gebhart/patrepeval huggingface dataset:
Erythropoietin‐dependent erythrocytosis associated with hepatic angiosarcoma (1982)

Erythropoietin (Ep) dependent erythrocytosis was discovered in a 77-year old man with angiosarcoma involving the liver and spleen. At autopsy, tissue from tumorous and normal sections of liver was obtained and extracts prepared for Ep assay in exhypoxic polycythemic mice. Neither tumor nor normal extracts had Ep activity; however, when the extracts were incubated with normal plasma prior to assay, significant amounts of Ep were generated. The normal liver tissue had three times the activity of the tumorous portion, 0.21 U/ml. These results suggest that the tissue contained an Ep activator, probably erythrogenin. It is proposed that the greater amount of erythrogenin activity in the normal tissue may reflect an attempt at liver regeneration following damage by an invading tumor, as regenerating liver has been identified as a stimulus for extrarenal EP and erythrogenin production.
Selective Inhibition of STAT3 with Respect to STAT1: Insights from Molecular Dynamics and Ensemble Docking Simulations (2016)

STAT3 protein, which is known to be involved in cancer development, is a promising target for anticancer therapy. Successful inhibitors of STAT3 should not affect an activity of closely related protein STAT1, which makes their development challenging. The mechanisms of selectivity of several existing STAT3 inhibitors are not clear. In this work, we studied molecular mechanisms of selectivity of 13 experimentally tested STAT3 inhibitors by means of extensive molecular dynamics and ensemble docking simulations. It is shown that all studied inhibitors bind to the large part of the protein surface in an unspecific statistical manner. The binding to the dimerization interface of the SH2 domain, which is usually considered as the main target region, is not energetically preferable. Binding in this region is remarkably similar for STAT1 and STAT3 proteins and cannot explain experimentally observed selectivity toward STAT3. We propose a new mechanism of selectivity called "selectivity by distraction" for existing STAT3 inhibitors. This mechanism is based on equilibrium statistical partitioning of inhibitor molecules between protein domains. The unspecific binding of inhibitors to the DNA-binding and the coil-coil domains is stronger in STAT1 in comparison to STAT3 while the energies of their binding to SH2 domains are comparable. This "distracts" inhibitor molecules from the SH2 domain of STAT1 and leads to higher effective concentration of inhibitors in the vicinity of the SH2 domain of STAT3.
A Biomimetic Approach to Enhancing Interfacial Interactions: Polydopamine-Coated Clay as Reinforcement for Epoxy Resin (2011)

A facile biomimetic method was developed to enhance the interfacial interaction in polymer-layered silicate nanocomposites. By mimicking mussel adhesive proteins, a monolayer of polydopamine was constructed on clay surface by a controllable coating method. The modified clay (D-clay) was incorporated into an epoxy resin, it is found that the strong interfacial interactions brought by the polydopamine benefits not only the dispersion of the D-clay in the epoxy but also the effective interfacial stress transfer, leading to greatly improved thermomechanical properties at very low inorganic loadings. Rheological and infrared spectroscopic studies show that the interfacial interactions between the D-clay and epoxy are dominated by the hydrogen bonds between the catechol-enriched polydopamine and the epoxy.
IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling (2005)

IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.
Quantitative Analysis of Trifluoroacetate in the Urine and Blood by Isotachophoresis (1980)

Trifluoroacetate (TFA), the major metabolite of halothane, was assayed by a newly developed isotachophoretic technique. This technique has several advantages over the presently used methods of analysis. It requires no special preparation of urine or blood samples. The sample volume is small (5--100 microliters) and the analysis time is short (30--90 min per sample). In addition, the method provides an analysis that is both qualitative and quantitative over a wide range of concentrations (from 2 nanomoles in 200 microliters to 200 nanomoles in 5 microliters). In this study, the assay was performed using HCl (0.001 M) in 1 per cent Triton X-100, titrated with beta-alanine to a pH value of 3.6--3.9 as the leading electrolyte and n-caproic acid (0.01 M) as the terminal electrolyte (50--100 muA migration current). Using this technique, daily urinary TFA excretion of seven patients was measured during halothane anesthesia and for 14 days postoperatively. The TFA values were highest on the second postoperative day (317--1,259 mg). The mean values of the urinary TFA excreted during the entire study (2,501 +/- 493 mg, mean +/- SEM) were much higher than those reported previously. The isotachophoretic technique provides a sensitive assay for future research into the biotransformation of halothane.
Regulation of the gastrin promoter by epidermal growth factor and neuropeptides. (1989)

The regulation of gastrin gene transcription was studied in GH4 pituitary cells transfected with constructs comprised of the first exon of the human gastrin gene and various lengths of 5' regulatory sequences ligated upstream of the reporter gene chloramphenicol acetyltransferase. Gastrin reporter gene activity in GH4 cells was equal to the activity of a reporter gene transcribed from the endogenously expressed growth hormone promoter. The effect of a variety of peptides on gastrin gene transcription including epidermal growth factor (normally present in the gastric lumen), gastrin-releasing peptide, vasoactive intestinal peptide, and somatostatin (present in gastric nerves) was assessed. Epidermal growth factor increased the rate of gastrin transcription almost 3-fold, whereas thyrotropin-releasing hormone and vasoactive intestinal peptide increased gastrin transcription 2- and 1.5-fold, respectively. Gastrin-releasing peptide, a peptide that strongly stimulates gastrin release, weakly increased gastrin transcription (1.3-fold). Somatostatin inhibited the increase in gastrin transcription induced by epidermal growth factor, thyrotropin-releasing hormone, and vasoactive intestinal peptide. Constructs containing various lengths of 5' regulatory sequences defined a response element -40 to -82 base pairs (bp) 5' to the transcription initiation site. This 40-bp sequence contains Sp1 and AP2 binding sites, which suggests that epidermal growth factor and thyrotropin-releasing hormone stimulate gastrin gene transcription through transcription factors that bind to Sp1 and/or AP2 motifs.
Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2 (2004)

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.
Inhibitors of the isoprenylated protein endoprotease (1993)

The isoprenylation pathway requires an endoprotease that cleaves the modified protein at the isoprenylated cysteine residue. This endoprotease was readily assayed with simple tetrapeptide substrates of the type N-acetyl-S-farnesyl-L-Cys-(AFC)-Val-Ile-Met, where AFC and the tripeptide are the products of the hydrolysis. The endoprotease proved to be unaffected by (1) serine protease inhibitors, including (4-amidinophenyl)methanesulfonyl fluoride, aprotinin, and leupeptin, by (2) cysteine protease inhibitors, including E-64 and leupeptin [the enzyme is, however, inhibited by p-(hydroxymercuri)benzoate], by (3) metalloprotease inhibitors, including phosphoramidon, EDTA, and 1,10-phenanthroline, or by (4) the aspartyl protease inhibitor pepstatin. The conclusion from these data is that the enzyme is probably not a metalloenzyme. N-Boc-S-all-trans-farnesyl-L-cysteine (BFC) derivatives containing a statine moiety are also not inhibitory, strongly suggesting that the enzyme is not an aspartyl protease. However, the enzyme is potently inhibited by the aldehyde derivative of BFC (K1 = 1.9 microM), which is consistent with the idea that the enzyme is a serine or cysteine protease. Potent tetrapeptide-based competitive inhibitors were prepared. Analogs with the scissile bond modified so that hydrolysis could not occur were excellent inhibitors. An analog containing BFC-statine-Val-Ile-Met inhibited the endoprotease with a K1 = 64 nM. The equivalent pseudopeptide psi (CH2-NH) analog was almost as potent, indicating that the statine moiety simply represents a nonhydrolyzable linker.
Characterization of Two Thermostable Cyanobacterial Phytochromes Reveals Global Movements in the Chromophore-binding Domain during Photoconversion (2008)

Photointerconversion between the red light-absorbing (Pr) form and the far-red light-absorbing (Pfr) form is the central feature that allows members of the phytochrome (Phy) superfamily to act as reversible switches in light perception. Whereas the chromophore structure and surrounding binding pocket of Pr have been described, those for Pfr have remained enigmatic for various technical reasons. Here we describe a novel pair of Phys from two thermophilic cyanobacteria, Synechococcus sp. OS-A and OS-B', that overcome several of these limitations. Like other cyanobacterial Phys, SyA-Cph1 and SyB-Cph1 covalently bind the bilin phycocyanobilin via their cGMP phosphodiesterase/adenyl cyclase/FhlA (GAF) domains and then assume the photointerconvertible Pr and Pfr states with absorption maxima at 630 and 704 nm, respectively. However, they are naturally missing the N-terminal Per/Arndt/Sim domain common to others in the Phy superfamily. Importantly, truncations containing only the GAF domain are monomeric, photochromic, and remarkably thermostable. Resonance Raman and NMR spectroscopy show that all four pyrrole ring nitrogens of phycocyanobilin are protonated both as Pr and following red light irradiation, indicating that the GAF domain by itself can complete the Pr to Pfr photocycle. (1)H-(15)N two-dimensional NMR spectra of isotopically labeled preparations of the SyB-Cph1 GAF domain revealed that a number of amino acids change their environment during photoconversion of Pr to Pfr, which can be reversed by subsequent photoconversion back to Pr. Through three-dimensional NMR spectroscopy before and after light photoexcitation, it should now be possible to define the movements of the chromophore and binding pocket during photoconversion. We also generated a series of strongly red fluorescent derivatives of SyB-Cph1, which based on their small size and thermostability may be useful as cell biological reporters.
Cloning of human satellite III DNA: different components are on different chromosomes (1979)

Two fragments cloned from purified human satellite III DNA do not cross-react with each other. One fragment, for which a partial sequence is reported, hybridises to satellite II as well as III and is shown to originate on chromosome 1. The other cloned fragment originates from the Y chromosome. This fragment has undergone considerable changes in size when cloned in lambda gt WES lambda B. Human satellite III is shown to consist of a number of non-cross-reacting sequences which nevertheless are related by the presence of closely spaced Hin F1 sites.
Application performance and flexibility on exokernel systems (1997)

The exokernel operating system architecture safely gives untrusted software efficient control over hardware and software resou rces by separating management from protection. This paper describes an exokernel system that allows specialized applications to achieve high performance without sacrificing the performance of unm odified UNIX programs. It evaluates the exokernel architectur e by measuring end-to-end application performance on Xok, an exokernel for Intel x86-based computers, and by comparing Xok’s performance to the performance of two widely-used 4.4BSD UNIX systems (FreeBSD and OpenBSD). The results show that common unmodified UNIX applications can enjoy the benefits of exoker nels: applications either perform comparably on Xok/ExOS and the BSD UNIXes, or perform significantly better. In addition , the results show that customized applications can benefit subst antially from control over their resources (e.g., a factor of eight fo r a Web server). This paper also describes insights about the exokernel approach gained through building three different exokernel systems, and presents novel approaches to resource multiplexing.
Assembly of the TAN-1057 A/B Heterocycle from a Dehydroalanine Precursor (2000)

A tandem reaction process was used to form the tetrahydropyrimidinone core of the TAN-1057 A and B dipeptide antibiotics. Michael addition of ammonia to a dehydroalanine derivative, followed by intramolecular displacement of an S-methylisothiourea assembles the tetrahydropyrimidinone in one-step.
Zip Nucleic Acids: new high affinity oligonucleotides as potent primers for PCR and reverse transcription (2009)

Most nucleic acid-based technologies rely upon sequence recognition between an oligonucleotide and its nucleic acid target. With the aim of improving hybridization by decreasing electrostatic repulsions between the negatively charged strands, novel modified oligonucleotides named Zip nucleic acids (ZNAs) were recently developed. ZNAs are oligonucleotide-oligocation conjugates whose global charge is modulated by the number of cationic spermine moieties grafted on the oligonucleotide. It was demonstrated that the melting temperature of a hybridized ZNA is easily predictable and increases linearly with the length of the oligocation. Furthermore, ZNAs retain the ability to discriminate between a perfect match and a single base-pair-mismatched complementary sequence. Using quantitative PCR, we show here that ZNAs are specific and efficient primers displaying an outstanding affinity toward their genomic target. ZNAs are particularly efficient at low magnesium concentration, low primer concentrations and high annealing temperatures, allowing to improve the amplification in AT-rich sequences and potentially multiplex PCR applications. In reverse transcription experiments, ZNA gene-specific primers improve the yield of cDNA synthesis, thus increasing the accuracy of detection, especially for genes expressed at low levels. Our data suggest that ZNAs exhibit faster binding kinetics than standard and locked nucleic acid-containing primers, which could explain why their target recognition is better for rare targets.
Constant-Voltage-Bias Stress Testing of a-IGZO Thin-Film Transistors (2009)

Constant-voltage-bias (V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DS</sub> = V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">GS</sub> = 30 V) stress measurements are performed for a period of 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">5</sup> s on thin-film transistors (TFTs) with amorphous indium-gallium-zinc-oxide (IGZO) channel layers fabricated via RF sputtering using a postdeposition annealing temperature of 200degC, 250degC, or 300degC. Thermal silicon dioxide is employed as a TFT bottom-gate insulator. All SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> /IGZO TFTs tested exhibit the following: 1) a positive rigid log(I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</sub> )- V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">GS</sub> transfer curve shift; 2) a continuous drain-current decrease over the entire stress duration; and 3) recovery of the log(I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</sub> )-V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">GS</sub> transfer curve toward the prestressed state when the stressed TFT is left unbiased in the dark at room temperature for an extended period of time. The SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> /IGZO TFTs subjected to a higher postdeposition annealing temperature are more stable. A small (and typically negligible) amount of clockwise hysteresis is present in the log(I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</sub> ) -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">GS</sub> transfer curves of IGZO TFTs. These instability and hysteresis observations are consistent with a SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> / IGZO TFT instability mechanism involving electron trapping within the IGZO channel layer.
Autoprotolysis constants in nonaqueous solvents and aqueous organic solvent mixtures (1987)

Abstract
Embedded algebraic vector quantizers (EAVQ) with application to wideband speech coding (2002)

A new lattice vector quantization scheme, namely embedded algebraic vector quantizers (EAVQ), is proposed. This scheme makes use of spherical subsets of the rotated Gosset lattice RE/sub 8/ to constitute a vector-quantizer codebook. The codebook consists of several sub-codebooks and has an embedded structure. The codewords can be generated using an algebraic method and do not have to be stored. In combination with transform coded excitation (TCX) coding, this quantization technique is applied to 16 kbps wideband speech coding in order to quantize the so-called target signal in the frequency domain. Compared to a stochastic complex vector quantization scheme, EAVQ can achieve better performance and lead to significant savings of memory requirements.
Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors (2010)

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R-/-, whereas MC3R-/- weighed the same as WT. In a food demand protocol, DKO and MC4R-/- were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R-/-, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R-/- and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R-/-, DKO, and WT, but it was unexpectedly absent in MC3R-/-. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R-/- than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.
Anti-tumor Activity of Indole Derivatives (1977)

Sixty-one indole derivatives containing oxindole, spiro-oxindole, and condensed-ring indole were prepared and their antitumor activity was examined using a solid type of Ehrlich carcinoma. 1-Methyl-3-(1-methylthio-1-morpholinomethylene) oxindole was found to have some antitumor effect, but no other derivatives were found effective.
Impaired cutaneous wound healing in interleukin‐6‐deficient and immunosuppressed mice (2000)

It has been postulated that an inflammatory response after cutaneous wounding is a prerequisite for healing, and inflammatory cytokines, such as interleukin-6 (IL-6), might be intimately involved in this process. IL-6-deficient transgenic mice (IL-6 KO) displayed significantly delayed cutaneous wound healing compared with wild-type control animals, requiring up to threefold longer to heal. This was characterized by minimal epithelial bridge formation, decreased inflammation, and granulation tissue formation. Using electrophoretic mobility shift assays of wound tissue from IL-6 KO mice, decreased AP-1 transcription factor activation was shown compared with wild-type mice 16 h after wounding. In situ hybridization of wound tissue from wild-type mice revealed IL-6 mRNA expression primarily in the epidermis at the leading edge of the wound. Delayed wound healing in IL-6 KO mice was reversed with a single dose of recombinant murine IL-6 or intradermal injection of an expression plasmid containing the full-length murine IL-6 cDNA. Treatment with rmIL-6 also reconstituted wound healing in dexamethasone-treated immunosuppressed mice. The results of this study may indicate a potential use for IL-6 therapeutically where cutaneous wound healing is impaired.