gebhart/patrepeval huggingface dataset:
Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes (1999)

Human rhinoviruses, the most important etiologic agents of the common cold, are messenger-active single-stranded monocistronic RNA viruses that have evolved a highly complex cascade of proteolytic processing events to control viral gene expression and replication. Most maturation cleavages within the precursor polyprotein are mediated by rhinovirus 3C protease (or its immediate precursor, 3CD), a cysteine protease with a trypsin-like polypeptide fold. High-resolution crystal structures of the enzyme from three viral serotypes have been used for the design and elaboration of 3C protease inhibitors representing different structural and chemical classes. Inhibitors having alpha,beta-unsaturated carbonyl groups combined with peptidyl-binding elements specific for 3C protease undergo a Michael reaction mediated by nucleophilic addition of the enzyme's catalytic Cys-147, resulting in covalent-bond formation and irreversible inactivation of the viral protease. Direct inhibition of 3C proteolytic activity in virally infected cells treated with these compounds can be inferred from dose-dependent accumulations of viral precursor polyproteins as determined by SDS/PAGE analysis of radiolabeled proteins. Cocrystal-structure-assisted optimization of 3C-protease-directed Michael acceptors has yielded molecules having extremely rapid in vitro inactivation of the viral protease, potent antiviral activity against multiple rhinovirus serotypes and low cellular toxicity. Recently, one compound in this series, AG7088, has entered clinical trials.
Synthesis of the Fully Phosphorylated GPI Anchor Pseudohexasaccharide of Toxoplasma gondii (2001)

Retrosynthesis of the fully phosphorylated glycosylphosphatidyl inositol (GPI) anchor pseudohexasaccharide 1a led to building blocks 2-6, of which 5 and 6 are known. The formation of pseudodisaccharide building block 2 is based on readily available building block 7, which gave, via derivative 11 and its glycosylation with known donor 12, the desired compound 2. Building block 3, with the required access to all hydroxy groups being permitted, was prepared from mannose in five steps. From a readily available precursor, building block 4 was obtained, which on reaction with 3 gave disaccharide 23. The synthesis of the decisive pseudohexasaccharide intermediate 32 was based on the reaction of 23 with 5, then with 6, and finally with 2. To obtain high stereoselectivity and good yields in the glycosylation reactions, anchimeric assistance was employed. To enable regioselective attachment of the two different phosphorus esters, the 6f-O-silyl group of 32 was first removed and the aminoethyl phosphate residue was attached. Then the MPM group was oxidatively removed, and the second phosphate residue was introduced. Unprotected 1a was then liberated in two steps: treatment with sodium methanolate removed the acetyl protecting groups, and finally, catalytic hydrogenation afforded the desired target molecule, which could be fully structurally assigned.
Mammalian cell lines expressing functional RNA polymerase II tagged with the green fluorescent protein (2000)

RNA polymerase II is a multi-subunit enzyme responsible for transcription of most eukaryotic genes. It associates with other complexes to form enormous multifunctional 'holoenzymes' involved in splicing and polyadenylation. We wished to study these different complexes in living cells, so we generated cell lines expressing the largest, catalytic, subunit of the polymerase tagged with the green fluorescent protein. The tagged enzyme complements a deficiency in tsTM4 cells that have a temperature-sensitive mutation in the largest subunit. Some of the tagged subunit is incorporated into engaged transcription complexes like the wild-type protein; it both resists extraction with sarkosyl and is hyperphosphorylated at its C terminus. Remarkably, subunits bearing such a tag can be incorporated into the active enzyme, despite the size and complexity of the polymerizing complex. Therefore, these cells should prove useful in the analysis of the dynamics of transcription in living cells.
Improved retrieval of foreign names from large databases (2003)

A description is given of enhancements made to name-search techniques currently used to access large databases of proper names. Improvements included use of a hidden-Markov-model (HMM) statistical classifier to identify the likely linguistic source of a proper name, and application of language-specific rules to generate plausible spelling variants of names. These two components were incorporated into a prototype front-end system driving existing name-search procedures. Preliminary evaluation indicates improved retrieval of 20-30% as measured by number of correct items retrieved.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Multi-pillar surrounding gate transistor (M-SGT) for compact and high-speed circuits (1991)

The M-SGT has a three-dimensional structure, which consists of the source, gate, and drain arranged vertically. The gate electrode surrounds the crowded multipillar silicon islands. Because all the sidewalls of the pillars are used effectively as the transistor channel, the M-SGT has a high-shrinkage feature. The area occupied by the M-SGT can be shrunk to less than 30% of that occupied by the planar transistor. The small occupied area and the mesh-structured gate electrode lead to the small junction capacitance and the small gate electrode RC delay, resulting in high-speed operation. The fabrication of the M-SGT CMOS inverter chain is discussed. The propagation delay reduces to 40%, compared with the planar transistor inverter chain.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Polyamine Transport Inhibitors: Design, Synthesis, and Combination Therapies with Difluoromethylornithine (2014)

The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer cells. Several design features were discovered which strongly influenced PTI potency, sensitivity to amine oxidases, and cytotoxicity. These included changes in (a) the number of polyamine chains appended to the ring system, (b) the polyamine sequence, (c) the attachment linkage of the polyamine to the aryl core, and (d) the presence of a terminal N-methyl group. Of the series tested, the optimal design was N(1),N(1'),N(1″)-(benzene-1,3,5-triyltris(methylene))tris(N(4)-(4-(methylamino)butyl)butane-1,4-diamine, 6b, which contained three N-methylhomospermidine motifs. This PTI exhibited decreased sensitivity to amine oxidases and low toxicity as well as high potency (EC50 = 1.4 μM) in inhibiting the uptake of spermidine (1 μM) in DFMO-treated L3.6pl human pancreatic cancer cells.
Mechanical properties of the bioabsorbable polyglycolic acid–collagen nerve guide tube (2006)

Abstract Bioabsorbable nerve tubes made from polyglycolic acid (PGA) coated with collagen are now used widely for patients who have suffered nerve injury. The main function of nerve tubes is to maintain a space for nerve regeneration in the body against rapid invasion by the surrounding tissue until the new nerve tissue has recovered. However, no precise mechanical testing has ever been carried out on bioabsorbable nerve tubes. The aim of this study was therefore to evaluate the mechanical properties of PGA–collagen tubes and to analyze the degree to which they are able to maintain the patency of the conduit for the recovering nerve. Nerve tubes with diameters of 3 and 4 mm were used in this experiment. The tubes were made from cylindrically woven PGA fibers that had been given 5, 10, or 27 coats of collagen, which was finally crosslinked dehydrothermally at 140°C for 24 h. Both in vitro and in vivo tests were carried out. For in vitro testing, the nerve tube samples were immersed in saline at 37°C for up to 8 weeks. For in vivo testing, samples were implanted subcutaneously into rabbits and observed for up to 16 weeks after implantation. Resistance during compression stress was measured for each sample with the aid of a tensile tester. The collagen coating enhanced the mechanical properties of the tubes, particularly in the first 2 weeks following immersion. The tubes coated with collagen 27 times (27T tubes) were 180% stronger than either the 5T or the 10T tubes. The time taken for the initial mechanical parameters, such as tube rigidity, to be reduced by half was 14 days or more. The reduction in the mechanical strength of the tubes in vivo occurred more rapidly than in vitro . POLYM. ENG. SCI. 46:1461–1467, 2006. © 2006 Society of Plastics Engineers
Replication and supercoiling of simian virus 40 DNA in cell extracts from human cells. (1985)

Soluble extracts prepared from the nucleus and cytoplasm of human 293 cells are capable of efficient replication and supercoiling of added DNA templates that contain the origin of simian virus 40 replication. Extracts prepared from human HeLa cells are less active than similarly prepared extracts from 293 cells for initiation and elongation of nascent DNA strands. DNA synthesis is dependent on addition of purified simian virus 40 tumor (T) antigen, which is isolated by immunoaffinity chromatography of extracts from cells infected with an adenovirus modified to produce large quantities of this protein. In the presence of T antigen and the cytoplasmic extract, replication initiates at the origin and continues bidirectionally. Initiation is completely dependent on functional origin sequences; a plasmid DNA containing an origin mutation known to affect DNA replication in vivo fails to replicate in vitro. Multiple rounds of DNA synthesis occur, as shown by the appearance of heavy-heavy, bromodeoxyuridine-labeled DNA products. The products of this reaction are resolved, but are relaxed, covalently closed DNA circles. Addition of a nuclear extract during DNA synthesis promotes the negative supercoiling of the replicated DNA molecules.
Abstract #835: First bivalent fully antagonist anti-c-Met antibody targeting the c-Met receptor: I) in vitro mechanism of action (2009)

c-Met is the prototypic member of a sub-family of receptor tyrosine kinases (RTK) which also includes RON and SEA. The c-Met RTK family is structurally different from other RTK families and is the only known high-affinity receptor for hepatocyte growth factor (HGF), also called scatter factor (SF). HGF and c-Met are widely expressed in a variety of tissues and their expression is normally restricted to cells of epithelial and mesenchymal origin, respectively. They are both required for normal mammalian development and have been shown to be particularly important for cell migration, morphogenic differentiation and organization of the three-dimensional tubular structures as well as cell growth and angiogenesis. While the controlled regulation of c-Met and HGF are essential for in mammalian development, tissue maintenance and repair, their deregulation is implicated in the progression of cancers. Aberrant signalling of c-Met can arise by ligand-dependent and independent mechanisms such as over-expression of c-Met, paracrine or autocrine activations, or through gain of function mutations. However, an oligomerization of the c-Met receptor, either in the presence or absence of the ligand, is required to regulate the binding affinity and binding kinetics of the kinase toward ATP and tyrosine-containing peptide substrates. An inappropriate c-Met activation plays a crucial role in tumorigenesis and metastasis. We have generated, for the first time a bivalent fully antagonist anti-c-Met monoclonal antibody (Mab 224G11) that has been humanized as an IgG1 antibody (Mab h224G11). The humanized Mab exhibits a high affinity for the receptor, blocks HGF binding, inhibits c-Met phosphorylation and c-Met dimerization. These effects are presumably responsible for the inhibition of the major functions of c-Met including cell proliferation, migration, invasion but also cell scattering, morphogenesis and angiogenesis, observed in vitro with different cell lines. The present results indicate that the h224G11 humanized antibody is powerful in vitro for impairing the major biological functions of c-Met. The results strongly suggest that h224G11 has a great potential for in vivo activity (see abstract 2) and for cancer therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 835.
Multiple juvenile idiopathic arthritis subtypes demonstrate proinflammatory IgG glycosylation (2012)

IgG glycosylation is skewed toward proinflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined.
Expression of the c-myb oncogene in human small cell lung carcinoma. (1985)

We have found that the oncogene c-myb is differentially expressed in human lung cancer cell lines and that myb-homologous RNA can be detected only in small cell lung cancer (SCLC) cell lines. Polyadenylic acid-RNA from 13 established cell lines was examined by Northern blotting for its ability to hybridize to a radiolabeled v-myb probe. A 3.5-kilobase RNA transcript homologous to v-myb is present in four of four lines of classic SCLC and in three of four SCLC variant lines but not in five of five non-small cell lung cancer lines tested. This transcript is the same size as that found in the immature myeloid cell lines KG1, but the amount of RNA is only about 10% of that in the KG1 line. A second transcript hybridizing to v-myb, 2.4 kilobases in size, is also present in the variant SCLC lines and the COLO 320 line, all of which have amplification of the c-myc gene and markedly increased c-myc messenger RNA. The presence of myb transcripts in SCLC suggests that the myb gene may have a specific role in the initiation or maintenance of an important human epithelial tumor.
Active-Pixel Image Sensor With Analog-To-Digital Converters (1995)

Proposed single-chip integrated-circuit image sensor contains 128 x 128 array of active pixel sensors at 50-micrometer pitch. Output terminals of all pixels in each given column connected to analog-to-digital (A/D) converter located at bottom of column. Pixels scanned in semiparallel fashion, one row at time; during time allocated to scanning row, outputs of all active pixel sensors in row fed to respective A/D converters. Design of chip based on complementary metal oxide semiconductor (CMOS) technology, and individual circuit elements fabricated according to 2-micrometer CMOS design rules. Active pixel sensors designed to operate at video rate of 30 frames/second, even at low light levels. A/D scheme based on first-order Sigma-Delta modulation.
Obtaining Site-Specific Calcium-Binding Affinities Of Calmodulin (2003)

Calmodulin (CaM) is an EF-hand Ca(II)-binding protein involved in the regulation of many important biological processes. To date, there is a wealth of information available concerning studies to obtain site-specific calcium binding affinities of CaM, and further to estimate the cooperativity of calcium binding using mutational studies, peptide models, and proteolytic fragmentation. In this paper, we will discuss the energetics of calcium binding and the strong relationship between calcium binding cooperativity and conformational change. We then explain the difficulty of studying key determinants of calcium binding affinity of CaM due to the large change of calcium binding affinity upon mutation. Subsequently, we will introduce "grafting" as a novel approach to obtain the site-specific metal binding properties of calmodulin.
Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein (2008)

In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
The use of biotic and abiotic elicitors to induce the formation of secondary plant products in cell suspension cultures of solanaceous plants (1988)

Conference Article| February 01 1988 The use of biotic and abiotic elicitors to induce the formation of secondary plant products in cell suspension cultures of solanaceous plants D. R. THRELFALL; D. R. THRELFALL 1Department of Plant Biology and Genetics, University of Hull, Hull HU6 7RX, U.K. Search for other works by this author on: This Site PubMed Google Scholar I. M. WHITEHEAD I. M. WHITEHEAD 1Department of Plant Biology and Genetics, University of Hull, Hull HU6 7RX, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1988) 16 (1): 71–75. https://doi.org/10.1042/bst0160071 Article history Received: April 13 1987 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation D. R. THRELFALL, I. M. WHITEHEAD; The use of biotic and abiotic elicitors to induce the formation of secondary plant products in cell suspension cultures of solanaceous plants. Biochem Soc Trans 1 February 1988; 16 (1): 71–75. doi: https://doi.org/10.1042/bst0160071 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: MS, minimal salts, NAA, naphthalene acetic acid, 2,4-D, 2,4-dichlorophenoxyacctic acid This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.
Comparative Toxicity of Acaricides to Honey Bee (Hymenoptera: Apidae) Workers and Queens (2012)

Acaricides are used to treat honey bee (Apis mellifera L.) colonies to control the varroa mite (Varroa destructor Anderson & Trueman), a worldwide threat to honey bee health. Although acaricides control a serious honey bee parasite and mitigate bee loss, they may cause harm to bees as well. We topically applied five acaricides, each with a different mode of action, to young adult queen and worker bees to generate dose-response curves and LD50. Twenty-four hours after treatment, queens were found to be three-times more tolerant of tau-fluvalinate and six-times more tolerant of thymol than workers when adjusted for body weight differences between workers (108 mg) and queens (180 mg). Queens survived the highest administered doses of fenpyroximate (1620 microg/g) and coumaphos (2700 microg/g) indicating that queens are at least 11-fold more tolerant of coumaphos and at least 54-fold more tolerant of fenpyroximate than workers. However, queens treated with as little as 54 microg/g of fenpyroximate exhibited reduced survival over 6 wk after treatment. Amitraz was the only acaricide tested for which queens were not more tolerant than workers. The striking difference in acaricide tolerance of queen and worker honey bees suggests physiological differences in how the two castes are affected by xenobiotics.
Predictability of Linear Coupled Systems. Part I: Theoretical Analyses (2004)

The predictability of stochastically forced linear systems is investigated under the condition that an ensemble of forecasts are each initialized at the true state but driven by different realizations of white noise. Some important issues of predictability are brought out by analytically investigating a stochastically driven, damped inertial oscillator. These issues are then studied in a generic context without reference to any specific linear stochastic system. The predictability is measured primarily by the mean-square forecast error normalized by the mean climatological variance. If the dynamical operator is normal, then this metric depends only on the real eigenvalues (i.e., the normal mode damping rates) and is independent of the existence of spectral peaks at nonzero frequency caused by oscillatory eigenmodes. It is shown that a nonnormal system is more predictable by this measure than a normal system with identical eigenvalues for short lead times. The noise structure that optimizes this metric can be calculated analytically and shown to approach the stochastic optimals in the limit of short lead times; this calculation gives bounds on predictability that depend only on the dynamical operator. The most predictable components, or spatial structures, can also be determined analytically and are shown to approach the empirical orthogonal functions (EOFs) of the variance in the limit of short lead times. In a companion paper, these concepts are applied to the predictability analysis of a simple coupled climate model of tropical Atlantic variability.
Measurement of nitric oxide in biological models (1993)

Nitric oxide (NO) is a small, gaseous, paramagnetic radical with a high affinity for interaction with ferrous hemoproteins such as soluble guanylate cyclase and hemoglobin. Interest in NO measurement increased exponentially with the discovery that NO or a related compound is the endothelium-derived relaxing factor (EDRF). In addition to being a potent endogenous vasodilator, NO has a role in inflammation, thrombosis, immunity, and neurotransmission. Measurement of NO is important as many of its effects (e.g., vasodilatation, inhibition of platelet aggregation) are similar to those of other substances produced by the endothelium, such as prostacyclin. NO is formed in small amounts in vivo and is rapidly destroyed by interaction with oxygen, making measurement difficult. A computerized search of the past five year's literature found NO measurements reported in fewer than 50 of 955 articles dealing with EDRF. Inhibitors of NO synthesis such as the arginine analogs or agents that inactivate NO, such as reduced hemoglobin, are commonly used as specific probes for NO, in vivo and in vitro; however, none of the NO inhibitors is completely specific. The most widely used assays use one of three strategies to detect NO: 1) NO is "trapped" by nitroso compounds, or reduced hemoglobin, forming a stable adduct that is detected by electron paramagnetic resonance (EPR) (detection threshold approximately 1 nmol); 2) NO oxidizes reduced hemoglobin to methemoglobin, which is detected by spectrophotometry (detection threshold approximately 1 nmol); 3) NO interacts with ozone producing light, "chemiluminescence" (detection threshold approximately 20 pmol). These assays can be performed to exclusively detect NO, or by adding acid and reducing agents to the sample, can measure NO and related oxides of nitrogen such as nitrite. Several new amperometric microelectrode assays offer the potential to measure smaller amounts of NO (10(-20) M), permitting NO measurement in intact issues and from single cells. This review describes the pharmacology and toxicology of NO and reviews the major techniques for measuring NO in biological models.