gebhart/patrepeval huggingface dataset:
Reversible inhibition of osteoclastic activity by bone‐bound gallium (III) (1992)

Gallium(III) is a new therapeutic agent for hypercalcemia. Ga3+ reduces osteoclast action, but how it inhibits the cell's physiology is unknown. In vivo, 7-12 microM Ga(III) reduces calcium release from bone, but surprisingly, 10-100 microM Ga3+ added to isolated avian osteoclasts did not reduce their degradation of L-(5-3H)-proline bone. 3H-proline labels bone collagen specifically, and collagenolysis is an excellent indicator of bone dissolution because collagen is the least soluble component of bone. Ga(III) greater than 100 microM inhibited osteoclasts in vitro, but also killed the cells. To resolve this apparent conflict, we measured 67Ga distribution between bone, cells, and media. Gallium binds avidly but slowly to bone fragments. One hundred micrograms of bone clears 60% of 1 microM gallium from 500 microliters of tissue culture medium, with steady state at greater than 24 h. Osteoclasts on bone inhibited gallium binding capacity approximately 40%, indicating a difference in available binding area and suggesting that osteoclasts protect their substrate from Ga binding. Less gallium binds to bone in serum-containing medium than in phosphate-buffered saline; 30% reduction of the affinity constant suggests that the serum containing medium competes with bone binding. Consequently, the effect of [Ga] on bone degradation was studied using accurately controlled amounts of Ga(III) pre-bound to the bone. Under these conditions, gallium sensitivity of osteoclasts is striking. At 2 days, 100 micrograms of bone pre-incubated with 1 ml of 1 microM Ga3+, with 10 pmoles Ga3+/micrograms bone, was degraded at 50% the rate of control bone; over 50 pM Ga3+/micrograms bone, resorption was essentially zero. In contrast, pre-treatment of bone with [Ga3+] as high as 15 microM had no significant effect on bone resorption rate beyond 3 days, indicating that gallium below approximately 150 pg/micrograms bone acts for a limited time and does not permanently damage the cells. We conclude that bone-bound Ga(III) from medium concentrations less than 15 microM inhibits osteoclasts reversibly, while irreversible toxicity occurs at solution [Ga3+] greater than 50 microM.
Stereochemistry of ephedrine and its environmental significance: Exposure and effects directed approach (2018)

Analysis of drugs and pharmaceuticals in the environment is typically performed with non-chiral chromatographic techniques. The environmental risks posed by chiral compounds analysed in this way must therefore be assumed to be independent of chirality, meaning that each enantiomer is equally potent in toxicity and long-lived in stability. This manuscript examines the degradation of each of the four isomers of ephedrine in river simulating microcosms and links this to toxicity data obtained by exposing three different organisms (D. magna, P. subcapitata and T. thermophila) to each of the isomers individually. Microcosms showed that significant degradation only occurred in biotic conditions and that only two isomers (1R,2S-(-)-ephedrine, 1S,2S-(+)-pseudoephedrine) degraded significantly over a period of fourteen days. This is concerning because at least one of the non-degraded isomers (1S,2R-(+)-ephedrine) has been observed in wastewater effluent, which discharges directly into rivers, meaning these isomers could be persistent in the environment. We also observed formation of 1S,2R-(+)-ephedrine in single isomer 1R,2S-(-)-ephedrine river simulating microcosms. Human liver microsome assays and mass spectrometry based data mining revealed that 1S,2R-(+)-ephedrine is not human derived but it could be formed as a results of microbial metabolic processes. Across all three organisms tested the persistent isomers (1S,2R-(+)-ephedrine and 1R,2R-(-)-pseudoephedrine) were more toxic than those that undergo degradation; meaning that if these isomers are entering or formed in the environment they might represent a potentially hazardous contaminant.
Polarisation-insensitive fibre optic Michelson interferometer (1991)

A polarisation-insensitive fibre optic Michelson interferometric sensor configuration is demonstrated. The approach is based on the use of birefringence compensation in a retraced fibre path using Faraday rotator mirror elements.
Isolation and molecular characterization of a novel albumin-binding protein from group G streptococci (1992)

Many streptococcal strains are known to bind the two most abundant plasma proteins, namely, immunoglobulin G and albumin. Protein G isolated from group C and G streptococci has been demonstrated to have separate binding regions for each of these proteins. However, some group G streptococcal strains bind only serum albumin. This report describes the isolation of a 48-kDa albumin-binding protein from such a strain (DG12). The affinity constant of this protein for human serum albumin was determined to be 5 x 10(9) M-1, and the protein interacted strongly also with serum albumin from several other mammalian species. The gene encoding the albumin-binding protein was cloned and expressed in Escherichia coli. DNA sequence analysis of this gene revealed a unique NH2-terminal sequence and three types of repeats in the encoded protein. One of these repeated sequences has significant homology with the albumin-binding domains of protein G, and it was demonstrated that the albumin binding of the DG12 protein was localized within these domains. Another type of repeat is localized in the putative wall-spanning region of the molecule. This repeat sequence, which has the length of only 4 amino acids (LysProGluVal), is repeated 14 times. The relationship of the albumin-binding protein to other cell-wall-associated proteins of pathogenic streptococci is discussed.
Structures of Staphylococcus aureus D-Tagatose-6-phosphate Kinase Implicate Domain Motions in Specificity and Mechanism (2007)

High resolution structures of Staphylococcus aureus d-tagatose-6-phosphate kinase (LacC) in two crystal forms are herein reported. The structures define LacC in apoform, in binary complexes with ADP or the co-factor analogue AMP-PNP, and in a ternary complex with AMP-PNP and D-tagatose-6-phosphate. The tertiary structure of the LacC monomer, which is closely related to other members of the pfkB subfamily of carbohydrate kinases, is composed of a large alpha/beta core domain and a smaller, largely beta "lid." Four extended polypeptide segments connect these two domains. Dimerization of LacC occurs via interactions between lid domains, which come together to form a beta-clasp structure. Residues from both subunits contribute to substrate binding. LacC adopts a closed structure required for phosphoryl transfer only when both substrate and co-factor are bound. A reaction mechanism similar to that used by other phosphoryl transferases is proposed, although unusually, when both substrate and co-factor are bound to the enzyme two Mg(2+) ions are observed in the active site. A new motif of amino acid sequence conservation common to the pfkB subfamily of carbohydrate kinases is identified.
Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs. (1987)

The purpose of this study was to contrast the effects of static and pulsatile pressure on carotid baroreceptor activity over a wide range of mean arterial pressure. Static and pulsatile pressure were applied to the isolated carotid sinus of dogs anesthetized with chloralose. Recordings were obtained from single baroreceptor units as well as from the whole sinus nerve or a large strand of the nerve. Three observations are reported. First, in single units the pulsatile pressure threshold, which averaged 48 +/- 8 (SEM) mm Hg, was far below the static pressure threshold, which averaged 79 +/- 8 mm Hg (p less than 0.05, n = 15). Thus, pulsatility decreased the threshold by an average of 31 mm Hg in contrast to the minimal or lack of decrease in threshold reported by others in aortic baroreceptors. Second, at moderate arterial pressures a shift from static to pulsatile pressure caused a decrease in single and multiple unit activities. In single units, the decrease approximated 15% (from 42.0 +/- 2.1 to 35.5 +/- 1.9 spikes/sec, p less than 0.05, n = 25). In all units, there was no diastolic nerve activity ("silence") when diastolic pressure was 1 to 10 mm Hg above static pressure threshold; 80% of the units exhibited "diastolic silence" when diastolic pressure was 20-30 mm Hg above threshold and 40% of the units showed silence at diastolic pressures 40-50 mm Hg above threshold. In whole nerve recordings, pulsatility increased activity from 57 +/- 15 to 142 +/- 29 spikes/sec (p less than 0.05) at low mean arterial pressures (50 and 75 mm Hg), as expected from the reduction in pressure threshold noted in single units, and decreased activity by approximately 15% (from 373 +/- 69 to 320 +/- 55 spikes/sec, p less than 0.05, n = 9) at mean arterial pressures of 125 and 150 mm Hg. This decrease in activity with a shift from static to pulsatile pressure at moderate arterial pressures has not been reported previously. Third, the static pressure-activity curve was sigmoid, and its gain peaked sharply at 75-100 mm Hg; in contrast, the pulsatile pressure-activity curve was linear between 25 and 150 mm Hg, and its maximum gain was half the maximum gain during static pressure. These differences between the static pressure-activity curve and the pulsatile pressure-activity curve were noted during both increases and decreases in carotid sinus pressure; both curves exhibited some hysteresis during the decreases in pressure.
Insulin-Like Growth Factor (IGF) Binding Protein-3 Inhibits Type 1 IGF Receptor Activation Independently of Its IGF Binding Affinity (2001)

Insulin-like growth factor binding proteins (IGFBPs) regulate the cellular actions of the IGFs owing to their strong affinities, which are equal to or stronger than the affinity of the type 1 IGF receptor (IGF-IR), the mediator of IGF signal transduction. We recently found that IGFBP-3 modulates IGF-I binding to its receptor via a different mechanism possibly involving conformational alteration of the receptor. We have now investigated the effects of IGFBP-3 on the initial steps in the IGF signaling pathway. MCF-7 breast carcinoma cells were preincubated with increasing concentrations of IGFBP-3 and then stimulated with IGF-I, des(1–3)IGF-I, or[ Q3A4Y15L16]-IGF-I, the latter two being IGF-I analogs with intact affinity for the type 1 IGF receptor, but weak or virtually no affinity for IGFBPs. Stimulation of autophosphorylation of the receptor and its tyrosine kinase activity was dose-dependently depressed. At 2.5 nm, IGFBP-3 provoked more than 50% inhibition of the stimulation induced by 3 nm des(1–3)IGF-1 and, at 10 nm, more than 80% inhibition. Similar results were obtained with[ Q3A4Y15L16]-IGF-I. Cross-linking experiments using iodinated or unlabeled IGFBP-3 and anti-IGF-IR antibodies indicated that the inhibitory effects do not involve direct interaction between IGFBP-3 and IGF-IR. The inhibition appeared to be specific to IGFBP-3, because IGFBP-1 and IGFBP-5 at 10 nm had no significant effect. Also, inhibition was restricted to the IGF receptor, because IGFBP-3 failed to inhibit the tyrosine kinase activity of the insulin receptor stimulated by physiological concentrations of insulin. Our results provide the first demonstration that IGFBP-3 can specifically modulate the IGF-I signaling pathway independently of its IGF-I-binding ability. They also reveal a regulatory mechanism specific to the type 1 IGF receptor, with no effect on insulin receptor activation.
Differential response of human acute myeloid leukemia cells to gemtuzumab ozogamicin in vitro: role of Chk1 and Chk2 phosphorylation and caspase 3 (2003)

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated to the anticancer agent calicheamicin, approved for the treatment of CD33+-relapsed acute myeloid leukemia. We have investigated the effects of GO on 4 human myeloid leukemia lines of different French-American-British (FAB) types (KG-1, THP-1, HL-60, and NB-4), observing 3 different types of response. Exposure to GO (10-1000 ng/mL) induced G2 arrest (up to 80% of the cells) followed by apoptosis (45% of the cells) in HL-60 and NB-4 cells. By contrast, in THP-1 cells we observed a strong G2 arrest (up to 75% of the cells) with little apoptosis. Finally, the KG-1 line was completely resistant to the same concentrations of GO. These different responses did not correlate with the levels of expression of either CD33 or multiple-drug resistance proteins, although the higher cyclosporin A (CsA)-inhibitable efflux activity of KG-1 cells may play a role in the resistance of this line to the drug. We could show that Chk1 and Chk2 phosphorylation, but not p53 or p21 expression, correlated with G2 arrest, implicating the ataxia-telangiectasia mutated/ataxia-telangiectasia related (ATM/ATR)-Chk1/Chk2 pathway in the cell cycle response to GO. However, apoptosis was associated with caspase 3 activation. Freshly isolated acute myeloid leukemia (AML) cells showed patterns of response to GO in vitro similar to those observed with the cell lines, including phosphorylation of Chk2 and caspase 3 activation. Our results suggest that the different molecular pathways induced by the drug in vitro may reflect, at least in part, the variable response to GO obtained in vivo.
Scalability of strained-Si nMOSFETs down to 25 nm gate length (2003)

Strained-Si nMOSFETs with a standard polysilicon gate process were fabricated down to 25 nm gate length with well-behaved characteristics and small difference in short channel effects. The performance enhancement degrades linearly as the gate length becomes shorter, due to not only the parasitic resistance but also heavy halo implant. Thus the key integration issues are how to manage threshold difference and As diffusion without excess doping. With comparable doping and well controlled parasitic resistance, up to 45% improvement in drive current is predicted for sub-50 nm gate length strained-Si nMOSFETs on the Si/sub 0.8/Ge/sub 0.2/ substrate. In this work approximately 45% enhancement is in fact demonstrated for 35 nm gate length devices, through advanced channel engineering and implementation of metal gates.
Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. (1986)

The purpose of this study was to determine whether the methods for isolating tumor cells from a human renal cell carcinoma (HRCC) influence the biological behavior of the cancer cells. Renal cell carcinoma obtained from a surgical specimen was dissociated by enzymatic treatment and cells were plated into culture dishes or injected s.c. into the kidney of BALB/c nude mice. The resultant kidney tumor produced liver metastasis and ascites. All tumors growing in nude mice (s.c., kidney, liver, ascites) were also established in culture. The human origin of all five lines was ascertained by karyotypic and isoenzyme analyses. Cells from all lines were injected, s.c., i.p., i.v., intrasplenically, and beneath the renal capsule of nude mice. All the lines were tumorigenic after s.c. or renal subcapsule injection, although the rate of tumor growth varied among the five lines. The metastatic behavior of the HRCC cells was influenced by both the nature of the tumor cells and the route of injection into nude mice. In general, cells derived from the liver metastasis produced more metastases in nude mice than other lines. The lines established in culture from the primary HRCC and the ascites were poorly metastatic. Even with highly metastatic cells, i.v. injection did not yield significant metastasis, but the injection of cells into the renal subcapsule resulted in extensive metastasis to the lungs and in all peritoneal organs. These results indicate that nude mice can be used for the isolation of populations of HRCC cells with different growth and metastatic potential and that, of the organ sites tested, the renal subcapsule is the most advantageous site for implantation of HRCC cells.
ras GENES (1987)

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More
Principles of medical pharmacology (1989)

I: GENERAL PRINCIPLES Introduction to General Pharmacology Drug solubility, absorption, and movement across body membranes Drug distribution Drug biotransformation Pharmacokinetics Clearance, the quantitative basis of drug dosage Drug clearance by specific organs Dose-response relationships Drug receptors Specificity of drug action Drug interactions Human pharmacogenetics. II: AUTONOMIC NERVOUS SYSTEM AND NEUROMUSCULAR JUNCTION Autonomic nervous system neurotransmitters Autonomic cholinergic agonists autonomic cholinergic antagonists Adrenoceptor agonists Adrenoceptor antagonists Drugs acting on adrenergic neurons (adrenergic neuronal blocking drugs) Neuromuscular transmission and drugs (muscle relaxants). III: CENTRAL NERVOUS SYSTEM Drugs acting on the basal ganglia Neuron-inhibitory amino acids anti-seizure drugs (anticonvulsants) Opioid analgesics and antagonists General anaesthetics Local anaesthetics The alcohols Anxiolytics, hypnotics and sedatives Neuroleptics (antipsychotics) Antidepressants and lithium Hallucinogens and psychotometics. IV: AUTACOIDS AND MEDIATORS/MODIFIERS OF TISSUE RESPONSES Autacoids Histamine and antihistamines Anti-inflammatory analgesics. V: CARDIOVASCULAR SYSTEM Digitalis glycosides Antiarrhythmic drugs Vasodilators, antianginal drugs, calcium channel blockers, and agents to prevent hyperlipidemia Pharmacotherapy of hypertension. VI: RESPIRATORY, RENAL AND BLOOD SYSTEMS Drugs and the respiratory system Diuretics Drugs affecting hemostasis Hematinic drugs. VII: ENDOCRINE SYSTEMS Vasopressin and Oxytocin Thyroid drugs Gonadal hormones Insulin and oral hypoglycemic agents Adrenocorticotropic hormone and adrenal steroids Drugs altering bone metabolism Vitamins. VII: GASTROINTESTINAL SYSTEM Pharmacotherapy of gastrointestinal acid-peptic disorders Laxatives and antidiarrheal drugs. IX: CHEMOTHERAPY General principles of antimicrobial therapy Antimicrobial agents which act upon bacterial cell wall formation: penicillins, cephalosporins, vancomycin, bacitracin, cycolserine Antimicrobial and antifungal agents which act upon cell membranes: polymixins, colistin, nystatin, amphotericin B Antimicrobial agents which affect synthesis of cellular proteins: aminoglycosides, spectinomycin, tetracyclines, chloramphenicol, erythromycin Drugs affecting cellular nucleic acid synthesis: rifampin, nalidixic acid, griseofulvin, 5-fluorocytosine, isoniazid, ethambutol, sulfonamides, para-aminosalicylic acid, trimethoprim, pyrimethamine Chemotherapy of common parasitic infections Antiviral agents Antiseptics, disinfection and sterilization Antineoplastic drugs Immunopharmacology. X: SPECIAL TOPICS Drugs, alcohol and the liver Carcinogenesis and mutagenesis by xenobiotic chemicals Chemical teratogenesis Adverse drug reactions Behavioural pharmacology Drug dependence and drug abuse
Numerical Simulation of Electro-Mechanical Impedance Response in Cable-Anchor Connection Interlace (2011)

In this study, a finite element(FE) analysis on electro-mechanical impedance response of cable-anchor connection interface under various anchor force is presented. In order to achieve the objective, the following approaches are implemented. Firstly, an interface washer coupled with piezoelectric(PZT) material is designed for monitoring cable-force loss. The interface washer is a small aluminum plate on which a PZT patch is surface-bonded. Cable-force loss could be monitored by installing the interface washer between the anchor plate and the anchorage of cable-anchor connection and examining the changes of impedance of the interface washer. Secondly, a FE model for cable-anchor connection is established to examine the effect of cable-force on impedance response of interface washer. Also, the effects of geometrical and material properties of the interface washer on impedance responses under various cable-forces are investigated. Finally, validation of the FE analysis is experimentally evaluated by a lab-scale cable-anchor connection.
Elimination of Microwave Effects on the Vitality of Nerves after Blockage of Active Transport (1986)

We have previously reported that exposure to microwave fields (a specific absorption rate of 10 W/kg at 2.45-GHz continuous wave) would consistently lower the survival time of isolated frog sciatic nerves stimulated at high repetition rates (50 pulse pairs per second, ppps). The time course of the loss of excitability of the exposed nerve (as compared to its unexposed contralateral mate) is reminiscent of that seen when the active transport of sodium (Na) and potassium (K) is blocked by certain agents--such as the cardiac glycoside ouabain. To assess the role that these microwaves may have in interfering with or counteracting active transport, we performed a series of experiments in which the active Na-K pump was substantially blocked by ouabain prior to microwave exposure. The paired nerves were soaked for 5 min in a high concentration (10(-3) g/liter) of ouabain to achieve the fastest and most complete blockage of the Na-K pump prior to stimulation at 50 ppps. The "rundown time course" was, as expected, accelerated in all ouabain-treated nerves, but the microwave-exposed nerves showed no additional shortening of survival time. The experiments were repeated at a slower stimulation rate (5 ppps) so that the survival time of the nerves more closely approximated that of nerves not treated with ouabain (1 to 2 h versus 30 min or less for ouabain-treated nerves stimulated at 50 ppps). Results of these lower stimulation rates also showed that there was no significant difference in the survival time of ouabain-treated exposed and control nerves. These results lend support to the view that the relative loss of excitability in microwave-exposed nerves is related to an interference with or counteraction of the Na-K pump.
The regulation of proliferation and differentiation in oligodendrocyte progenitor cells by αv integrins (2000)

We have previously shown that oligodendrocyte progenitor cells exhibit developmental switching between alphav-associated beta integrin subunits to sequentially express alphavbeta1, alphavbeta3 and alphavbeta5 integrins during differentiation in vitro. To understand the role that alphavveta3 integrin may play in regulating oligodendrocyte progenitor cell behaviour, cells of the rat cell line, CG-4, were genetically engineered to constitutively express alphavbeta3 integrin by transfection with full-length human beta3 integrin subunit cDNA. Time-lapse videomicroscopy showed no effect of beta3 expression on cell migration but revealed enhanced proliferation on vitronectin substrata. Comparison of mitotic indices, as measured by 5-bromo-2'-deoxyuridine incorporation, confirmed that human beta3 integrin-expressing cells exhibited enhanced proliferation, as compared to both vector-only transfected, and wild-type CG-4 cells when switched to differentiation medium from growth medium, but only in cultures grown on vitronectin and not on poly-D-lysine. The effects on proliferation were inhibited by a function-blocking antibody specifically directed against the human beta3 integrin subunit. Human beta3 integrin-expressing cells also exhibited reduced differentiation. This differentiation could be reduced still further by a function-blocking monoclonal antibody against alphavbeta5 integrin, as could differentiation in the wild-type CG-4 cells. Taken together, these results suggest that alphavbeta3 integrin may regulate oligodendroglial cell proliferation and that both downregulation of alphavbeta3 integrin expression and signalling through alphavbeta5 integrin may be critical to continued differentiation in vitro.