gebhart/patrepeval huggingface dataset:
In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. (1993)

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]- phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resistance (MDR). The potency of GF120918 is assessed by dose-dependent sensitization of CHRC5, OV1/DXR and MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine respectively: GF120918 fully reverses multidrug resistance at 0.05 to 0.1 microM and is half maximally active at 0.02 microM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR phenotype. In CHRC5 cells, 0.01-0.1 microM GF120918 enhances the uptake of [3H]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being taken away from the culture medium showing that it is not, like verapamil, effluxed rapidly by P-glycoprotein. GF120918 effectively competes with [3H]azidopine for binding P-glycoprotein, pointing to this transport membrane protein as its likely site of action. After i.v. administration to mice, GF120918 penetrates thoroughly various organs that have a tissue level/blood level ratio above 10. It is eliminated from organs and blood with a half-time of approximately 2.7 h. It is well absorbed after p.o. administration. In mice implanted i.p. with the MDR P388/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitivity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin administered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarly, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) associated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the moderately MDR C26 tumor implanted s.c. as assessed by tumor size at day 19. GF120918 does not modify significantly the distribution or the elimination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interactions.
Fabrication of a biodegradable polysaccharide hydrogel with riboflavin, vitamin B2, as a photo‐initiator and L‐arginine as coinitiator upon UV irradiation (2009)

Abstract The objective of this study is to develop a completely natural material based photo‐initiation system for fabricating biologically compatible hydrogels, that is, free of any synthetic materials like conventional synthetic photo‐initiators. The resulting biodegradable hydrogels would be completely free of conventional toxic synthetic substances. Dextran‐based precursor was used as a model system for this study. The natural material based photo‐initiation system used riboflavin (vitamin B2) as photo‐initiator and L ‐arginine as a coinitiator. Dextran‐methacrylate precursor was prepared to introduce photosensitive unsaturated moieties into dextran for subsequent photo‐induced gel formation. Riboflavin alone could not initiate the photo‐crosslinking reaction of the dextran methacrylate solution upon UV irradiation. L ‐arginine, which can act as an electron donor in the photo‐initiation process, was used as a coinitiator. The optimum gel formulation conditions in terms of the concentrations of riboflavin and L ‐arginine as well as different pH media were extensively investigated. The dextran‐methacrylate hydrogels were formed well and fast at low riboflavin concentration range (0.2–1 wt %), and L ‐arginine promoted the photo‐initiation at all concentrations. The gelation was promoted most in the neutral pH and the least in the alkaline pH. The turbidity of the dextran‐methacrylate hydrogel precursor solution affected the polymerization because UV penetration was significantly hindered as the opacity of the solution increased. The swelling property and structural visualization of the prepared hydrogels were also investigated. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Kinetic Mechanism for p38 MAP Kinase (1997)

p38 has been shown to be a critical enzyme in the pro-inflammatory cytokine pathway and is a member of the mitogen-activated protein (MAP) kinase family. While the details for p38 activation and subsequent signal transduction have begun to be elucidated, little is known about the kinetic mechanism for p38. In this study, we have determined the kinetic mechanism for p38 MAP kinase. Data from initial velocity patterns in the presence and absence of a dead-end inhibitor and two triarylimidazole p38 inhibitors were consistent with an ordered sequential mechanism for p38 with protein substrate, glutathione S-transferase-activating transcription factor 2 (GST-ATF2), binding before ATP. The ATP analog, adenylyl methylenediphosphonate (AMP-PCP), and two triarylimidazoles were competitive inhibitors versus ATP and uncompetitive inhibitors versus GST-ATF2. Equilibrium binding studies utilizing a tritiated ATP-competitive inhibitor were also consistent with this mechanism and suggest an inability of ATP to bind to p38 in the absence of protein substrate. Moreover, the Michaelis constant for GST-ATF2 was 12-fold greater than the dissociation constant, indicating that the binding of ATP affected the binding of GST-ATF2. An ordered sequential mechanism with protein substrate binding first is unique to p38 compared to cyclic AMP-dependent protein kinase (cAPK) and most tyrosine kinases and helps to explain the interaction between enzyme, substrates, and inhibitors.
Effects of β-hydroxy-β-methylbutyrate on muscle damage after a prolonged run (2000)

This study examined the effects of supplemental beta-hydroxy-beta-methylbutyrate (HMB) on muscle damage as a result of intense endurance exercise. Subjects (n = 13) were paired according to their 2-mile run times and past running experience. Each pair was randomly assigned a treatment of either HMB (3 g/day) or a placebo. After 6 wk of daily training and supplementation, all subjects participated in a prolonged run (20-km course). Creatine phosphokinase and lactate dehydrogenase (LDH) activities were measured before and after a prolonged run to assess muscle damage. The placebo-supplemented group exhibited a significantly greater (treatment main effect, P = 0.05) increase in creatine phosphokinase activity after a prolonged run than did the HMB-supplemented group. In addition, LDH activity was significantly lower (treatment main effect, P = 0.003) with HMB supplementation compared with the placebo-supplemented group. In conclusion, supplementation with 3.0 g of HMB results in a decreased creatine phosphokinase and LDH response after a prolonged run. These findings support the hypothesis that HMB supplementation helps prevent exercise-induced muscle damage.
A variable rate multimodal speech coder with gain-matched analysis-by-synthesis (2002)

In general, a variable rate coder can obtain the same speech quality as a fixed rate coder, while reducing the average bit rate. We have developed a variable-rate multimodal speech coder with an average bit rate of 3 kb/s for a speech activity factor of 80% and quality comparable to the GSM full rate coder. The coder has four coding modes and uses a robust classification method involving the pitch gain, zero crossings, and a peakiness measure. Also the coder employs a novel gain-matched analysis-by-synthesis technique for very low rate coding of unvoiced frames and an improved noise-level-dependent postfilter. This paper describes the details of our algorithm and presents the results from subjective listening tests.
Synthesis and surfactant properties of novel fluoroalkylated amphiphilic oligomers (1996)

New fluoroalkylated oligomers containing morpholino groups are prepared by the reactions of fluoroalkanoyl peroxides with acryloyl morpholine; these oligomers show a good solubility in not only water but also common organic solvents, including non-polar solvents, and are applicable to non-ionic fluorinated amphiphilic oligosurfactants owing to reducing the surface tension of both water and in particular m-xylene quite effectively.
Electrochemistry of Nanopore Electrodes in Low Ionic Strength Solutions (2006)

The steady-state voltammetric behavior of truncated conical nanopore electrodes (20-200 nm orifice radii) has been investigated in low ionic strength solutions. Voltammetric currents at the nanopore electrode reflect both diffusive and migrational fluxes of the redox molecule and, thus, are strongly dependent on the charge of the redox molecule and the relative concentrations of the supporting electrolyte and redox molecule. In acetonitrile solutions, the limiting current for the oxidation of the positively charged ferrocenylmethyltrimethylammonium ion is suppressed at low supporting electrolyte concentrations, while the limiting current for the oxidation of the neutral species ferrocene is unaffected by the ionic strength. The dependence of the limiting current on the relative concentrations of the supporting electrolyte and redox molecule is accurately predicted by theory previously developed for microdisk electrodes. Anomalous values of the voltammetric half-wave potential observed at very small nanopore electrodes (<50 nm radius orifice radii) are ascribed to a boundary potential between the pore interior and bulk solution (i.e., a Donnan-type potential).
A mobile radio antenna system having a self-diplexing function (1979)

A coupled N-element antenna system on a mobile unit for simultaneous transmission and reception is discussed. A diplexer is required when an antenna for transmission and that for reception are installed with mutual coupling between them. An attempt is made to reduce coupling between the transmitting point and the receiving point by a lossless network and coupled antennas. The network is connected between the antenna and the input and output ports. The decoupled antenna is analyzed and theoretical and experimental results, which show the feasibility of the antenna system, are described.
The barrier-to-autointegration protein is a host factor for HIV type 1 integration (1998)

In vivo, retroviral integration is mediated by a large nucleoprotein complex, termed the preintegration complex (PIC). PICs isolated from infected cells display in vitro integration activity. Here, we analyze the roles of different host cell factors in the structure and function of HIV type 1 (HIV-1) PICs. PICs purified by size exclusion after treatment with high salt lost their integration activity, and adding back an extract from uninfected cells restored this activity. In parallel, the native protein-DNA intasome structure detected at the ends of HIV-1 by Mu-mediated PCR footprinting was abolished by high salt and restored by the crude cell extract. Various purified proteins previously implicated in retroviral PIC function then were analyzed for their effects on the structure and function of salt-treated HIV-1 PICs. Whereas relatively low amounts (5-20 nM) of human barrier-to-autointegration factor (BAF) protein restored integration activity, substantially more (5-10 microM) human host factor HMG I(Y) was required. Similarly high levels (3-8 microM) of bovine RNase A, a DNA-binding protein used as a nonspecific control, also restored activity. Mu-mediated PCR footprinting revealed that of these three purified proteins, only BAF restored the native structure of the HIV-1 protein-DNA intasome. We suggest that BAF is a natural host cofactor for HIV-1 integration.
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. (2006)

Immune cells within the brain display gene profiles that suggest heterogeneous, functional phenotypes that range from a pro-inflammatory, classical activation state to an alternative activation state involved in repair and extracellular matrix remodeling. Our data suggest that innate immune cells in AD may exhibit a hybrid activation state that includes characteristics of classical and alternative activation.
Detection of OOV words using generalized word models and a semantic class language model (2001)

This paper describes an approach to detect out-of-vocabulary words in spontaneous speech using a language model built on semantic categories and a new type of generalized word models consisting of a mixture of specific and general acoustic units. We demonstrate the construction of the generalized word models as replacements for surnames in a German spontaneous travel planning task GSST [1]. We show that the use of our generalized word models improves recognition accuracy in cases where out-of-vocabulary words appear and does not lead to a degradation of the overall recognition accuracy. In our experiments we measured recall and precision rates of OOV-detection which are close to their theoretic optimum. Furthermore, we compared the effect of using cross-word-triphones vs. using context-independent cross-word models. We show that when using generalized word models with cross-word-triphones, the expected number of consequential errors following an OOV word can be reduced significantly by 37%.
Conformation of thiocolchicine and two B-ring-modified analogs bound to tubulin studied with optical spectroscopy (1991)

The interaction of tubulin with thiocolchicine and two thiocolchicine analogues, one lacking the B ring and one with a six-membered B ring, has been studied by using near-UV and CD spectroscopies. Rapid, reversible binding of the latter analogue to tubulin demonstrates the ability of the colchicine binding site to accommodate the phenyltropone system with a more coplanar conformation than is present in free colchicine. There is no evidence, however, that bound thiocolchicine should have a much less twisted conformation than free thiocolchicine. Thiocolchicine and the bicyclic analogue appear to have approximately the same conformation of the phenyltropone system, in both the free and the bound states, suggesting that this conformation has an optimal arrangement of the phenyl and tropone rings for binding to tubulin. In contrast to colchicine and related derivatives, the three thiocolchicine analogues show pronounced near-UV CD bands upon association to tubulin. No simple relation could be found between the sign pattern of the CD components in the near-UV band of the thiocolchicinoid chromophore and its axial chirality.
Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. (1991)

Nude mice given inoculations s.c. of a human squamous carcinoma--HEp3 (1.5 x 10(6) cells/mouse)--developed invasive tumors that produced high levels of urokinase-type plasminogen activator (uPA) and metastasized predictably to the lungs and lymph nodes of the host. To investigate the role of uPA in invasion and metastasis, mice given inoculations of tumor cells were treated daily with s.c. injections of specific, anti-human uPA antibodies (rabbit polyclonal, 150 inhibitory units; mouse monoclonal, 3000 inhibitory units/mouse/day). Control mice received either saline or preimmune rabbit immunoglobulins. A total of approximately 50 mice was studied. The tumors were surgically excised 10 to 17 days postinoculation when weighing 1 to 2 g. Antibody administration was discontinued after tumor excision. Two strategies were used: (a) following the removal of tumors the mice were maintained and observed until respiratory distress, indicative of lung metastasis, was evident; or (b) their lungs were examined for evidence of metastasis on the day of tumor removal. While histological sections of s.c. tumors excised from control mice indicated extensive local invasion, evidence of invasion was absent in most tumors excised from mice in which tumor uPA was inhibited by the antibody (P less than 0.025). The inhibition of local invasion did not, however, lead to a reduced incidence of distant metastasis. Since we found that the presence of HEp3 tumors in mice elicits a pronounced granulocytosis, we propose that this response may facilitate the spread of tumor cells by a mechanism independent of endogenous tumor proteases.
Mechanisms Underlying the Exquisite Sensitivity of Candida albicans to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes (2014)

Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress--a phenomenon we term stress pathway interference--lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy. Importance: The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.
Engineered CD3 antibodies for immunosuppression (2003)

Organ transplantation offers the potential to improve quality of life and prolong survival for increasing numbers of patients with organ failure, and bone marrow or peripheral stem cell transplantation may constitute the only curative approach for patients with select haematological diseases. Since the early sixties, heterologous polyclonal sera against human thymocytes or lymphocytes (ATG or ALG) are employed for immunosuppression, but significant progress in transplantation medicine was achieved with the introduction of novel oral immunosuppressive agents like calcineurin inhibitors, mycophenolate mofetil and – more recently – sirolimus. However, acute rejection episodes or high risk clinical situations, e.g. in pretransplanted patients may require even more pronounced immunosuppression. In these situations, several monoclonal antibodies against defined antigens broaden the therapeutic armentarium today [1]. Among these are antibodies against the IL-2 receptor (CD25) or CD3, and antibodies against other antigens are expected to follow along this line [2].
Haynesville Shale—One Operator's Approach to Well Completions in this Evolving Play (2009)

Abstract The Haynesville-Bossier (HB) Shale is an extensive gas resource that has received significant publicity over the past two years, and is currently being developed by numerous operators. Since the HB is a relatively new play, it is anticipated that there will be many learnings in the future that will further improve well completions. However, the more quickly data-sharing and adoption of best practices occurs, the more effectively this tremendous resource will be developed. This paper will describe some of the reservoir and completion concerns that have driven this operator's current completion philosophy, particularly as they affect well stimulation. Some of the topics described in the paper include: Consideration of vertical and horizontal wellboresHorizontal lateral placement within the vertical pay sectionOrientation of wellbores with respect to anticipated fracture azimuthFracture stage isolation considerationsPerforation strategyDesign and implementation of hydraulic fracture treatmentsConsiderations to accommodate elevated temperatures and stresses in the frac designManagement of closure stresses on proppant Hydraulic fractures are the key to unlock the potential of most low permeability shale reservoirs such as the Haynesville Shale, and many drilling and completion decisions must be made to ensure successful placement of the stimulation treatment. Although the approach used on initial wells is expected to evolve with future experimentation and optimization, it is hoped that this early discussion of current design philosophy will be useful to the SPE audience, and allow the industry to optimize their Haynesville completions in a timelier manner.
IV. Visceral afferents: an update (2003)

The number of articles published in American Journal of Physiology Gastrointestinal and Liver Physiology over the last 15 years on visceral afferents has increased dramatically. This reflects our growing ability to study the characteristics and function of visceral afferents and also the recognition of their importance in the maintenance of homeostasis and also in a number of pathophysiological conditions. However, there are several key unanswered questions concerning the function of visceral afferents that await further investigation.
Targeted elimination of zygotic messages in Xenopus laevis embryos by modified oligonucleotides possessing terminal cationic linkages (2000)

We have designed a new class of modified antisense oligodeoxyribonucleotides (ODN) consisting of a central contiguous stretch of 6-8 unmodified nucleotides flanked by 3'- and 5'-regions containing several nucleotides joined by cationic internucleoside linkages. The positive charge results from modification of the internucleoside linkages as N, N -diethylethylene-diamine phosphoramidates. These zwitterionic compounds show improved antisense activity in both Xenopus oocytes and embryos compared to our previously described chimeric oligonucleotides possessing neutral terminal internucleoside linkages. Using the localized maternal mRNA An2 as a target, we have shown that chimeric oligonucleotides with terminal positive charges are very effective in the sequence-specific elimination of maternal messages present in both oocytes and embryos. In addition, using the embryonic mRNA GS17 as a target, we have shown that these oligonucleotides can direct RNase H-mediated cleavage of messages produced at the onset of zygotic transcription, after the mid-blastula stage. These new compounds should be useful in attenuating embryonic gene expression to study the role of specific proteins in early vertebrate development.