gebhart/patrepeval huggingface dataset:
Synergistic effect of amphotericin B and tyrosol on biofilm formed by Candida krusei and Candida tropicalis from intrauterine device users (2014)

The presence of intrauterine contraceptive devices (IUDs) provides a solid surface for attachment of microorganisms and an ideal niche for the biofilm to form and flourish. Vaginal candidiasis is often associated with the use of IUDs. Treatment of vaginal candidiasis that develops in connection with IUD use requires their immediate removal. Here, we present in vitro evidence to support the use of combination therapy to inhibit Candida biofilm. Twenty-three clinical Candida isolates (10 C. krusei and 13 C. tropicalis) recovered from endocervical swabs obtained from IUD and non-IUD users were assessed for biofilm-formation ability. The rate of isolation of Candida did not differ significantly among IUD and non-IUD users (P = 0.183), but the biofilm-formation ability of isolates differed significantly (P = 0.02). An in vitro biofilm model with the obtained isolates was subjected to treatment with amphotericin B, tyrosol, and a combination of amphotericin B and tyrosol. Inhibition of biofilm by amphotericin B or tyrosol was found to be concentration dependent, with 50% reduction (P < 0.05) at 4 mg/l and 80 μM, respectively. Hence, a combination effect of tyrosol and amphotericin B was studied. Interestingly, approximately 90% reduction in biofilm was observed with use of 80 μM tyrosol combined with 4 mg/l amphotericin B (P < 0.001). This represents a first step in establishing an appropriate antibiofilm therapy when yeasts are present.
Interprocedural Data Flow Based Optimizations for Distributed Memory Compilation (1997)

Data parallel languages like High Performance Fortran (HPF) are emerging\nas the architecture independent mode of programming distributed memory\nparallel machines. In this paper, we present the interprocedural\noptimizations required for compiling applications having irregular data\naccess patterns, when coded in such data parallel languages. We have\ndeveloped an Interprocedural Partial Redundancy Elimination (IPRE)\nalgorithm for optimized placement of runtime preprocessing routine and\ncollective communication routines inserted for managing communication in\nsuch codes. We also present three new interprocedural optimizations: \nplacement of scatter routines, deletion of data structures and use of\ncoalescing and incremental routines. We then describe how program slicing\ncan be used for further applying IPRE in more complex scenarios. We have\ndone a preliminary implementation of the schemes presented here using the\nFortran~D compilation system as the necessary infrastructure. We present\nexperimental results from two codes compiled using our system to\ndemonstrate the efficacy of the presented schemes. \n(Also cross-referenced as UMIACS-TR-95-108)
An inhibitor of plasminogen activation from human placenta. Purification and characterization. (1987)

Placental extracts contain inhibitors of human urinary urokinase. These extracts form a heterogeneous population of complexes with 125I-urokinase that are recognizable by changes in gel filtration profile and mobility during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Treatment with reducing agents eliminated the size heterogeneity without loss of activity, thereby allowing the placental inhibitor to be purified. Active inhibitor has been isolated in apparently homogeneous form after an eight-step procedure that included salt extraction, ammonium sulfate fractionation, column chromatography on CM-cellulose, DEAE-Sepharose, and hydroxylapatite, chromatofocusing, preparative gel electrophoresis, and hydrophobic chromatography. The purified inhibitor has Mr = 47,000. The inhibitor is relatively specific for plasminogen activators since it does not inhibit the action of plasmin, factor XIIa, plasma kallikrein, or thrombin. The inhibitor forms complexes with 1:1 stoichiometry that block the active sites of urokinase (but not prourokinase) and both one- and two-chain forms of tissue plasminogen activator. The stability of these complexes in sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggest that they are based on covalently bonded structures. Although both types of plasminogen activator are inhibited, the rate of interaction is significantly faster with urokinase, tissue plasminogen activator being inhibited less efficiently. The complexes formed can be dissociated by mild alkali or hydroxylamine, thereby regenerating both enzymes and inhibitor at their original molecular weights. The results suggest that the complexes are stabilized by ester-like bonds; these might involve the hydroxyl of serine at the active site of the proteases and a carboxyl group in the inhibitor.
Valve-based flow focusing for drop formation (2009)

Microfluidic devices can produce highly monodisperse drops at kilohertz rates using flow-focus drop formation. We use single-layer membrane valves to control, in real time, the dimensions of the flow-focus drop makers. This allows drop size and frequency to be controlled in real time and without adjusting flow rates.
Benefits and risks of estrogen replacement therapy (1995)

Estrogen replacement therapy (ERT) has been shown to reduce the risk of cardiovascular disease (CVD) and osteoporosis in postmenopausal women. Studies also indicate a reduced risk of stroke and its consequent mortality among estrogen users, and ERT may also have a role in reducing the risk of Alzheimer's disease and increasing a woman's overall quality of life. On the negative side, some studies show a small duration-related risk of breast cancer with estrogen use and a significant increase in endometrial cancer; the latter is virtually eliminated with the addition of a progestin to the regimen. Although the definitive answer is not yet available, recent epidemiologic data suggest no reduction in protection against CVD and bone fracture with the addition of progestin, which is referred to as hormone replacement therapy, as opposed to using estrogen alone. A woman's potential risks associated with ERT or hormone replacement therapy must be weighed against her lifetime risks of developing CVD, stroke, and bone fracture. The reduction in mortality and morbidity rates with hormone use is generally viewed to be substantial and cost-effective. Health care professionals have an important role in shaping their patients' attitudes. Patients need more information from their physicians about the risks and benefits of estrogen therapy.
Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. (1997)

To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 +/- 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-alpha2-antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-alpha1-antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P > .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.
A mutant insulin receptor with defective tyrosine kinase displays no biologic activity and does not undergo endocytosis. (1987)

The cDNAs encoding the normal human insulin receptor (HIRc) and a receptor that had lysine residue 1018 replaced by alanine (A/K1018) were used to transfect Rat 1 fibroblasts. Lysine 1018 is a critical residue in the ATP binding site of the tyrosine kinase domain in the receptor beta-subunit. Untransfected Rat 1 cells express 1700 endogenous insulin receptors. Expressed HIRc receptors had levels of insulin-stimulable autophosphorylation in vitro comparable to normal receptors, whereas A/K1018 receptors had less than 1% of that activity. Stimulation by insulin of HIRc receptors in situ in intact cells led to phosphorylation of beta-subunit tyrosine residues and activation of tyrosine kinase activity that could be preserved and assayed in vitro after receptor purification. In contrast, A/K1018 receptors showed no such activation, either of autophosphorylation or of kinase activity toward histone. Cells expressing HIRc receptors display enhanced sensitivity to insulin of 2-deoxyglucose transport and glycogen synthase activity. This increased sensitivity was proportional to insulin receptor number at low but not at high levels of receptor expression. A/K1018 receptors were unable to mediate these biologic effects and actually inhibited insulin's ability to stimulate glucose transport and glycogen synthase through the endogenous Rat 1 receptors. Expressed HIRc receptors mediated insulin internalization and degradation, whereas A/K1018 receptors mediated little, if any. Endocytotic uptake of the expressed A/K1018 insulin receptors was also markedly depressed compared to normal receptors. Unlike HIRc receptors, A/K1018 receptors also fail to undergo down-regulation after long (24 h) exposures to high (170 nM) concentrations of insulin. We conclude the following. 1) Normal human insulin receptors expressed in Rat 1 fibroblasts display active tyrosine-specific kinase, normal intracellular itinerary after endocytosis, and normal coupling to insulin's biologic effects. 2) A receptor mutated to alter the ATP binding site in the tyrosine kinase domain had little if any tyrosine kinase activity. 3) This loss of kinase activity was accompanied by a nearly complete lack of both endocytosis and biologic activity.
Oncolytic Vesicular Stomatitis Viruses Are Potent Agents for Intravesical Treatment of High-Risk Bladder Cancer (2008)

Bladder cancer is the second most common genitourinary malignancy. At initial diagnosis, approximately 70% of cases are non-muscle-invasive; however, current treatment options for superficial disease are of limited efficacy because many patients will develop recurrent tumors. The purpose of this study was to examine two replication-competent oncolytic vesicular stomatitis virus (VSV) strains as intravesical agents in an orthotopic murine model of high-grade bladder cancer. Four human bladder cancer cell lines (RT4, MGH-U3, UM-UC3, and KU-7) were treated with either wild-type VSV or a mutant Delta51M variant (AV3) in vitro. Both wild-type VSV and AV3, which has an impaired ability to shutdown innate immunity, preferentially killed the more aggressive, IFN-nonresponsive cell lines UM-UC3 and KU-7, whereas IFN-responsive RT4 and MGH-U3 cells were less susceptible. In vivo, KU-7-luc bladder tumor cells, which stably express firefly luciferase, were inoculated into nude mice by intravesical instillation and tumor growth was quantified using bioluminescence imaging. Mice with established xenografts were administered VSV intravesically on days 4, 9, and 14, and necropsy was performed after 3 weeks. AV3 as well as wild-type VSV significantly inhibited KU-7-luc tumor growth by 90% (AV3) and 98% (wild-type), respectively, as compared with controls treated with UV-inactivated VSV. Despite using immunocompromised hosts, there was no evidence of toxicity in either group. In conclusion, VSV instillation therapy showed promising antitumor activity and safety in an orthotopic model of bladder cancer. These findings provide preclinical proof-of-principle for the intravesical use of VSV against non-muscle-invasive bladder cancer, especially in IFN-refractory patients.
Recent Advances in the Search for the N-Opioidergic System: Isolation and Distribution of Endomorphins in the Central Nervous System (2002)

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) have the highest affinity and selectivity for the mu-opioid receptor (MOP-R) of all known mammalian opioids. They were isolated from bovine and human brain, and are structurally distinct from the other endogenous opioids. Both EM-1 and EM-2 have potent antinociceptive activity in a variety of animal models of acute, neuropathic and allodynic pain. They regulate cellular signaling processes in a manner consistent with MOP-R-mediated effects. The EMs are implicated in the natural modulation of pain by extensive data localizing EM-like immunoreactivity (EM-LI) near MOP-Rs in several regions of the nervous system known to regulate pain. These include the primary afferents and their terminals in the spinal cord dorsal horn, where EM-2 is well-positioned to modulate pain in its earliest stages of perception. In a nerve-injury model of chronic pain, a loss of spinal EM2-LI occurs concomitant with the onset of chronic pain. The distribution of the EMs in other areas of the nervous system is consistent with a role in the modulation of diverse functions, including autonomic, neuroendocrine and reward functions as well as modulation of responses to pain and stress. Unlike several other mu opioids, the threshold dose of EM-1 for analgesia is well below that for respiratory depression. In addition, rewarding effects of EM-1 can be separated from analgesic effects. These results indicate a favorable therapeutic profile of EM-1 relative to other mu opioids. Thus, the pharmacology and distribution of EMs provide new avenues both for therapeutic development and for understanding the neurobiology of opioids.
Elucidation of the structure of an alanine‐lacking core tetrasaccharide trisphosphate from the lipopolysaccharide of Pseudomonas aeruginosa mutant H4 (1999)

Lipopolysaccharide (LPS) of Pseudomonas aeruginosa rough mutant H4 was isolated by hot water/phenol extraction followed by a modified phenol/chloroform/petroleum ether procedure. Upon SDS/PAGE, the LPS showed a strong major band corresponding to the expected rough-type LPS. Additional faint high molecular-mass bands revealed that the O-chain was present, indicating that the H4 mutant is genetically unstable. Mild acid hydrolysis of the LPS removed lipid A and released a phosphorylated core oligosaccharide that was purified by gel-permeation chromatography and high-performance anion-exchange liquid chromatography. The oligosaccharide contained two residues of L-glycero-D-manno-heptose (Hep) and one residue each of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) and GalNAc. Upon matrix-assisted laser desorption/ionization mass spectroscopy in the negative ion mode, the main fraction expressed a peak for the molecular ion [M-H]- at m/z 1106.41, which was compatible with a carbamoylated, trisphosphorylated tetrasaccharide. The structure was further investigated using one- and two-dimensional homonuclear and heteronuclear correlated NMR spectroscopy at pD 3 and, after borohydride reduction, at pD 9. The NMR data of the two phosphorylated tetrasaccharides recorded at different pD allowed determination of the positions of the three phosphate (P) groups and the carbamoyl group (Cm) thus establishing the following structure of the core oligosaccharide: [equation: see text] Two unusual structural features in the core oligosaccharide of P. aeruginosa were identified for the first time, i.e. the replacement of an amide-linked alanyl group in GalN with an acetyl group and the phosphorylation at position 6 of HepII.
Paralleling GaN HEMTs for diode-free bridge power converters (2015)

GaN devices have superior performance over Sibased devices, and high voltage normally-off GaN HEMTs with cascode structure have been available for industry application as they can be easily driven by mature commercial Si-MOSFET drivers. Due to the very fast switching speed, the PCB layout and driver circuit design should be very careful to keep the parasitic parameters as small as possible. Paralleling semiconductor devices is an effective and simple way for higher power application. It is very challenging to parallel GaN HEMTs in hard-switching bridge power converter application, especially for discrete leaded package devices. However, leaded packages are still dominant in industrial applications because of their simplicity for PCB assembly and capability for a wide variety of heat-sinking techniques. In this paper, a solution to paralleling GaN HEMTs for diode-free bridge power converters is proposed, and GaN device driver design is discussed. The partial phase method is also suitable for the low power application to improve the efficiency. Simulations of driving circuit and experimental results on a 5 kW half bridge operating in synchronous boost mode with 4 paralleling GaN HEMTs are provided for validation.
P-selectin mediates spontaneous leukocyte rolling in vivo (1993)

Rolling represents the initial step leading to leukocyte extravasation from blood vessels during an inflammatory reaction. In vitro studies indicate that P-selectin could be one of the ligands on endothelium involved in the rolling phenomenon, although the molecular determinants responsible for this transient attachment in vivo are still undefined. Our objectives were to develop a blocking monoclonal antibody against canine P-selectin and to use it to investigate the role of P-selectin in leukocyte rolling in vivo using the technique of intravital microscopy. P-selectin was immunoaffinity purified from canine platelets and used for the production of monoclonal antibodies. One of the hybridomas generated, MD6, was shown by enzyme-linked immunosorbent assay and by flow cytometry to bind preferentially to stimulated platelets and to completely prevent binding of stimulated platelets to neutrophils. Visualization of canine mesenteric venules by intravital microscopy showed that administration of MD6 resulted in a marked inhibition in the number of rolling leukocytes (18.96 +/- 9.92 v 156.40 +/- 19.50 leukocytes/min, P &lt; .05; 88.3% +/- 6.0% inhibition). Control antibody MD3 (which recognizes a nonfunctional epitope of canine P- selectin) had no effect on the number of rolling leukocytes or on their rolling velocity. These results show for the first time that P-selectin plays an essential role in leukocyte rolling in vivo, and therefore may be a key participant of the inflammatory response.
Liposome mitigation of curcumin inhibition of cardiac potassium delayed-rectifier current (2012)

Background: The duration of the QT interval on the standard electrocardiogram (ECG) is measured from the beginning of the QRS complex (depolarization of the cardiac myocyte) to the end of the T-wave (completion of the repolarization phase of the cardiac myocyte). Repolarization is a result of currents generated by the outward flow of K + through the K + channels. Obstruction of ion flow in the channel leads to delayed repolarization, evidenced by a prolonged QT interval. Clinically, this is known as the long QT syndrome (LQTS), which, when expressed, can lead to severe cardiac arrhythmias and sudden death. Obstruction of K + ion flow can result from gene mutations (eg, the human ether-a-go-go-related gene [hERG]) resulting in phenotypic abnormalities in K + channels and/or common structurally diverse drugs. These gene abnormalities or drug-induced changes result in decreased cardiac delayed-rectifier K + current (I Kr , or KV11.1) in congenital or acquired LQTS, respectively. Increased risk of LQTS is a major drug development hurdle, and many drugs have been withdrawn during preclinical development, assigned black box warnings following approval, or withdrawn from the market. Autosomal recessive or dominant LQTS based upon 500 possible mutations in ten different genes coding for K + channels has an incidence of 1:3000 or about 100,000 persons in the USA. Prolonged QT intervals or risk of LQTS occurs in 2.5% of the asymptomatic US population. The probability of cardiac death in patients with asymptomatic congenital LQTS who are concomitantly medicated with LQTS-inducing drugs appears to have increased. Methods: E-4031 (methanesulfanalide), terfenadine (Seldane ® ), curcumin, liposomal curcumin, empty liposomes, empty liposomes vortexed with E-4031, or terfenadine and empty liposomes vortexed with curcumin were assayed for their effects on the K + -selective I Kr tail current inhibition using human embryonic kidney (HEK 293) cells stably transfected with the hERG gene via the whole-cell manual patch clamp technique. Results: E-4031, terfenadine, and curcumin inhibit I Kr channel following nM-to-µM exposures. Empty liposomes had no effect on I Kr . Both the liposomal curcumin formulation and vortexed mixtures of empty liposomes and curcumin prevented the I Kr inhibitory effect of curcumin in a dose-dependent manner. Empty liposomes vortexed with E-4031 prevented the effect of E-4031 to a lesser extent, while empty liposomes vortexed with terfenadine did not alter its I Kr inhibitory activity. Conclusion: Curcumin causes an inhibition of the hERG tail current density. The liposomal curcumin formulation, as well as a mixture of empty liposomes with curcumin or with E-4031, blocked drug-induced IKr inhibition. However, empty liposomes mixed with terfenadine did not alter terfenadine’s I Kr inhibitory effects. The liposomes protected against the inhibitory effect of some compounds on the K + -selective I Kr current, independent of their potency. Keywords: torsade de point, hERG, ion channel
Evidence for a repeating 3,4-dihydroxyphenylalanine- and hydroxyproline-containing decapeptide in the adhesive protein of the mussel, Mytilus edulis L. (1983)

Previous work has shown that the permanent adhesive of the marine mussel Mytilus edulis is a protein containing large amounts of hydroxyproline (13%) and 3,4-dihydroxyphenylalanine (Dopa, 11%). The protein also known as the polyphenolic protein is produced and stored in the exocrine phenol gland of the mussel and deposited onto marine surfaces by the animal's foot during the formation of new adhesive plaques. The adhesive protein has been purified by a combination of ion exchange on sulfonylpropyl-Sephadex and gel filtration on low surface energy chromatographic media. Polyacrylamide gel electrophoresis of the protein at acidic pH shows it to consist of two components having a molecular weight of about 130,000. Treatment of the protein with clostridial collagenase reduced the molecular weight by less than 10%. The collagenase-resistant fragment contains most or all of the Hyp and Dopa. Trypsin treatment of the polyphenolic protein results in extensive degradation. The major tryptic peptide (80%) contains 10 amino acids including Hyp and Dopa and was shown by sequence analysis to be H2N-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Dopa-Lys-COOH. Calculations suggest that this and related sequences may be repeated as often as 75 times in the polyphenolic protein.