gebhart/patrepeval huggingface dataset:
Amino acids in SRS1 and SRS6 are critical for furanocoumarin metabolism by CYP6B1v1, a cytochrome P450 monooxygenase (2002)

CYP6B1v1 is the principal cytochrome P450 monooxygenase (P450) that detoxifies dietary furanocoumarins in the guts of Papilio polyxenes, the black swallowtail caterpillar. Sequence alignments and structure comparisons of CYP6B1v1 with the mouse CYP2A5 and bacterial CYP102 proteins, which are also capable of metabolizing the linear furanocoumarin xanthotoxin (8-methoxypsoralen), suggested that Phe116, His117, Val368 and Phe484 might be active site residues. In a homology model developed for CYP6B1v1, the side chains of Phe116 and His117 located in the B'-C loop of SRS1 are predicted to be positioned above the haem plane, while the side chain of Phe484 located in SRS6 is predicted near the entrance of the catalytic pocket. Site-directed mutagenesis of residues Phe116, His117 and Phe484 indicated that these residues represent several of those that determine this protein's stability and substrate specificity. Whereas all aromatic mutants of Phe116 and Phe484 generated CO-difference spectra with maxima at 450 nm indicative of correctly configured monooxygenases, aromatic mutants of Phe116 exhibited reduced reactivities toward some furanocoumarins and aromatic mutants of Phe484 eliminated all reactivities toward furanocoumarins. All single and double aliphatic mutants of Phe116, His117 and Phe484 and aromatic mutants of His117 generated carbon monoxide (CO) difference spectra with maxima at 420 nm (P420) indicative of incorrectly configured monooxygenases. These studies define residues Phe116, His117 and Phe484 as determinants of this insect P450's catalytic site integrity and residues Phe116 and Phe484 as determinants of its substrate specificity. Conservation of Phe116 and His117 in an array of lepidopteran CYP6B proteins implies that these amino acids serve a similar function in other monooxygenases of the insect CYP6B subfamily.
Periodate-oxidized adenosine induction of murine thymidine kinase: role of DNA methylation in the generation of tumor cell heterogeneity. (1986)

We previously reported that thymidine kinase (TK) activity in a spontaneously TK-deficient (TK-) murine tumor cell line (called L61-M) could be partially restored following brief treatment of the cells in vitro with the potent DNA-hypomethylating agent 5-azacytidine. We now show here that similar results may be obtained by exposing cells in vitro to periodate-oxidized adenosine, a potent inactivator of the S-adenosylhomocysteine hydrolase enzyme. The ability of periodate-oxidized adenosine to induce TK activity within the L61-M cell line was dependent upon the concentration of drug used and the treatment period. Inhibiting DNA synthesis completely prevented the effects of periodate-oxidized adenosine from being observed. Periodate-oxidized adenosine had no obvious mutagenic effect upon the L61-M cell line and had a slight but significant inhibitory effect upon the methylation of the cytosine nucleotides which were incorporated into DNA during the treatment period. These results suggest that during tumor development, alterations in the relative levels of S-adenosylhomocysteine and S-adenosylmethionine may lead to the inhibition of DNA methylation, resulting in the activation of previously quiescent genes, thereby promoting the phenotypic diversification of tumor cell populations as well as their progression from a relatively benign to a highly malignant state.
Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition (2010)

Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, resistance to apoptosis, evading immune surveillance, and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here, we show that activation of peroxisome proliferator-activated receptor γ (PPAR-γ) inhibits transforming growth factor β (TGF-β)-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (troglitazone and rosiglitazone) or by a constitutively active form of PPAR-γ prevents TGF-β-induced loss of E-cadherin expression and inhibits the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and matrix metalloproteases. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA-mediated knockdown of PPAR-γ, indicating that the ligand-induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA showed that TGF-β-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently, PPAR-γ activation prevented TGF-β-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells significantly inhibited TGF-β-induced experimental metastasis in SCID-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis.
Epidermal growth factor or transforming growth factor alpha is required for kidney tubulogenesis in matrigel cultures in serum-free medium. (1990)

The ability of matrigel, a reconstituted basement membrane gel, to induce the differentiation of baby mouse kidney cells has been examined in a hormonally defined serum-free medium. Primary cultures of baby mouse kidney cells were observed to form tubules over a time interval of 1-2 weeks in matrigel. Electron microscopic studies showed that tubules with lumens were present, and the tubule morphology was similar to that of the collecting duct. When using matrigel from which the growth factors had been removed, tubule formation no longer occurred, unless the medium was further supplemented with epidermal growth factor (10 ng/ml). Transforming growth factor alpha stimulated tubule formation as effectively as epidermal growth factor, whereas transforming growth factor beta had an inhibitory effect on tubule formation. These data suggest that both an extracellular matrix and specific growth factors may regulate kidney differentiation during development.
Group-specific identification of polioviruses by PCR using primers containing mixed-base or deoxyinosine residue at positions of codon degeneracy (1996)

We have developed a method for differentiating polioviruses from nonpolio enteroviruses using PCR. A pair of panpoliovirus PCR primers were designed to match intervals encoding amino acid sequences within VP1 that are strongly conserved among polioviruses. The initiating primer hybridizes with codons of a 7-amino-acid sequence that has been found only in polioviruses; the second primer matches codons of a domain thought to interact with the cell receptor. The panpoliovirus PCR primers contain mixed-base and deoxyinosine residues to compensate for the high degeneracy of the targeted codons. All RNAs from 48 vaccine-related and 110 wild poliovirus isolates of all three serotypes served as efficient templates for amplification of 79-bp product. None of the genomic sequences of 49 nonpolio enterovirus reference strains were amplified under equivalent reaction conditions. Sensitivities of poliovirus detection were as low as 100 fg (equivalent to approximately 25,000 genomic copies or 25 to 250 PFU) when the amplified products were visualized by ethidium bromide fluorescence. These degenerate PCR primers should aid in the detection of all polioviruses, including those wild poliovirus isolates for which genotype-specific reagents are unavailable.
The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms (2011)

The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation and studied 62 patients with HCL, 1 with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases and in only 2 of the remaining 178 patients. These 2 subjects had B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the positive PCR finding, the mutation could not be detected by Sanger sequencing in these 2 cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V600E mutation is present in all patients with HCL and that, in combination with clinical and morphologic features, represents a reliable molecular marker for this condition.
White Stacked Electrophosphorescent Organic Light‐Emitting Devices Employing MoO3 as a Charge‐Generation Layer (2006)

White stacked electrophosphorescent organic light-emitting devices employing three metallorganic phosphors in a compound emission layer (see Figure) are demonstrated. They show an external efficiency of 51 % and power efficiency of 20.7 lm W–1 at practical illumination intensities. A transparent MoO3 film between two adjacent electrophosphorescent elements efficiently injects charge into the stacked elements.
Structure-Based in Vitro Engineering of the Anthranilate Synthase, a Metabolic Key Enzyme in the Plant Tryptophan Pathway (2005)

Rice (Oryza sativa) anthranilate synthase alpha-subunit, OASA2, was modified by in vitro mutagenesis based on structural information from bacterial homologs. Twenty-four amino acid residues, predicted as putative tryptophan binding sites or their proximal regions in the OASA2 sequence, were selected and 36 mutant OASA2 genes were constructed by PCR-based site-directed mutagenesis. Corresponding mutant proteins were synthesized in a combination of two in vitro systems, transcription with a bacteriophage SP6 RNA polymerase and translation with a wheat-embryo cell-free system. Enzymatic functions of the mutant proteins were simultaneously examined, and we found six mutants with elevated catalytic activity and five mutants with enhanced tolerance to feedback inhibition by tryptophan. Moreover, we observed that some sets of specific combinations of the novel mutations additively conferred both characteristics to the mutant enzymes. The functions of the mutant enzymes were confirmed in vivo. The free tryptophan content of mutant rice calli expressing OASA2 enzyme with a double mutation was 30-fold of that of untransformed calli. Thus, our in vitro approach utilizing structural information of bacterial homologs is a potent technique to generate designer enzymes with predefined functions.
The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. (1994)

The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acids that functions as a hepatic endocytosis receptor for several plasma proteins. These include alpha 2-macroglobulin-protease complexes, free plasminogen activators as well as plasminogen activators complexed with their inhibitors, and beta-migrating very low density lipoproteins complexed with either apolipoprotein E or lipoprotein lipase. In the current study we used human and rat hepatoma cell lines to demonstrate that LRP can mediate the degradation of tissue factor pathway inhibitor (TFPI), a Kunitz-type plasma serine protease inhibitor that regulates tissue factor-induced blood coagulation. The cellular degradation of 125I-labeled TFPI (125I-TFPI) was inhibited more than 80% both by antibodies directed against LRP and by the LRP-associated 39-kDa protein, a protein that inhibits the binding and/or cell-mediated degradation of all ligands by LRP. Using rat hepatoma cells, we report that at 4 degrees C, 125I-TFPI binds to approximately 2 x 10(6) sites per cell with an equilibrium dissociation constant of approximately 30 nM. 125I-TFPI binding to the cell surface is not inhibited by the 39-kDa protein. Taken together, our results suggest that TFPI binds to an as-yet-unidentified cell surface molecule. After binding, LRP mediates the cellular degradation of TFPI.
The Functions of Five Distinct Mammalian Phospholipase A2s in Regulating Arachidonic Acid Release (1998)

We examined the relative contributions of five distinct mammalian phospholipase A2 (PLA2) enzymes (cytosolic PLA2 (cPLA2; type IV), secretory PLA2s (sPLA2s; types IIA, V, and IIC), and Ca2+-independent PLA2 (iPLA2; type VI)) to arachidonic acid (AA) metabolism by overexpressing them in human embryonic kidney 293 fibroblasts and Chinese hamster ovary cells. Analyses using these transfectants revealed that cPLA2 was a prerequisite for both the calcium ionophore-stimulated immediate and the interleukin (IL)-1- and serum-induced delayed phases of AA release. Type IIA sPLA2 (sPLA2-IIA) mediated delayed AA release and, when expressed in larger amounts, also participated in immediate AA release. sPLA2-V, but not sPLA2-IIC, behaved in a manner similar to sPLA2-IIA. Both sPLA2s-IIA and -V, but not sPLA2-IIC, were heparin-binding PLA2s that exhibited significant affinity for cell-surface proteoglycans, and site-directed mutations in residues responsible for their membrane association or catalytic activity markedly reduced their ability to release AA from activated cells. Pharmacological studies using selective inhibitors as well as co-expression experiments supported the proposal that cPLA2 is crucial for these sPLA2s to act properly. The AA-releasing effects of these sPLA2s were independent of the expression of the M-type sPLA2 receptor. Both cPLA2, sPLA2s-IIA, and -V were able to supply AA to downstream cyclooxygenase-2 for IL-1-induced prostaglandin E2 biosynthesis. iPLA2 increased the spontaneous release of fatty acids, and this was further augmented by serum but not by IL-1. Finally, iPLA2-derived AA was not metabolized to prostaglandin E2. These observations provide evidence for the functional cross-talk or segregation of distinct PLA2s in mammalian cells in regulating AA metabolism and phospholipid turnover.
Purification and Characterization of Geranylgeranylglyceryl Phosphate Synthase from a Thermoacidophilic Archaeon, Thermoplasma acidophilum (2003)

We purified a geranylgeranylglyceryl phosphate (GGGP) synthase from Thermoplasma acidophilum by several steps of chromatography. Based on the proteinase-fragment-mass-pattern analysis of the SDS-PAGE band of the partially purified protein, the DNA sequence encoding the protein was identified from the whole genome sequence database of the species. The gene encoding GGGP synthase in T. acidophilum was cloned after PCR amplification of the gene from the genomic DNA. The recombinant enzyme was expressed in Escherichia coli and purified. A single band with a molecular mass of 27 kDa was obtained by SDS-PAGE analysis. The apparent native molecular mass of the enzyme was about 50 kDa based on gel filtration chromatography, suggesting that the enzyme is active as a homodimer. As the GGGP synthase from Methanobacterium thermoautotrophicum has been reported as a pentamer, the enzymes of the two organisms have different oligomeric structures. Other characteristics, including substrate specificity, are similar for the GGGPs of these organisms.
Plug-and-play control and optimization in microgrids (2014)

A hierarchical layering of primary, secondary, and tertiary control is the standard operation paradigm for bulk power systems. Similar hierarchical decision architectures have been proposed for microgrids. However, the control objectives in microgrids must be achieved while allowing for robust plug-and-play operation and maximal flexibility, without hierarchical decision making, time-scale separations, and central authorities. Here, we explore control and optimization strategies for the three decision layers and illuminate some possibly-unexpected connections and dependencies among them. Our analysis builds upon first-principle models and decentralized droop control. We investigate distributed architectures for secondary frequency regulation and find that averaging-based distributed controllers using communication among the generation units offer the best combination of flexibility and performance. We further leverage these results to study constrained AC economic dispatch in a tertiary control layer. We show that the minimizers of the economic dispatch problem are in one-to-one correspondence with the set of steady-states reachable by droop control. This equivalence results in simple guidelines to select the droop coefficients, which include the known criteria for load sharing.
Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors (2003)

Membrane lipids were once thought to be homogenously distributed in the 2D surface of a membrane, but the lipid raft theory suggests that cholesterol and sphingolipids partition away from other membrane lipids. Lipid raft theory further implicates these cholesterol-rich domains in many processes such as signaling and vesicle traffic. However, direct characterization of rafts has been difficult, because they cannot be isolated in pure form. In the first functional proteomic analysis of rafts, we use quantitative high-resolution MS to specifically detect proteins depleted from rafts by cholesterol-disrupting drugs, resulting in a set of 241 authentic lipid raft components. We detect a large proportion of signaling molecules, highly enriched versus total membranes and detergent-resistant fractions, which thus far biochemically defined rafts. Our results provide the first large-scale and unbiased evidence, to our knowledge, for the connection of rafts with signaling and place limits on the fraction of plasma membrane composed by rafts.
SSDT-site selection diversity transmission power control for CDMA forward link (2000)

This paper proposes site selection diversity transmission power control (SSDT), an advanced form of transmission power control (TPC) for CDMA forward link, SSDT realizes site selection transmission diversity instead of full site transmission diversity used in conventional TPC during soft hand over (SHO) mode. The major intention of the site selection is to mitigate interference caused by multiple site transmission done at conventional TPC. Simulation results indicated that the higher the capacity gain of SSDT is in comparison to conventional TPC, the lower the mobile station (MS) speed is. Capacity gain of about 55% for a pedestrian MS is achieved by SSDT in case of MS reception diversity and 6 finger RAKE reception. This paper also presents the benefits of SSDT in terms of its high path capturing efficiency and the mitigation of power imbalance among active BSs due to TPC command reception error.
Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721 (1987)

DuP 721 (p-acetylphenyloxooxazolidinylmethylacetamide) and DuP 105 (a methylsulfinyl derivative) are orally active representatives of the oxazolidinones, a new class of synthetic antibacterial agents. Their antibacterial spectrum includes staphylococci, streptococci, and Bacteroides fragilis strains. The compounds have equal activity against staphylococcal strains susceptible or resistant to beta-lactam antibiotics, including methicillin-resistant strains. The MICs for 90% of the strains (MIC90s) against staphylococcal isolates were 1 to 4 micrograms/ml for DuP 721 and 4 to 16 micrograms/ml for DuP 105, compared with 1 to 2 micrograms/ml for vancomycin, 0.5 microgram/ml for ciprofloxacin, and 2 to greater than 16 micrograms/ml for imipenem. The MIC90s against group D streptococci were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 2 micrograms/ml for vancomycin, ciprofloxacin, and imipenem. MIC90s against B. fragilis isolates were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 8 micrograms/ml for cefoxitin. DuP 721 and DuP 105 administered by either the oral or the parenteral route were protective against staphylococcal and streptococcal infections in mice. The 50% effective doses were 2 to 10 mg/kg for DuP 721, 9 to 23 mg/kg for DuP 105, and 2 to 12 mg/kg for vancomycin. These results indicate that further studies of compounds of the oxazolidinone series are warranted.
Inhibitors of Emerging Epigenetic Targets for Cancer Therapy: a Patent Review (2010–2014) (2015)

Gene regulatory pathways comprise an emerging and active area of chemical probe discovery and investigational drug development. Emerging insights from cancer genome sequencing and chromatin biology have identified leveraged opportunities for development of chromatin-directed small molecules as cancer therapies. At present, only six agents in two epigenetic target classes have been approved by the US FDA, limited to treatment of hematological malignancies. Recently, new classes of epigenetic inhibitors have appeared in literatures. First-in-class compounds have successfully transitioned to clinical investigation, importantly also in solid tumors and pediatric malignancies. This review considers patent applications for small-molecule inhibitors of selected epigenetic targets from 2010 to 2014. Included are exemplary classes of chromatin-associated epigenomic writers (DOT1L and EZH2), erasers (LSD1) and readers (BRD4).
Compartmental Syndromes in Peripheral Vascular Surgery (1975)

The need to relieve muscle swelling and secondary vascular impairment of an extremity may occur following a variety of conditions. Regardless of the type of insult, massive swelling of an extremity can result in ischemic necrosis of muscle as a result of tamponade produced by restrictive circulferential fascia. When intracompartmental pressure approaches or exceeds arterial pressure, a portion or the entire extremity may be in jeopardy. Fasciotomy is one of the most important adjunctive procedures available to assure survival of an extremity with altered distal circulation resulting from massive swelling. Its importance has been stressed infrequently in the literature. The indications for its use are outlined in a variety of clinical situations. The proper techniques have few complications and much to offer with regard to limb salvage and reduction of morbidity. Fasciotomy does not preclude correction of the underlying cause for restrictive muscle tamponade when possible, nor can it be expected to reverse well established ischemia. Early and liberal use of fasciotomy is advocated when the outlined indications prevail.
The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice (2006)

cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.
Understanding and using sensitivity, specificity and predictive values (2008)

In this article, we have discussed the basic knowledge to calculate sensitivity, specificity, positive predictive value and negative predictive value. We have discussed the advantage and limitations of these measures and have provided how we should use these measures in our day-to-day clinical practice. We also have illustrated how to calculate sensitivity and specificity while combining two tests and how to use these results for our patients in day-to-day practice.