gebhart/patrepeval huggingface dataset:
Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to <i>d</i>‐tubocurarine (1979)

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.
Efficiently Updating Materialized Views (1999)

Query processmg can be sped up by keeping frequently accessed users' views materlahzed However, the need to access base relations m response to queues can be avoided only If the materlahzed view ls adequately maintainedWe propose a method m which all database updates to base relations are first filtered to remove from consideration those that cannot possibly affect the view The condltlons given for the detection of updates of this type, called arrelevant updates, are necessary and sufficient and are mdependent of the database state For the remammg database updates, a dzfferentlal algonthm can be apphed to re-evaluate the view expression The algonthm proposed exploits the knowledge provided by both the view defimtlon expression and the database update operations
Role for Peroxisome Proliferator-Activated Receptor α in Oxidized Phospholipid–Induced Synthesis of Monocyte Chemotactic Protein-1 and Interleukin-8 by Endothelial Cells (2000)

The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPARalpha ligand-binding domain by MM-LDL, Ox-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycero-phosphocholine and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine; these lipids also activated a consensus peroxisome proliferator-activated receptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPARalpha with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPARgamma agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPARalpha null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPARalpha in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.
Platelet aggregation inhibitory activity of tea extracts. (1991)

Inhibitory effect of the hot water extracts prepared from various kinds of teas on the platelet aggregation induced by collagen or ADP was investigated by use of turbidimetry.
<b>Post‐transcriptional silencing of chalcone synthase in petunia using a geminivirus‐based episomal vector</b> (1998)

A vector that produces DNA replicons (multicopy plant episomes) was constructed using elements of the geminivirus tobacco yellow dwarf virus (TYDV). All plant cells contain an integrated chromosomal T-DNA copy of the TYDV elements that provides a template for the production of episomes in the cell nucleus. Transgenic Petunia hybrida plants containing a CaMV 35S promoter-driven chalcone synthase A (ChsA) gene cloned into the episomal vector produced flowers with a white-spotted phenotype at high frequency. The spots were found at random locations in the petals and occurred in corresponding positions in both the upper and lower epidermis, indicating that the spots were non-clonal. The spotted phenotype was somatically stable and was inherited through meiosis. In white-spotted flower tissue, steady-state ChsA mRNA levels were downregulated but rates of RNA transcription were unaffected, suggesting that the phenotype resulted from post-transcriptional gene silencing of the endogenous and episomal ChsA genes. Increases in both the frequency and extent of gene silencing in flowers correlated with increases in episome copy number in mature flowers, flower buds and young and fully expanded leaves. Relatively small increases in episome copy number (less than threefold) appeared sufficient to trigger the gene-silenced phenotype.
Amorphous Zr&ndash;Al&ndash;TM (TM=Co, Ni, Cu) Alloys with Significant Supercooled Liquid Region of Over 100 K (1991)

Amorphous alloys exhibiting a wide supercooled liquid region above 100 K were found to form in a compositional range from 0 to 3%Co, 0 to 15%Ni and 10 to 23%Cu in Zr65Al7.5Cu2.5(Co1−x−yNixCuy)25 system by melt spinning. The temperature span ΔTx(=Tx−Tg) between glass transition temperature (Tg) and crystallization temperature (Tx) reaches as large as 127 K for Zr65Al7.5Ni10Cu17.5. The Tg and hardness (Hv) increase from 622 to 685 K and 426 to 502 with increasing Co content while the Tx decreases from 749 to 690 K, resulting in the decrease of ΔTx from 127 to 30 K with increasing Co content. The compositional effect on Tg, Tx, ΔTx and Hv indicates that there is no close relation between the magnitude of the attractive bonding force and the stability of the supercooled liquid. The high stability of the supercooled liquid against the nucleation and growth of a crystalline phase in the limited composition range seems to result from a highly dense random packing structure consisting of atoms with an optimum atomic size ratio and a large negative enthalpy of mixing.
Short‐term phytohaemagglutinin‐activated mononuclear cells induce endothelial progenitor cells from cord blood CD34<sup>+</sup> cells (2001)

Endothelial progenitor cells (EPCs) were recently demonstrated to exist in human cord blood. Phytohaemagglutinin (PHA), a potent mitogen for mononuclear cells was used to induce EPCs from unsorted cord blood mononuclear cells (CBMCs). Adherent cells in clusters appeared approximately 24 h after CBMCs were cultured in plain Roswell Park Memorial Institute media containing 10% fetal bovine serum (culture media) and PHA. Adherent cells were further propagated for 1 week in plain culture media. Flow cytometry and Di-I staining analyses showed that CD45-, CD34+, Flk-1+, CD31+ or VE-cadherin+ EPCs were induced and that they were mainly from the CD34+ cell compartment. When enriched CD34+ cells alone were stimulated with culture supernatant of the PHA-activated CBMCs, they neither proliferated readily nor induced EPCs. Because EPCs first appeared within the clustering cells that expressed high levels of fibronectin and vascular endothelial growth factor (VEGF), our data suggest that both cell-cell/cell-matrix interaction and the local VEGF action are important in the induction of EPCs. Thus, we demonstrate for the first time that EPCs are induced from human cord blood stem cell populations that interact with neighbouring PHA-activated CBMCs. This finding may have a significant implication in inflammatory cell-mediated vasculogenesis and angiogenesis in vivo.
Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid. (1995)

Both normal and malignant prostatic epithelial cells in culture secrete urokinase-type plasminogen activator (u-PA) into the culture medium. u-PA has been shown to have a direct association with invasive and metastatic potential of many types of cancers. We propose that prostate cancer has the intrinsic ability to invade and metastasize because of its inherent ability to secrete the serine protease u-PA. We further propose that in prostate cancer, u-PA is the key enzyme which occupies a place at the apex of the proteolytic cascade and initiates the degradative process. Subsequently, collagenases are recruited after activation of procolla-genases by another serine protease plasmin formed by the activation of plasminogen by u-PA. Extracellular proteolysis involving plasmin can cause massive degradation of the extracellular matrix. We show that u-PA alone can use fibronectin as a substrate and degrade it, but u-PA alone did not degrade laminin. Serum-free conditioned medium from DU-145 human prostatic carcinoma cells has the ability to degrade both fibronectin and laminin. However, treatment of cultures with 1 microM all-trans retinoic acid (RA) for 48 h reduced the ability of serum-free conditioned medium to cause u-PA-mediated degradation of fibronectin and laminin. Thus, RA had a protective effect on these extracellular matrix glycoproteins. Treatment of cells with RA also decreased their ability to invade Matrigel in the in vitro invasion assay in a dose-dependent manner. RA at the 0.5, 1, and 10 microM level reduced invasion to 65.7%, 46.7%, and 34.3% of control, respectively. RA reduced extracellular proteolysis and thus inhibited extracellular matrix degradation and invasion. These results may also explain one mechanism by which retinoids inhibit invasion and metastasis in vitro and in vivo. These studies have important translational value in the chemoprevention of progression of prostatic intraepithelial neoplasia to invasive carcinoma.
Thiol‐blocking electrophiles interfere with labeling and detection of protein sulfenic acids (2013)

Cellular exposure to reactive oxygen species induces rapid oxidation of DNA, proteins, lipids and other biomolecules. At the proteome level, cysteine thiol oxidation is a prominent post-translational process that is implicated in normal physiology and numerous pathologies. Methods for investigating protein oxidation include direct labeling with selective chemical probes and indirect tag-switch techniques. Common to both approaches is chemical blocking of free thiols using reactive electrophiles to prevent post-lysis oxidation or other thiol-mediated cross-reactions. These reagents are used in large excess, and their reactivity with cysteine sulfenic acid, a critical oxoform in numerous proteins, has not been investigated. Here we report the reactivity of three thiol-blocking electrophiles, iodoacetamide, N-ethylmaleimide and methyl methanethiosulfonate, with protein sulfenic acid and dimedone, the structural core of many sulfenic acid probes. We demonstrate that covalent cysteine -SOR (product) species are partially or fully susceptible to reduction by dithiothreitol, tris(2-carboxyethyl)phosphine and ascorbate, regenerating protein thiols, or, in the case of ascorbate, more highly oxidized species. The implications of this reactivity on detection methods for protein sulfenic acids and S-nitrosothiols are discussed.
Laser and Micro-Plasma Welding of Single Crystal Blades: Advantages of Total Process Control (1993)

The single crystal superalloys, used in the manufacture of advanced gas turbine blades, are known to suffer from poor weldability and have a tendency to form cracks during and after welding. These cracks are largely related to the amount of heat input and metallurgical reactions that occur in the Heat Affected Zone (HAZ) adjacent to the weld. Experience has shown that cracks can be avoided by minimizing the HAZ through the use of proper heat management or process control. Automation systems can offer the level of process control necessary to significantly reduce weld cracking. The systems have proven to be more repeatable, reliable, and efficient, compared to conventional techniques or earlier attempts at automation. In order to succeed, welding automation requires a complete integration of the process, consisting of tooling, robotic accuracy, vision measurement system, filler material, and welding parameter control. With the proper process control technology, it is possible to weld the tips of single crystal blades with difficult to weld oxidation resistant alloys as well as repair conventional compressor, high pressure and low pressure turbine blades. This paper describes the welding of LT101 single crystal gas producer (GP) blade tips with highly alloyed filler metals for greater oxidation resistance. Results are presented for blades welded using a Laser beam with powder feed and compared to those welded using Micro-Plasma with the same filler alloys in wire form. The experience emphasizes the need for proper selection and integration of the welding processes, and confirms the importance of total process control to achieve the desired results in difficult and unique welding applications.
Gene transcription during in vitro activation of human B lymphocytes with <i>Staphylococcus aureus</i> Cowan I strain. (1990)

With the use of nuclear transcription run-off assays we have determined the kinetics of transcriptional activity for the c-fos, c-myc, DR beta, DQ beta, (TfR), Blast-1, and Ig kappa genes in human tonsillar B lymphocytes of high to intermediate density after stimulation with Staphylococcus aureus Cowan I strain (SAC). Nuclei were isolated at various times after stimulation with SAC. Stimulation with SAC resulted in significant increase in the transcription of all of the genes. Maximum expression of the c-fos, transferrin receptor, DR beta, and DQ beta genes was obtained within 0.5 h after stimulation. Maximum expression of c-myc and Blast-1 was obtained within 3 h. Peak expression of Ig kappa was observed at 8 h. Transcriptional activities of all genes examined, except for the Blast-1 and Ig kappa, decreased rapidly after their respective peaks; they remained at higher levels than their base line. Inhibition of protein synthesis by cycloheximide did not significantly affect the kinetics of transcription of these genes. These data demonstrate the cascade of transcriptional activity of various genes associated with human B cell activation and indicate that the induction of their transcription is independent of de novo protein synthesis.
Solid dispersions of clofazimine with improved dissolution. (1993)

Clofazimine is one of the important drugs used in the multi drug therapy of leprosy. Being highly lipophilic, it is practically insoluble in water and and has a variable oral bioavailability in man.Physical mixtures and solid dispersions of clofazimine with mannitol and polyethylesglycol 6000 in different drug- carrier ratios were prepared in an attempt to improve its dissolution. Differential thermal analysis (DTA), X-ray diffraction (XRD) analusis and dissolution studies were performed to evaluate the formulations. The dissolution rate of clofazimine was markedly increased in solid dispersions of PEG 6000 as well as mannitol. The former material was more promising as a carrier. DTA and XRD studies revealed that clofazimine does not enter crystal lattice of the two carriers studied.
Laminin overrides the inhibitory effects of peripheral nervous system and central nervous system myelin‐derived inhibitors of neurite growth (1995)

Axon growth inhibitory proteins associated with central nervous system (CNS) myelin are responsible in part for the absence of long distance axon regeneration in the adult mammalian CNS. We have recently reported that myelin-associated glycoprotein (MAG), which is also present in peripheral nerves, is a potent inhibitor of neurite growth. This was surprising given the robust regenerative capacity of peripheral nerves. We now provide evidence that myelin purified from peripheral nerve also has neurite growth inhibitory activity. However, this activity can be masked by laminin, which is a constituent of the Schwann cell basal lamina. We also report that laminin, which is largely absent from the normal adult mammalian CNS, when added to purified CNS myelin, can override the neurite growth inhibitory activity in CNS myelin. These results have important implications for the development of strategies to foster axon regeneration in the adult mammalian CNS where multiple growth inhibitors exist.
Impact of a Higher Radiation Dose on Local Control and Survival in Breast-Conserving Therapy of Early Breast Cancer: 10-Year Results of the Randomized Boost Versus No Boost EORTC 22881-10882 Trial (2007)

After a median follow-up period of 10.8 years, a boost dose of 16 Gy led to improved local control in all age groups, but no difference in survival.
High-speed optical coherence tomography using fiberoptic acousto-optic phase modulation (2003)

We report a new rapid-scanning optical delay device suitable for high-speed optical coherence tomography (OCT) in which an acousto-optic modulator (AOM) is used to independently modulate the Doppler frequency shift of the reference light beam for optical heterodyne detection. Experimental results show that the fluctuation of the measured Doppler frequency shift is less than +/-0.2% over 95% duty cycle of OCT imaging, thus allowing for enhanced signal-to-noise ratio of optical heterodyne detection. The increased Doppler frequency shift by AOM also permits complete envelop demodulation without the compromise of reducing axial resolution; if used with a resonant rapid-scanning optical delay, it will permit high-performance real-time OCT imaging. Potentially, this new rapid-scanning optical delay device will improve the performance of high-speed Doppler OCT techniques.
The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development (2004)

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KO brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KO neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.
Synthetic neuromuscular‐ and ganglion‐blocking agents. N‐Alkylated bipyridyls, bipiperidyls, and their methylene and ethylene “homologues” (1955)

Abstract The synthesis is reported of N.N′‐alkylated α,α′‐, β,β′ and γ,γ′‐bipyridylium diiodides (Type I), and of N,N′‐alkylated α, α′‐, β,β′‐ and γ,γ′‐bipiperidylium diiodides (Type II) listed in Table I. It was found that when the bipyridyls were hydrogenated in absolute methanolic or ethanolic solution in the presence of a nickel catalyst not only reduction of the pyridine rings took place, but also N‐alkylation by the alcohols . This nickel‐catalyzed “hydrogenation‐alkylation” gave satisfactory yields. In table II some N‐alkylated di‐(α‐pyridylium) and di‐(α‐piperidylium)‐methane and ethane diiodides of the Types III and IV are summarized. Syntheses are described of di‐(α‐pyridyl)‐methane and 1,2‐di‐(α‐pyridyl)‐ethane, which compounds were needed as intermediates for the preparation of III and IV. The compounds listed in the Tables I and II were prepared because of their possible neuromuscular‐ and ganglion‐blocking activity.
Transformations of Hydroxy Cyclic Sulfates: Stereospecific Conversion into 2,3,5-Trisubstituted Tetrahydrofurans. (1993)

1,2-Cyclic sulfates have been prepared from O-protected ricinoleate and ricinelaidate esters. Upon deprotection of the 12-hydroxy moiety, the resulting 12-hydroxy-9,10-cyclic sulfates underwent stereospecific cyclization to the corresponding 2,3,5-trisubstituted tetrahydrofurans. The cyclization occurs by backside attack of the hydroxy oxygen on the distal carbon of the 1,2-cyclic sulfate, with inversion at that center.
Large-scale identification of selenium metabolites by online size-exclusion-reversed phase liquid chromatography with combined inductively coupled plasma (ICP-MS) and electrospray ionization linear trap-Orbitrap mass spectrometry (ESI-MSn) (2012)

A method was developed for the comprehensive cartography of the selenium metabolites synthesized in the process of conversion of selenite [Se(iv)] into organic compounds and enrichment of yeast with selenium. The number of compounds detected was considerably increased (49) owing to the optimization of the fractionation procedure and the use of UPLC. The increased purity of the minor selenoorganic amino acids and oligopeptides allowed successful on-line de-novo identification based on the exact mass (<1 ppm) and fragmentation (MS(2)/MS(3)) mass spectra obtained with high resolution and high mass accuracy. The quality of mass spectra allowed the re-interpretation of previously reported structures of some selenium species.