whole-blood clotting time (WBCT) and activated partial thromboplastin time (aPTT) of the treated dogs have been greatly decreased since the treatment. No anti-canine factor IX antibodies have been detected in the treated animals. Importantly, no bleeding has been observed in the dog that expresses a therapeutic level of cFIX for 7 months following vector administration. Moreover, no persistent significant hepatic enzyme abnormalities were detected in the treated dogs. Thus, a single intraportal injection of a rAAV vector expressing cFIX successfully corrected the bleeding disorder of hemophilia B dogs, supporting the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases.
The Sequence of a Large L1Md Element Reveals a Tandemly Repeated 5′ End and Several Features Found in Retrotransposons (1986)

The complete nucleotide sequence of a 6,851-base pair (bp) member of the L1Md repetitive family from a selected random isolate of the BALB/c mouse genome is reported here. Five kilobases of the element contains two overlapping reading frames of 1,137 and 3,900 bp. The entire 3,900-bp frame and the 3' 600 bp of the 1,137-bp frame, when compared with a composite consensus primate L1 sequence, show a ratio of replacement to silent site differences characteristic of protein coding sequences. This more closely defines the protein coding capacity of this repetitive family, which was previously shown to possess a large open reading frame of undetermined extent. The relative organization of the 1,137- and 3,900-bp reading frames, which overlap by 14 bp, bears resemblance to protein-coding, mobile genetic elements. Homology can be found between the amino acid sequence of the 3,900-bp frame and selected domains of several reverse transcriptases. The 5' ends of the two L1Md elements described in this report have multiple copies, 4 2/3 copies and 1 2/3 copy, of a 208-bp direct tandem repeat. The sequence of this 208-bp element differs from the sequence of a previously defined 5' end for an L1Md element, indicating that there are at least two different 5' end motifs for L1Md.
Multiple-Valued Reversible Benchmarks and Extensible Quantum Specification (XQS) Format (2013)

In this paper we introduce a set of resources used to describe multiple-valued (MV) functions: a set of multiple-valued benchmarks and a file format specifically designed to accommodate the requirements of multiple-valued function representation. The proposed functions are intended for use as reference benchmarks for automated synthesis algorithms of multiple-valued circuits. In the MV domain, functions can be represented using fixed radices (e.g. ternary, quaternary, etc) or using mixed radices (hybrid functions). Since such functions are harder to represent with the existing PLA specification, in this paper, we introduce the eXtensible Quantum Specification (XQS) file format which is based on the well-known YAML file specification.
Low-Temperature ALE Deposition of Y2O3 Thin Films from β-Diketonate Precursors (2001)

Yttrium oxide thin film deposition by atomic layer epitaxy (ALE) was studied at 200–425 °C using Y(thd)3, Y(thd)3(bipyridyl), or Y(thd)3(1,10-phenanthroline) (thd = 2,2,6,6-tetramethyl-3,5-heptanedione) as an yttrium precursor, and ozone as an oxygen source. All yttrium precursors were analyzed by thermogravimetry/differential thermal analysis (TG-DTA) and mass spectrometry (MS). Soda lime glass and Si(100) were used as substrates. With all precursors, a constant deposition rate of 0.22–0.23 Å (cycle)–1 was observed at 250–350 °C on both substrates, indicating a surface-controlled growth and similar surface species at the deposition temperatures used. The effect of growth parameters, such as reactant pulsing times, was investigated in detail at 350 °C using Y(thd)3. Deposited films were characterized by X-ray diffraction (XRD) and atomic force microscopy (AFM) in order to determine crystallinity and surface morphology, while ion-beam analysis and X-ray photoelectron spectroscopy (XPS) were used to analyze stoichiometry and impurity levels. Infrared (IR) measurements were performed to determine the type of carbon impurity. Crystalline films with a (400) dominant orientation were obtained when depositions were carried out within the ALE window (temperature range of 250–375 °C), but films deposited below 250 °C were nearly amorphous. Preferential orientation changed from (400) to (222) when deposition temperatures were raised slightly above the ALE window to 375 °C, where a partial decomposition of Y(thd)3 probably takes place. Judging from the impurity levels of the films and growth rates, the adducting of Y(thd)3 does not bring about any advantages in the ALE growth of Y2O3.
Biodegradable and pH sensitive hydrogels: synthesis by a polymer‐polymer reaction (1996)

Abstract pH sensitive hydrogels containing azoaromatic crosslinks were synthesized by a polymer‐polymer reaction. To minimize cyclization, a three step synthesis was employed. First, a polymeric precursor (P‐ONp) containing side‐chains terminated in reactive p ‐nitrophenyl ester groups was synthesized by free radical precipitation copolymerization of N , N ‐dimethylacrylamide, acrylic acid, N‐tert ‐butylacrylamide, and N ‐methacryloylglycylglycine p ‐nitrophenyl ester. In the second step, the p ‐nitrophenyl ester groups of P‐ONp were converted to NH 2 groups (P‐NH 2 ) by a polymer‐analogous reaction with an excess of a diamine, namely N , N′ ‐(ω‐aminocaproyl)‐4,4′‐diaminoazobenzene. The hydrogel was then prepared in the third step by a polymer‐polymer reaction of P‐ONp with P‐NH 2 . The linear copolymers were characterized by the content of functional groups and molecular weights. The hydrogels were characterized by equilibrium degree of swelling, modulus of elasticity in compression at pH 7.4, the network structure, and in vitro degradability. The swelling, mechanical properties, and rate of degradation depended on the crosslinking density. Although we were able to restrict cyclization, other side reactions such as unreacted pendent groups and hydrolysis need to be controlled. These hydrogels have potential for colon‐specific drug delivery.
Hypertext habitats (1987)

This paper reports on an investigation into the use of the NoteCards hypertext system for writing. We describe a wide variety of personal styles adopted by 20 researchers at Xerox as they “inhabit” NoteCards. This variety is displayed in each of their writing activities: notetaking, organizing and reorganizing their work, maintaining references and bibliographies, and preparing documents. In addition, we discuss the distinctive personal decisions made as to which activities are appropriate for NoteCards in the first place. Finally, we conclude with a list of recommendations for system designers arising from this work.
Skutterudites as thermoelectric materials: revisited (2015)

A review of the progress on skutterudites over the last years and future prospects.
Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit (2014)

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.
Randomized Trial of Adjunctive Interleukin-2 in Adults with Pulmonary Tuberculosis (2003)

Interleukin (IL)-2 has a central role in regulating T cell responses to Mycobacterium tuberculosis. Adjunctive immunotherapy with recombinant human IL-2 was studied in a randomized, placebo-controlled, double-blinded trial in 110 human immunodeficiency virus-seronegative adults in whom smear-positive, drug-susceptible pulmonary tuberculosis was newly diagnosed. Patients were randomly assigned to receive twice-daily injections of 225, 000 IU of IL-2 or placebo for the first 30 days of treatment in addition to standard chemotherapy. Subjects were followed for 1 year. The primary endpoint was the proportion of patients with sputum culture conversion after 1 and 2 months of treatment. After 1 month, the proportion of patients for whom sputum culture converted to negative was 17% for the IL-2 group compared with 30% in the control group (p = 0.14; chi2). After 2 months, 77% in the IL-2 group were culture negative compared with 85% of those receiving placebo (p = 0.29, chi2). Results were similar when patients with isoniazid monoresistance were included in the analysis. There were no differences in weight gain and no improvement in fever, cough, and chest pain between groups. One patient in each arm relapsed. IL-2 did not enhance bacillary clearance or improvement in symptoms in human immunodeficiency virus-seronegative adults with drug-susceptible tuberculosis.
Adrenomedullin, a Multifunctional Regulatory Peptide* (2000)

Since the discovery of adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting adrenomedullin and of the mechanisms regulating gene expression. The data on circulating adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research.
Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution (2005)

S134N copper-zinc superoxide dismutase (SOD1) is one of the many mutant SOD1 proteins known to cause familial amyotrophic lateral sclerosis. Earlier studies demonstrated that partially metal-deficient S134N SOD1 crystallized in filament-like arrays with abnormal contacts between the individual protein molecules. Because protein aggregation is implicated in SOD1-linked familial amyotrophic lateral sclerosis, abnormal intermolecular interactions between mutant SOD1 proteins could be relevant to the mechanism of pathogenesis in the disease. We have therefore applied NMR methods to ascertain whether abnormal contacts also form between S134N SOD1 molecules in solution and whether Cys-6 or Cys-111 plays any role in the aggregation. Our studies demonstrate that the behavior of fully metallated S134N SOD1 is dramatically different from that of fully metallated wild type SOD1 with a region of subnanosecond mobility located close to the site of the mutation. Such a high degree of mobility is usually seen only in the apo form of wild type SOD1, because binding of zinc to the zinc site normally immobilizes that region. In addition, concentration-dependent chemical shift differences were observed for S134N SOD1 that were not observed for wild type SOD1, indicative of abnormal intermolecular contacts in solution. We have here also established that the two free cysteines (6 and 111) do not play a role in this behavior.
Autotrophic CO2Fixation byChloroflexus aurantiacus: Study of Glyoxylate Formation and Assimilation via the 3-Hydroxypropionate Cycle (2001)

ABSTRACT In the facultative autotrophic organism Chloroflexus aurantiacus , a phototrophic green nonsulfur bacterium, the Calvin cycle does not appear to be operative in autotrophic carbon assimilation. An alternative cyclic pathway, the 3-hydroxypropionate cycle, has been proposed. In this pathway, acetyl coenzyme A (acetyl-CoA) is assumed to be converted to malate, and two CO 2 molecules are thereby fixed. Malyl-CoA is supposed to be cleaved to acetyl-CoA, the starting molecule, and glyoxylate, the carbon fixation product. Malyl-CoA cleavage is shown here to be catalyzed by malyl-CoA lyase; this enzyme activity is induced severalfold in autotrophically grown cells. Malate is converted to malyl-CoA via an inducible CoA transferase with succinyl-CoA as a CoA donor. Some enzyme activities involved in the conversion of malonyl-CoA via 3-hydroxypropionate to propionyl-CoA are also induced under autotrophic growth conditions. So far, no clue as to the first step in glyoxylate assimilation has been obtained. One possibility for the assimilation of glyoxylate involves the conversion of glyoxylate to glycine and the subsequent assimilation of glycine. However, such a pathway does not occur, as shown by labeling of whole cells with [1,2- 13 C 2 ]glycine. Glycine carbon was incorporated only into glycine, serine, and compounds that contained C 1 units derived therefrom and not into other cell compounds.
Molecular cloning and expression of the spsB gene encoding an essential type I signal peptidase from Staphylococcus aureus (1996)

The gene, spsB, encoding a type I signal peptidase has been cloned from the gram-positive eubacterium Staphylococcus aureus. The gene encodes a protein of 191 amino acid residues with a calculated molecular mass of 21,692 Da. Comparison of the protein sequence with those of known type I signal peptidases indicates conservation of amino acid residues known to be important or essential for catalytic activity. The enzyme has been expressed to high levels in Escherichia coli and has been demonstrated to possess enzymatic activity against E. coli preproteins in vivo. Experiments whereby the spsB gene was transferred to a plasmid that is temperature sensitive for replication indicate that spsB is an essential gene. We identified an open reading frame immediately upstream of the spsB gene which encodes a type I signal peptidase homolog of 174 amino acid residues with a calculated molecular mass of 20,146 Da that is predicted to be devoid of catalytic activity.
Alumina in Methanesulfonic Acid (AMA) as a New Efficient Reagent for Direct Acylation of Phenol Derivatives and Fries Rearrangement. A Convenient Synthesis of o-Hydroxyarylketones (1998)

H. Sharghi and B. Kaboudin, J. Chem. Res. (S), 1998, 628 DOI: 10.1039/A800158H
AN ASSESSMENT OF GAMMA RAY INDUCED MUTATIONS IN RICE (ORYZA SATIVA L.) (1998)

Gamma ray seed treatment (10, 20 and 30 kR doses) of two cultivars, namely, MPRI-7 and Lanjhi was found to affect pollen and spikelet fertility in M1 generation at higher dose. Chlorophyll and morphological mutations having wider spectrum were also obsrved in M2 generation.