gebhart/patrepeval huggingface dataset:
Inhibition of cMet activation by a one-armed antibody (2004)

1424 The proto-oncogene cMet is a receptor tyrosine kinase that is expressed in many epithelial cancers. On binding by its ligand, HGF, cMet activates cellular pathways that promote proliferation and invasive growth, characteristics of aggressive tumor behavior. We have produced a panel of monoclonal antibodies to the extracellular domain of cMet, one of which, 5D5, inhibits binding by HGF. As a normal, bivalent antibody, 5D5 is a potent cMet activator, but the monovalent Fab is a potent HGF antagonist that inhibits HGF-induced proliferation and migration. However, the Fab has a very short half-life in vivo, which limits its utility in animal models. To address that issue, we have produced a one-armed version of 5D5 by co-expressing 3 polypeptides in E coli. The first is a chimeric light chain consisting of the VL domain from the 5D5 murine hybridoma fused to human kappa constant domain. The second is a chimeric heavy chain consisting of the VH domain from the 5D5 murine hybridoma fused to the constant domains of human IgG1. And the third is an Fc domain, beginning at the hinge and ending with the normal carboxy terminus. The heavy chain covalently associates with both the light chain, through the normal heavy-light disulfide bond, and the truncated Fc, through the normal heavy-heavy disulfide bonds at the hinge. The result is a dimeric Fc from which emanates a single antigen-binding arm. Also produced are smaller amounts of bivalent antibody and dimers of truncated Fc. To further promote formation of the desired product, a “knob” (T366W) was introduced into the truncated Fc construct and a corresponding “hole” (T366S, L368A, Y407V) into the heavy chain. With this modification, >95% of the protein produced is the one-armed antibody. The one-armed version of 5D5 binds cMet with a Kd ∼4 nM and retains the ability to displace HGF binding (IC50 ∼ 5 nM). Like the Fab, it inhibits HGF-stimulated tyrosine phosphorylation of cMet, and inhibits HGF-induced proliferation and migration. Unlike the Fab, which has a half-life in mice of ∼15 minutes, the one-armed 5D5 has a half-life of 4.3 days, approaching that for a normal human IgG1 (∼7 days). As judged by SDS PAGE, the one-armed 5D5 remained intact in circulation for the entire 14 days of the PK experiment. Treatment of nude mice with the one-armed 5D5 (10 mg/kg weekly x 4) at the same time that the mice were inoculated with U87 glioma cells, which express cMet and produce HGF in an autocrine manner, completely prevented tumor development. Moreover, the one-armed 5D5 caused complete, dose-dependent regression of U87 glioma tumors when treatment was delayed until tumors were established. These results suggest that the one-armed 5D5 could have therapeutic utility in HGF-dependent neoplasias.
„Diabetes in Germany” (DIG)-Studie (2009)

Type 2 diabetics in Germany received an acceptable level of treatment for hyperglycaemia, but still more than 60 % of the patients have HbA (1c) values higher than 6,5 %. There are serious deficits in the management of hypertension, hypercholesterolemia and the use of aspirin. Because intensive, multifactorial care of type 2 diabetics leads to reduced rates of death and cardiovascular disorders, these results indicate that the early and meticulous implementation of current treatment guidelines remains a major challenge.
Epoprostenol (Prostacyclin) Therapy in HIV-associated Pulmonary Hypertension (2000)

Although HIV-associated pulmonary hypertension and primary pulmonary hypertension (PPH) are clinically and histologically similar, treatment options for the former are limited. Treatment with calcium channel blockers (CCB), proven to be beneficial in a subset of patients with PPH, has been disappointing in HIV-associated pulmonary hypertension and there are no data examining the effects of long-term epoprostenol in this entity. Six patients with severe HIV-associated pulmonary hypertension were treated with continuous intravenous epoprostenol infusions. Acute infusion of epoprostenol resulted in a significant (p < 0.05) decrease in mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) of 16. 4 and 32.7%, respectively, and a significant (p < 0.05) increase in mean cardiac output (CO) of 36.9%. At 1 yr, mean PAP and PVR had decreased by 21.7 and 54.9% (p < 0.05), respectively, and mean CO had increased by 51.4% (p < 0.05) when compared with baseline values. Repeat catheterizations of three patients at 2 yr and one patient at 40 mo demonstrated further improvement or maintenance of hemodynamics. In addition, NYHA functional class improved in all patients. We conclude that epoprostenol infusion is effective in improving hemodynamic and functional status in this cohort of six patients with HIV-associated pulmonary hypertension acutely and long-term.
Adherence to buccal epithelial cells, enzymatic and hemolytic activities ofCandida isolatesfrom HIV-infected individuals (2010)

Candida spp., along with other microorganisms are usually found in the normal flora of the human oral mucosa. However in HIV-infected individuals these yeasts can become opportunistic pathogens and lead to mucosal infections. The transformation from a harmless commensal to a virulent pathogen under conditions of dysfunctional host defense system is attributable to an extensive repertoire of selectively expressed virulence determinants. The present study was undertaken to analyze the production of four important virulence factors viz. adherence to buccal epithelial cells (BEC), proteinase activity, phospholipase activity and hemolysis, and to evaluate the correlation between these virulence factors in 65 Candida isolates from HIV-infected individuals with oral candidiasis. A total of 95.3%, 67.7%, 41.5% and 100% of the Candida isolates showed adherence to BEC, and proteinase, phospholipase and hemolytic activities, respectively. Production of proteinase and phospholipase enzymes was seen in 89.7% and 59.0% of C. albicans isolates and 34.6% and 15.4% of non-Candida albicans Candida (NAC) isolates, respectively. C. albicans showed significantly greater level of virulence factor expression with regards to adherence to BEC (P < 0.001), phospholipase production (P < 0.044) and hemolysis (P = 0.037) as compared to NAC. A correlative relationship between proteinase activity and adherence to BEC, as well as phospholipase production was noted.
FKBP Family Proteins: Immunophilins with Versatile Biological Functions (2008)

Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunophilins and most of FKBP family members bind FK506 and show peptidylprolyl cis/trans isomerase (PPIase) activity. Small size FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains, calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription. FKBP family proteins play important functional roles in the T-cell activation, when complexed with their ligands. The roles of immunophilins in protein transportation and apoptosis through their molecular interactions with receptors or proteins have emerged recently. Moreover, therapeutic implications of immunophilin ligands in treating neurodegenerative disorders have been accumulating. FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical FKBP members such as FKBP12, which shows PPIase activity. These immunophilin ligands show variable efficacy in animal models for Parkinson's disease, dementia, and spinal cord injury, where the canonical immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither PPIase activity nor affinity to FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical FKBP family members and the biological functions of their ligands in performing neuroprotective and neurotrophic activities.
Analysis of Chalk Petrophysical Properties by Means of Submicron-Scale Pore Imaging and Modeling (2007)

Summary For many rocks of high economic interest such as chalk, diatomite, shale, tight gas sands, or coal, a submicron-scale resolution is needed to resolve the 3D pore structure, which controls the flow and trapping of fluids in the rocks. Such a resolution cannot be achieved with existing tomographic technologies. A new 3D imaging method based on serial sectioning, which uses the focused-ion-beam (FIB) technology, has been developed. FIB technology allows for the milling of layers as thin as 10 nm by using accelerated gallium (Ga+) ions to sputter atoms from the sample surface. After each milling step, as a new surface is exposed, a 2D image of this surface is generated, and the 2D images are stacked to reconstruct the 3D pore structure. Next, the maximum-inscribed-spheres (MIS) image-processing method computes the petrophysical properties by direct morphological analysis of the pore space. The computed capillary pressure curves agree well with laboratory data. Applied to the FIB data, this method generates the fluid distribution in the chalk pore space at various saturations.
Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis. A randomized, double-blind, placebo-controlled trial (1993)

A multicentre, randomized, double-blind, controlled crossover clinical trial was conducted on 33 patients with severe refractory atopic dermatitis, to determine the effects of cyclosporin (5 mg/kg/day) on their health-related quality of life. Treatments were administered for 8-week periods. One group (n = 16) received placebo followed by cyclosporin, and the other (n = 17) received cyclosporin and then placebo. Health-related quality of life was assessed at 0, 8 and 16 weeks using a general measure, the United Kingdom Sickness Impact Profile (UKSIP), an eczema-specific measure, the Eczema Disability Index (EDI), and a global 5-point rating scale of overall health (very good to very poor). In addition, clinical assessments (i.e. extent and activity of disease) were made by the investigators. UKSIP and EDI scores indicated significant improvement in quality of life (P < 0.05-P < 0.01) of patients with atopic dermatitis after treatment with cyclosporin. Although no patient required withdrawal from the study, 20 patients receiving cyclosporin reported adverse events, compared with eight taking placebo. There was a close correlation (P < 0.05-P < 0.01) between the UKSIP and EDI scores. In contrast, there was either no correlation, or only a very poor correlation, between the quality of life parameters and clinical measures of extent and activity of eczema. When cyclosporin was stopped, relapse was rapid, but the mean scores for disease activity and extent of disease were less than their baseline values (i.e. an improvement of greater than 25% was maintained in 11 patients at week 4).(ABSTRACT TRUNCATED AT 250 WORDS)
Expert maintenance systems in telecommunications (2002)

An admissible heuristic algorithm for generating a network troubleshooting expert system that minimizes the expected troubleshooting cost and learns better troubleshooting techniques during its operation is presented. The algorithm requires three kinds of input: network topology, component failure rate, and relative costs of tests. It uses a modification of Huffman code that is proven to be an admissible heuristic on the A* search. Learning is shown to be facilitated by recomputing the optimal troubleshooting strategy when any of the inputs has changed. The algorithm is implemented in Prolog.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
[Expression of the LC3A protein in prostate cancer and its implications]. (2014)

The expression of the LC3A protein might be involved in the development, differentiation, and prognosis of prostate cancer.
Hyaluronan Oligosaccharides Inhibit Anchorage-independent Growth of Tumor Cells by Suppressing the Phosphoinositide 3-Kinase/Akt Cell Survival Pathway (2002)

Hyaluronan oligosaccharides (molecular weight: approximately 2.5 x 10(3)) inhibit growth of several types of tumors in vivo. In vitro, the oligomers inhibit anchorage-independent growth of several tumor cell types. In accordance with this finding, the oligomers also induce apoptosis and stimulate caspase-3 activity under anchorage-independent conditions. Since inhibitors of phosphoinositide 3-kinase (PI 3-kinase) mimic the action of hyaluronan oligomers and since the PI 3-kinase/Akt (protein kinase B) cell survival pathway has previously been implicated in anchorage-independent growth of tumor cells, we examined the effect of oligomers on PI 3-kinase and its downstream activities in TA3/St murine mammary carcinoma and HCT 116 human colon carcinoma cells. We observed that 50-150 microg/ml hyaluronan oligomers inhibit PI 3-kinase activity and phosphorylation of Akt to approximately the same extent as optimal doses of wortmannin and LY294002, known inhibitors of PI 3-kinase. Similar inhibition of downstream events, i.e. phosphorylation of BAD and FKHR, was also observed. These effects were not observed on treatment with similar concentrations of chitin oligomers, chondroitin sulfate, or hyaluronan polymer. High molecular weight (approximately 2 x 10(6)) and low molecular weight (approximately 8 x 10(4)) preparations of hyaluronan polymer were equally ineffective. The effects of hyaluronan oligomers on these parameters were similar in magnitude to the effect of treatment with activity-blocking antibody against CD44. We interpret these results to indicate that the oligomers competitively block binding of endogenous hyaluronan polymer to CD44, consequently giving rise to attenuated signaling. Finally, we observed that hyaluronan oligomers, but not chitin oligomers, chondroitin sulfate, or hyaluronan polymer, stimulate expression of PTEN, a phosphatase that degrades the major signaling product of PI 3-kinase action, phosphoinositide 3,4,5-trisphosphate. We conclude that perturbation of hyaluronan-CD44 binding leads to suppression of the PI 3-kinase/Akt cell survival pathway and consequently to inhibition of anchorage-independent growth in culture and tumor growth in vivo.
Chimeric prion protein expression in cultured cells and transgenic mice (1992)

The efficient expression of exogenous prion protein (PrP) molecules in mouse neuroblastoma cells that are chronically infected with murine scrapie prions (ScN2a cells; Butler, D.A., et al., 1988, J. Virol. 62, 1558-1564) and in transgenic mice is described. This technology allows investigation of the PrP molecule for structural regions involved in determining species specificity, as well as ablation experiments designed to address the functionality of particular regions of the PrP molecule. Previous reports demonstrated that the PrP gene specifies the host range for susceptibility of transgenic animals to prions (Scott, M., et al., 1989, Cell 59, 847-857; Prusiner, S.B., et al., 1990, Cell 63, 673-686). Consistent with these results, we showed that Syrian hamster (SHa) PrP is ineligible for efficient conversion to PrPSc in ScN2a cells. By constructing a series of chimeric mouse (Mo)/SHaPrP genes, we developed an epitopically tagged functional variant of the MoPrP gene, which can efficiently form protease-resistant PrP molecules upon expression in ScN2a cells. The presence of a defined epitope for an SHa-specific monoclonal antibody allows the products of this chimeric gene to be discriminated from endogenous MoPrP and creates a useful reagent for exploring structure/function relationships via targeted mutagenesis. In addition, we developed a transgenic mouse expression vector by manipulation of an SHaPrP cosmid clone. This vector permits the efficient expression of foreign PrP genes in the brains of transgenic animals, enabling pathological consequences of in vitro mutagenesis to be studied.
An Iterative and Regenerative Method for DNA Sequencing (1997)

This paper presents, to our knowledge, the first iterative DNA sequencing method that regenerates the product of interest during each iterative cycle, allowing it to overcome the critical obstacles that impede alternative iterative approaches to DNA sequencing: loss of product and the accumulation of background signal due to incomplete reactions. It can sequence numerous double-stranded (ds) DNA segments in parallel without gel resolution of DNA fragments and can sequence DNA that is almost entirely double-stranded, preventing the secondary structures that impede sequencing by hybridization. This method uses ligation of an adaptor containing the recognition domain for a class-IIS restriction endonuclease and digestion with a class-IIS restriction endonuclease that recognizes the adaptor's recognition domain. This generates a set of DNA templates that are each composed of a short overhang positioned at a fixed interval with respect to one end of the original dsDNA fragment. Adaptor ligation also appends a unique sequence during each iterative cycle, so that the polymerase chain reaction can be used to regenerate the desired template-precursor before class-IIS restriction endonuclease digestion. Following class-IIS restriction endonuclease digestion, sequencing of a nucleotide in each overhang occurs by template-directed ligation during adaptor ligation or through a separate template-directed polymerization step with labeled ddNTPs. DNA sequencing occurs in strides determined by the number of nucleotides separating the recognition and cleavage domains for the class-IIS restriction endonuclease encoded in the ligated adaptor, maximizing the span of DNA sequenced for a given number of iterative cycles. This method allows the concurrent sequencing of numerous dsDNA segments in a microplate format, and in the future it can be adapted to biochip format.
Discovery of a biofilm electrocline using real-time 3D metabolite analysis (2011)

Bacteria are social organisms that possess multiple pathways for sensing and responding to small molecules produced by other microbes. Most bacteria in nature exist in sessile communities called biofilms, and the ability of biofilm bacteria to sense and respond to small molecule signals and cues produced by neighboring biofilm bacteria is particularly important. To understand microbial interactions between biofilms, it is necessary to perform rapid, real-time spatial quantification of small molecules in microenvironments immediately surrounding biofilms; however, such measurements have been elusive. In this study, scanning electrochemical microscopy was used to quantify small molecules surrounding a biofilm in 3D space. Measuring concentrations of the redox-active signaling molecule pyocyanin (PYO) produced by biofilms of the bacterium Pseudomonas aeruginosa revealed a high concentration of PYO that is actively maintained in the reduced state proximal to the biofilm. This gradient results in a reduced layer of PYO that we have termed the PYO "electrocline," a gradient of redox potential, which extends several hundred microns from the biofilm surface. We also demonstrate that the PYO electrocline is formed under electron acceptor-limiting conditions, and that growth conditions favoring formation of the PYO electrocline correlate to an increase in soluble iron. Additionally, we have taken a "reactive image" of a biofilm surface, demonstrating the rate of bacterial redox activity across a 2D surface. These studies establish methodology for spatially coordinated concentration and redox status measurements of microbe-produced small molecules and provide exciting insights into the roles these molecules play in microbial competition and nutrient acquisition.
The effects of processing inhibitors of N-linked oligosaccharides on the intracellular migration of glycoprotein E2 of mouse hepatitis virus and the maturation of coronavirus particles. (1985)

We have studied the effects of tunicamycin and inhibitors of the processing of N-linked glycans including N-methyl-1-deoxynojirimycin, castanospermine, mannodeoxynojirimycin, and swainsonine on the transport of glycoprotein E2 and the intracellular maturation of the coronavirus mouse hepatitis virus A59. Indirect immunofluorescence staining with monoclonal antibodies revealed that glycoprotein E2 exhibits different antigenic properties depending on the presence and on the structure of the N-linked oligosaccharides and that efficient transport of glycoprotein E2 to the plasma membrane requires the removal of glucose residues. In the presence of tunicamycin in the nonglycosylated E2 apoprotein was synthesized in normal amounts and readily acylated throughout the infectious cycle. This E2-species could not be detected on the surface of mouse hepatitis virus A59-infected cells with indirect immunofluorescence staining or lactoperoxidase labeling. N-Methyl-1-deoxynojirimycin and castanospermine, both of which selectively inhibited the processing glucosidases, caused a drop in virion formation by two log steps and a drastic delay in the surface expression of glycoprotein E2. The E2 species synthesized under such conditions was acylated but accumulated intracellularly in a compartment distinct from the Golgi. Concomitantly, synthesis of the matrix glycoprotein E1 of mouse hepatitis virus A59 was drastically impaired. Mannodeoxynojirimycin and swainsonine, which block later stages of the processing pathway, had less or no effect on the transport of glycoprotein E2 and the formation of virus particles.
Posttranslational modification and intracellular transport of a trypanosome variant surface glycoprotein. (1986)

After synthesis on membrane-bound ribosomes, the variant surface glycoprotein (VSG) of Trypanosoma brucei is modified by: (a) removal of an N-terminal signal sequence, (b) addition of N-linked oligosaccharides, and (c) replacement of a C-terminal hydrophobic peptide with a complex glycolipid that serves as a membrane anchor. Based on pulse-chase experiments with the variant ILTat-1.3, we now report the kinetics of three subsequent processing reactions. These are: (a) conversion of newly synthesized 56/58-kD polypeptides to mature 59-kD VSG, (b) transport to the cell surface, and (c) transport to a site where VSG is susceptible to endogenous membrane-bound phospholipase C. We found that the t 1/2 of all three of these processes is approximately 15 min. The comparable kinetics of these processes is compatible with the hypotheses that transport of VSG from the site of maturation to the cell surface is rapid and that VSG may not reach a phospholipase C-containing membrane until it arrives on the cell surface. Neither tunicamycin nor monensin blocks transport of VSG, but monensin completely inhibits conversion of 58-kD VSG to the mature 59-kD form. In the presence of tunicamycin, VSG is synthesized as a 54-kD polypeptide that is subsequently processed to a form with a slightly higher Mr. This tunicamycin-resistant processing suggests that modifications unrelated to N-linked oligosaccharides occur. Surprisingly, the rate of VSG transport is reduced, but not abolished, by dropping the chase temperature to as low as 10 degrees C.