gebhart/patrepeval huggingface dataset:
Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. (1991)

Retinal degeneration in the mouse mutant, rd, was previously shown to be a disorder of cyclic nucleotide metabolism involving a deficiency in the activity of the rod photoreceptor cGMP phosphodiesterase (PDE). We have characterized the normal and rd PDE beta-subunit gene, and their respective transcripts, by PCR and direct sequence analysis. We show that the gene consists of at least 22 exons ranging in size from 48 base pairs to several hundred base pairs, covering greater than 25 kilobases. Within a 67-base-pair exon of the rd PDE beta-subunit gene, we identified a nonsense ochre mutation (a C----A transversion in codon 347) that truncates the normal gene product, eliminating more than one-half of the peptide chain, including the putative catalytic domain. The consequences of the truncation are consistent with the observed phenotypes in rd mice heterozygous and homozygous for the disorder. The nonsense mutation was also found in another related and in six unrelated strains displaying the rd phenotype, indicating that the rd allele arose from a single genetic event. The results strongly argue for the nonsense mutation being responsible for retinal degeneration in the rd mouse.
ChemInform Abstract: The Anomalous Stille Reaction of 5‐Stannylimidazole with 3‐Iodoindole. (1998)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Structure of saframycin D, a new dimeric isoquinolinequinone antibiotic. (1987)

The structure of saframycin D (4), a new dimeric isoquinolinequinone antibiotic, is described.
A central region in the hepatitis C virus NS4A protein allows formation of an active NS3-NS4A serine proteinase complex in vivo and in vitro (1995)

A virus-encoded serine proteinase mediates four site-specific cleavages in the hepatitis C virus polyprotein. In addition to the catalytic domain, which is located in the N-terminal one-third of nonstructural protein NS3, the 54-residue NS4A protein is required for cleavage at some but not all sites. Here, we provide evidence for a non-ionic detergent-stable interaction between NS4A and the NS3 serine proteinase domain and demonstrate that the central region of NS4A plays a key role in NS4A-dependent processing. Hydrophobic residues, in particular Ile-29, were shown to be important for NS4A activity, and a synthetic peptide, spanning NS4A residues 22 to 34, could substitute for intact NS4A in a cell-free trans cleavage assay. Furthermore, NS4A mutations, which abolished or inhibited processing, correlated with destabilization of the NS3-NS4A complex. These results suggest that a stable interaction exists between the central region of NS4A and the NS3 catalytic domain which is required for NS4A-dependent processing. Since NS4A is required for processing at certain serine proteinase-dependent cleavage sites, this interaction may represent a new target for development of antiviral compounds.
Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors (2018)

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.
Successful Acid Treatments in Horizontal Openholes Using Dynamic Diversion and Downhole Mixing—An In-Depth Postjob Evaluation (2002)

Abstract This paper discusses a relatively new acid-stimulation process that uses dynamic fluid energy to divert flow into a specific fracture point in the well, which can initiate and accurately place a fracture. The acid-stimulation process often uses two independent fluid streams: one in the pipe and one in the annulus. With this process, two different fluids can be mixed downhole with high energy to form a homogenous mixture. Four such treatments in four openhole, horizontal wells were performed in one formation. The first well was acidfractured with coiled tubing to replace many small fractures along the open hole. The second well was acid-fractured with coiled tubing, but downhole mixing concepts were used to provide in-situ generation of CO2 foam. Fewer, yet larger, fractures were placed in this well. The third and fourth wells were treated with acid using rotating and nonrotating jetting tools while mixing the acid with CO2 downhole. Many small, near-wellbore fractures were expected in these wells. Investigating the mechanism that may have contributed to these successes in the field is important. Laboratory tests were performed to analyze the jetting mechanism exposed to rock. The findings of these tests are reported in this paper.
Immunological Activation of Polymorphonuclear Neutrophils for Fungal Killing: Studies With Murine Cells and Blastomyces dermatitidis In Vitro (1984)

The interaction of elicited murine polymorphonuclear neutrophils (PMN) and the thermally dimorphic fungal pathogen Blastomyces dermatitidis in vitro was studied. The PMN elicited intraperitoneally with thioglycollate, in normal mice or mice immune to B dermatitidis, failed to reduce colony forming units (CFU) of B dermatitidis in the inoculum in a 4-hr in vitro assay, even in the presence of 10% fresh immune serum. In contrast, PMN elicited intraperitoneally in immune mice by injection of nonviable B dermatitidis cells significantly reduced inoculum CFU (60 +/- 5%) under the same conditions. Furthermore, nonviable B dermatitidis intraperitoneally (i.p.) in normal mice or nonviable Candida albicans i.p. in immune mice failed to elicit peritoneal exudate cells that reduced inoculum CFU in this system. These results support the concept that PMN, elicited in a site by means of an immunological reaction, acquired enhanced microbicidal activity. The fungicidal activity of immunologically elicited PMN was shown to be most effective at high effector to target cell ratios (1,000:1), maximal within 2 hr of coculture, and significantly enhanced in the presence of fresh immune serum compared to heat-inactivated immune serum, normal mouse serum, or fetal bovine serum. Such PMN also had significantly enhanced fungicidal activity against C albicans compared to normal PMN. Fungicidal activity was abrogated in the presence of catalase, implicating hydrogen peroxide generation as the killing mechanism in the activated cells.
Osteoinduction by Functionally Graded Apatites of Bovine Origin Loaded with Bone Morphogenetic Protein‐2 (2005)

Bioresorbable and functionally graded apatites (fg‐HAp) ceramics, which are characterized by gradations in crystallinity and the grain size of hydroxyapatite (HAp:Ca 10 (PO 4 ) 6 (OH) 2 ), were designed using bovine bone by the calcination and partial dissolution–precipitation method. The fg‐HAp ceramics had macropores of 100–600 μm originated from spongy bone, and micropores of 10–160 nm. Fg‐HAp ceramics loaded with recombinant human bone morphogenetic protein‐2 (rhBMP‐2/fg‐HAp) were implanted into the subcutaneous tissue of rats. Eight weeks after the implantation, the surface and bulk degradations of the fg‐HAp‐containing body fluid occured, and small pieces of fg‐HAp were incorporated into the induced bone and fatty marrow, suggesting that osteoinduction occurred in conjunction with bone remodeling. The rhBMP‐2/fg‐HAp ceramics developed could become a resorbable biomimetic material with fast bioresorption and osteoinduction characteristics.
RENAL KALLIKREIN IN CHRONIC HYPOXIC RATS (1996)

1. We have studied the role of kallikrein (KK) in the maintenance of renal function in chronic hypoxic rats (high altitude; HA), compared with control rats kept at sea level (SL). Hypoxia was induced by placing female Wistar rats (198-290 g) in an altitude chamber (5500 m) 15 h/day for 4 weeks. Experiments were also conducted to study the interaction of KK with renal nerve activity and endothelin (ET), two parameters previously shown to be altered in this model. 2. It was found that renal cortex tissue KK activity (TKA) was not significantly different in 10 SL and 10 HA rats. However, the urinary KK activity (UKA) was reduced nearly to half (from 35.2 +/- 4.6 to 18.5 +/- 1.7 pkat/min) in HA rats after 4 weeks of chronic hypoxia. 3. Acute renal denervated diuresis was accompanied by a significant increase in UKA (from 9 +/- 2 to 14 +/- 2 pkat/min in HA and denervated HA rats, respectively; P < 0.05) in HA rats. Intrarenal arterial pretreatment of aprotinin reduced the denervated diuresis. 4. Endothelin (600 ng/kg per h) reduced urine flow, sodium and potassium excretion in the ipsilateral kidney in another 10 SL and 10 HA rats. The extent of the drop of these parameters was significantly less in HA rats. Urinary KK activity was correlated significantly with the measured renal functional parameters (r ranging from 0.472 to 0.612) in SL rats, but was insignificant in HA rats (r ranging from 0.032 to 0.192). 5. We have demonstrated that chronic exposure to hypoxia decreases urinary KK excretion and that KK is involved in acute renal denervated diuresis generated in these animals. The present study suggests that KK plays a partial role in the maintenance of renal function in chronic hypoxic rats.
Thromboxane A2 stimulates vascular smooth muscle hypertrophy by up-regulating the synthesis and release of endogenous basic fibroblast growth factor (1993)

We have shown previously that thromboxane A2 stimulates hypertrophy of cultured rat aortic smooth muscle cells defined as protooncogene expression and protein synthesis without DNA synthesis or cellular proliferation (Dorn, G.W., II, Becker, M.W., Davis, M.G. (1992) J. Biol. Chem. 267, 24897-24905). Since endogenous growth modulators could possibly regulate vascular smooth muscle growth to this vasoconstrictor, we tested the hypothesis that thromboxane-stimulated vascular smooth muscle hypertrophy was due to increased expression of endogenously produced basic fibroblast growth factor (bFGF). The thromboxane mimetic (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619) (1 microM) increased cultured rat aorta derived smooth muscle cell immunoreactive bFGF content by 331 +/- 40% over untreated controls after 24 h. Co-incubation of vascular smooth muscle cells with a specific antisense oligodeoxynucleotide (AS) against codon 60 of bFGF coding sequence reduced thromboxane-stimulated bFGF expression by 72 +/- 5% and prevented thromboxane-stimulated hypertrophy (nonsense oligonucleotide had no effects). Addition of exogenous bFGF (20 ng/ml) restored growth to AS-treated/thromboxane-stimulated vascular smooth muscle cells. Furthermore, addition to the culture medium of neutralizing antibody against bFGF inhibited U46619-stimulated vascular smooth muscle hypertrophy by 69 +/- 17%, whereas nonimmune IgG had no effect. Since protein tyrosine phosphorylation is a cell signal associated with growth, thromboxane-stimulated tyrosine phosphorylation was also examined. Exposure to 1 microM U46619 for 10 min increased vascular smooth muscle immunoreactive phosphotyrosine content of 130-144-, 86-, 80-, 75-, and 58-kDa proteins. The tyrosine kinase inhibitor herbimycin A (5 microM) prevented thromboxane-stimulated tyrosine phosphorylation, but not thromboxane-stimulated hypertrophy, suggesting that tyrosine phosphorylation was not required for thromboxane-stimulated vascular smooth muscle growth. These results indicate that increased expression and release of endogenous bFGF, but not direct tyrosine phosphorylation, mediates the hypertrophic vascular smooth muscle response to thromboxane.
Apoptotic Activity of REAPER Is Distinct from Signaling by the Tumor Necrosis Factor Receptor 1 Death Domain (1996)

REAPER (RPR) is a 65-amino acid protein that is critical activator of programmed cell death in Drosophila. On the basis of sequence alignment data, it was recently proposed that RPR might represent an ancestral molecule from which the death domain in a number of proteins may have evolved. We tested this idea by examining the activity of mutations in RPR that parallel inactivation mutations of the tumor necrosis factor receptor 1 death domain. The RPR mutants retained potent apoptotic function, suggesting that cell death activity mediated by RPR is distinct from signaling by the tumor necrosis factor receptor 1 death domain.
Rehabilitating the "Idea of Community" (2001)

All manuscn"pts must focus clearly on basic wnh"ng and must add substantively to the existing literature.We seek manuscripts that are original, stimulating, well-grounded in theory, and clearly related to practice.Work that reiterates
关于马克思主义革命理论的争论——对波兰马克思主义史学家奥任霍夫斯基·马利安《进步》一书的评价 (1989)

波兰著名的马克思主义史学家马利安·奥任霍夫斯基在其所著《进步》一书里对社会发展的一系列最复杂的问题——从资本主义向社会主义过渡的道路和形式,建设新社会的规律性——都进行了建设性的、科学的研究。作者通过同沙夫(曾经是波兰统一工人党党员,后来走上了修正主义道路。他利用新的社会现实,利用世界革命进程中的一系列复杂问题,首先是向新的社会制度过渡、过渡中的机制和规律等问题进行了政治
A shut‐down in expression of an insulin‐like peptide, ILP‐1, halts ovarian maturation during the overwintering diapause of the mosquito Culex pipiens (2009)

Short day-length is used to programme adult diapause in the mosquito, Culex pipiens. The downstream endocrine event that halts ovarian maturation is a shut-down in juvenile hormone (JH) production, and recent evidence suggests that the insulin signalling pathway may be a key upstream player in executing this developmental arrest. Genes encoding insulin-like peptides-1, -2 and -5 were identified in C. pipiens, and we report that transcript levels of insulin-like peptides-1 and -5 were significantly lower in diapausing females than in their nondiapausing counterparts. Genes encoding both insulin-like peptides-1 and -5 were suppressed using RNA interference in mosquitoes programmed for nondiapause, and ovarian maturation was monitored. Knocking down insulin-like peptide-1 with RNAi in nondiapausing mosquitoes resulted in a cessation of ovarian development akin to diapause, and this arrest in development could be reversed with an application of JH. Knocking down insulin-like peptide-5 did not alter ovarian development. These results are consistent with a role for insulin-like peptide-1 in the signalling pathway leading from the perception of short day-lengths to the shut-down in JH production that characterizes adult diapause in C. pipiens.
Adhesion of endothelial cells to extracellular matrix proteins (1983)

Human and bovine endothelial cells were used in a series of studies examining cell adhesion to extracellular matrix macromolecules. Collagen types I and III, an acetic acid extract of bovine lens capsule basement membrane, laminin, and fibronectin were demonstrated to affect, in varying degrees, cell adhesion, cell growth, and "sprout cell" formation in endothelial cell cultures. All the matrix macromolecules tested promoted endothelial cell adhesion, and the adhesion to the basement membrane extract was blocked by antibodies to fibronectin. When human endothelial cells were grown on defined matrices, the level of serum required for optimum growth was decreased, while bovine endothelium grown on defined matrices did not show sprout cell formation. These data suggest that endothelial cells are able to adhere to a wide variety of connective tissue components and that extracellular matrices significantly influence cell behavior.
Construction of chimeric proteins from the σ;N‐associated transcriptional activators VnfA and AnfA of Azotobacter vinelndii shows that the determinants of promoter specificity lie outside the‘recognition’helix of the HTH motif in the C‐terminal domain (1993)

Functional chimeras have been generated from the transcriptional activators VnfA and AnfA, which control expression of the alternative nitrogenases in Azotobacter vinelandii. The activation profiles of the native and chimeric proteins have been determined using lacZ fusions to A. vinelandii anf and vnf promoters in Klebsiella pneumoniae. Replacing the C-terminal domain of AnfA with that of VnfA gives a protein with the promoter specificity of VnfA, confirming that the C-terminal domain contains the determinants of promoter specificity. However, substituting the VnfA sequence from the turn in the helix-turn-helix motif to the C-terminus does not alter the promoter specificity of AnfA. These changes in promoter specificity were reflected in changes in affinity for a VnfA-binding site, as measured by an in vivo repression assay using a lacZ fusion to a synthetic promoter. This supports the assumption that promoter recognition is determined by activator binding to enhancer--like sequences, and shows that the principal determinants of specific DNA-binding lie outside the 'recognition' helix. This may be a general feature of transcriptional activators dependent on sigma N (sigma 54). The chimera with the promoter specificity of VnfA retained the dependence on nitrogenase Fe protein characteristic of AnfA, indicating that this property is not related to particular promoter sequences, but is a function of the central or N-terminal domains of AnfA.
Separation and characterization of mobilized and unmobilized peripheral blood progenitor cells by counterflow centrifugal elutriation. (1995)

Peripheral blood stem cell (PBSC) harvests are highly contaminated with lymphocytes. In allogeneic transplantations with PBSC, this might lead to an increased risk of graft-vs.-host disease (GVHD). Marrow graft T cells depletion (TCD) by counterflow centrifugal elutriation (CCE) has been performed to decrease the incidence of GVHD, but in some cases, it has also led to a reduction in the PBSC content of the graft due to the distinct elutriation properties of these cells. We studied the ability of CCE to deplete lymphocytes from recombinant human granulocyte colony-stimulating factor (rhG-CSF)-mobilized PB mononuclear cells (PBMNC) and from unmobilized PBMNC from healthy volunteers. We characterized the elutriation properties of circulating mobilized and unmobilized hematopoietic progenitors. With an experimental three-flow rate CCE procedure, originally described for separation of bone marrow, fractions 24, 28, and Rotor Off (RO) were obtained without impairing yield or viability. This CCE procedure can also be used for the separation of PBMNC harvests by reducing the T cell contamination to or below the range seen in bone marrow grafts; CD3+ cell contamination in the RO fractions of mobilized and unmobilized PBMNC was reduced to < 10% of the input. This could bring allogeneic PBSCT within the range of feasibility. In unmobilized PBMNC, 25% of the recovered CD34+ cells were found in fraction 24, where no colonies were detected, and 50% of the recovered CD34+ cells were found in fraction RO, where most of the colonies were detected. In mobilized PBMNC, 80% of the recovered CD34+ cells were found in fraction RO, together with 90% of the colonies, but almost no colonies or CD34+ cells were detected in fraction 24. CD34+ cells in fraction 24 expressed less CD13, and antigen found on more mature myeloid cells. Mobilization with rhG-CSF causes a shift of CD34+ cells from smaller cells (fraction 24) to larger cells (fractions 28 and RO).
Characterization of a recombinant chimeric plasminogen activator composed of a fibrin fragment‐d‐dimer‐specific humanized monoclonal antibody and a truncated single‐chain urokinase (1992)

A recombinant chimeric plasminogen activator, MA-15C5Hu/scu-PA-32k, composed of a humanized fibrin fragment-D-dimer-specific monoclonal antibody (MA-15C5Hu) and a recombinant low-molecular-mass single-chain urokinase-type plasminogen activator, comprising amino acids Leu144-Leu411 (scu-PA-32k), was produced by cotransfecting Chinese hamster ovary (CHO) cells with the cDNA encoding the MA-15C5Hu light-chain sequence and the cDNA encoding the MA-15C5Hu heavy-chain sequence fused with the cDNA encoding scu-PA-32k. Purified MA-15C5Hu/scu-PA-32k migrated as a 215-kDa band on non-reducing SDS/PAGE, which is consistent with a molecule composed of one antibody and two scu-PA-32k moieties. However, the chimera was obtained as a mixture of single-chain u-PA-32k (37%) and amidolytically inactive (50%) and active (13%) two-chain u-PA-32k, the latter of which was removed by immunoadsorption on a monoclonal antibody specific for two-chain urokinase. The fragment-D-dimer affinity and enzymatic properties of MA-15CHu/scu-PA-32k were similar to those of MA-15C5Hu or of scu-PA-32k. In an in vitro system composed of a 125I-fibrin-labeled human plasma clot submerged in citrated human plasma, MA-15C5Hu/scu-PA-32k had a 12-fold higher fibrinolytic potency than scu-PA-32k: 50% lysis in 2 h required 0.43 +/- 0.12 micrograms u-PA-32k equivalent of the chimera/ml versus 5.4 +/- 0.3 micrograms/ml of scu-PA-32k (mean +/- SEM, n = 4). Addition of purified fibrin fragment-D dimer reduced the fibrinolytic potency of MA-15C5Hu/scu-PA-32k in a concentration-dependent way, indicating that the increased potency is the result of antibody targeting. Thus, a recombinant humanized antifibrin antibody/u-PA chimera has been obtained in which only the variable domains of the antibody moiety are of non-human origin. The chimera has intact antigen-binding capacity, u-PA enzymatic activity and a significantly increased fibrinolytic potency in a plasma medium in vitro.
Online Optimization of VM Deployment in IaaS Cloud (2012)

Infrastructure-as-a-Service (IaaS) clouds provide on-demand virtual machines (VMs) to users. How to improve the quality of IaaS cloud services is important for service providers. Currently, the VMs in an IaaS cloud are usually deployed with respect to the maximum utilization of resources. In this paper, we propose an online VM optimization method for IaaS clouds. Our method mainly optimizes the VM deployment in IaaS clouds according to the traffics among VMs. VMs are allocated with respect to cabinet capacities at the beginning. At runtime, we monitor the traffics among VMs to get the traffic topology, based on which related VMs are migrated to neighbors to improve performance and reduce the traffics across cabinets. Preliminary simulation experiments are conducted on a well-know simulator, and the experimental results indicate that our method is effective and promising.