gebhart/patrepeval huggingface dataset:
Structural modification of plasma HDL by phospholipids promotes efficient ABCA1-mediated cholesterol release (2005)

It has been suggested that ABCA1 interacts preferentially with lipid-poor apolipoprotein A-I (apoA-I). Here, we show that treatment of plasma with dimyristoyl phosphatidylcholine (DMPC) multilamellar vesicles generates prebeta(1)-apoA-I-containing lipoproteins (LpA-I)-like particles similar to those of native plasma. Isolated prebeta(1)-LpA-I-like particles inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than HDL(3) (IC(50) = 2.20 +/- 0.35 vs. 37.60 +/- 4.78 microg/ml). We next investigated the ability of DMPC-treated plasma to promote phospholipid and unesterified (free) cholesterol efflux from J774 macrophages stimulated or not with cAMP. At 2 mg DMPC/ml plasma, both phospholipid and free cholesterol efflux were increased ( approximately 50% and 40%, respectively) in cAMP-stimulated cells compared with unstimulated cells. Similarly, both phospholipid and free cholesterol efflux to either isolated native prebeta(1)-LpA-I and prebeta(1)-LpA-I-like particles were increased significantly in stimulated cells. Furthermore, glyburide significantly inhibited phospholipid and free cholesterol efflux to DMPC-treated plasma. Removal of apoA-I-containing lipoproteins from normolipidemic plasma drastically reduced free cholesterol efflux mediated by DMPC-treated plasma. Finally, treatment of Tangier disease plasma with DMPC affected the amount of neither prebeta(1)-LpA-I nor free cholesterol efflux. These results indicate that DMPC enrichment of normal plasma resulted in the redistribution of apoA-I from alpha-HDL to prebeta-HDL, allowing for more efficient ABCA1-mediated cellular lipid release. Increasing the plasma prebeta(1)-LpA-I level by either pharmacological agents or direct infusions might prevent foam cell formation and reduce atherosclerotic vascular disease.
Characterization of naive CD4+ T cells with specificity to self-antigen (137.21) (2009)

Abstract During thymic development, T cells with specificity to self-antigens are deleted, thereby ensuring that the peripheral repertoire is devoid of potentially autoreactive clones. However, the ultra-low frequency of naive epitope-specific T cells has made the direct test of this theory technically unfeasible in the past. Using peptide:MHC (pMHC) multimers coupled with magnetic bead enrichment, we have directly studied endogenous polyclonal populations of naive CD4+ T cells with specificity for an I-Ab-restricted model antigen, 2W1S, that is foreign in C57BL/6 mice (B6) or self in mice transgenically expressing the model antigen (Act-2W). Act-2W mice contained a population of 2W1S-specific T cells that was about 25% the size of that in B6 mice, demonstrating that thymic deletion of self-antigen specific T cells is incomplete. Nonetheless, these cells were tolerant to 2W1S, as they did not develop autoimmune responses or respond to large doses of exogenous 2W1S antigen administered in vivo. Antigen receptors expressed by these cells exhibited features of reduced pMHC ligand binding affinity, indicating a preferential loss of high-affinity 2W1S-specific clones during thymic selection. Moreover, a greater proportion of 2W1S-specific T cells expressed FoxP3 in Act-2W mice than in B6 counterparts, suggesting that regulatory T cell development may also function as a mechanism of T cell tolerance to self-antigens. This work was funded by NIH grants PO1-AI35296 and F32-AI063793.
Implications of early inflammation and infection in cystic fibrosis: A review of new and potential interventions (1997)

Airway infection and inflammation occur early in cystic fibrosis (CF) lung disease, suggesting the need for early treatment. Our current approach to routine management of CF includes a comprehensive, CF center-directed program that aims at maintaining normal nutrition and delaying the progression of lung disease. Regular secretion clearance, frequent antibiotics, and bronchodilators are commonly used. However, despite this early, aggressive comprehensive management, airway inflammation and infection progress. Several other recent approaches such as the use of corticosteroids and ibuprofen to decrease inflammation, as well as dornase alfa to thin secretions and improve pulmonary function, are under investigation in young children. Other potential treatments include amiloride/uridine triphosphate and hypertonic saline aerosol. Early treatment offers the promise of reducing morbidity as well as delaying the progression of later disease.
NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis (2014)

In breast cancer, overexpression of the nuclear coactivator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor-forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating breast cancer cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating colony-simulating factor 1 (CSF1) expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and breast cancer cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade, and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes breast cancer metastasis, offering a novel therapeutic target for impeding this process.
Sweat lactate secretion during exercise in relation to women's aerobic capacity (1987)

The purpose of this investigation was to determine whether sweat lactate secretion during exercise [approximately 70% maximum O2 consumption (VO2max), 60 min] differed in active vs. sedentary female subjects. Sweat rate, total sweat lactate secretion, and sweat lactate concentration were monitored in a group of sedentary (VO2max = 41.0 +/- 1.62 ml X kg-1 X min-1) and active (VO2max = 51.2 +/- 3.20 ml X kg-1 X min-1) women. Sweat rate was significantly (P less than 0.05) greater in the active subjects. There was a significant difference between groups in total amount of sweat lactate secreted (P less than 0.05), with the active group secreting less lactate (29.8 +/- 5.03 mmol, mean +/- SE) than the sedentary group (50.2 +/- 6.61 mmol). Concomitant with the lower total sweat lactate secretion in the active subjects was a significantly (P less than 0.05) more dilute sweat lactate concentration (42.6 +/- 14.08 vs. 100.4 +/- 32.37 mM). In these female subjects, sweat lactate concentration was inversely correlated (r = -0.79, P less than 0.01, n = 10) to sweat rate. It is concluded that total sweat lactate loss is significantly less in active than in sedentary women and that the active subjects secrete a greater quantity of lactate dilute sweat.
[Phase II clinical study of topotecan hydrochloride in patients with recurrent advanced ovarian cancer]. (2002)

Topotecan is effective for treating the patients with recurrent ovarian cancer who failed with platinum-based regimes.
Adaptive parallel aggregation algorithms (1995)

Aggregation and duplicate removal are common in SQL queries. However, in the parallel query processing literature, aggregate processing has received surprisingly little attention; furthermore, for each of the traditional parallel aggregation algorithms, there is a range of grouping selectivities where the algorithm performs poorly. In this work, we propose new algorithms that dynamically adapt, at query evaluation time, in response to observed grouping selectivities. Performance analysis via analytical modeling and an implementation on a workstation-cluster shows that the proposed algorithms are able to perform well for all grouping selectivities. Finally, we study the effect of data skew and show that for certain data sets the proposed algorithms can even outperform the best of traditional approaches.
Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. (2003)

Histone deacetylase inhibitors (HDACIs) are a new class of chemotherapeutic drugs able to induce tumor cell apoptosis and/or cell cycle arrest; however, the molecular mechanisms underpinning their anticancer effects are poorly understood. Herein, we assessed the apoptotic pathways activated by three HDACIs, suberoylanilide hydroxamic acid, oxamflatin, and depsipeptide. We determined that all three drugs induced the accumulation of cells with a 4n DNA content and apoptosis mediated by the intrinsic apoptotic pathway. HDACI-induced mitochondrial membrane damage and apoptosis were inhibited by overexpression of Bcl-2, but not by the polycaspase inhibitor N-tert-butoxy-carbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk). Moreover, induction of a G(1)-S checkpoint through overexpression of p16(INK4A) or suppression of de novo protein synthesis also inhibited HDACI-induced cell death. Proteolytic cleavage of caspase-2, which is poorly inhibited by zVAD-fmk, was concomitant with HDACI-induced death; however, full processing of caspase-2 to the p19 active form was blocked by Bcl-2. Whereas all three drugs induce the activation of the proapoptotic Bcl-2 protein Bid upstream of mitochondrial membrane disruption, Bid cleavage in response to depsipeptide was significantly attenuated by zVAD-fmk. Suberoylanilide hydroxamic acid and oxamflatin could kill both P-glycoprotein (P-gp)(+) MDR cells and their P-gp(-) counterparts, whereas depsipeptide was shown to be a substrate for P-gp and was less effective in killing P-gp(+) cells. These data provide insight into the functional profile of three HDACIs and are important for the development of more rational approaches to chemotherapy, where information regarding the genetic profile of the tumor is matched with the functional profile of a given chemotherapeutic drug to promote favorable clinical responses.
E-beam inspection for detection of sub-design rule physical defects (2012)

E-beam inspection provides a complementary approach to brightfield inspection for detection of otherwise difficult to detect physical defects. Advantages of E-beam inspection include superior resolution, the ability to classify defects using patch images and automatic filtering of prior level defects. A key limitation, however, is throughput. Therefore brightfield inspection should always be used for defection of physical defects when effective. For challenging defects, E-beam inspection data may be used as a gold standard for development of the best optical inspection conditions. For very challenging defects, it may be necessary to rely on E-beam inspection. An efficient inspection should be developed. Three examples are presented of challenging defects to illustrate the usefulness of E-beam inspection for physical defect detection.
Cell cycle arrest, apoptosis and p53 expression in nickel(II) acetate- treated Chinese hamster ovary cells (1998)

Nickel(II) compounds are known human and animal carcinogens. In this study, the effects of nickel(II) acetate on cell cycle, apoptosis and p53 expression were investigated in order to unveil the elements of early cellular responses to the metal. Chinese hamster ovary (CHO) cells were grown for 72 h in Ham's F-12 medium containing 0, 40, 80, 160, 240, 320, 480 or 640 microM nickel(II) acetate. DNA fragmentation, representative of apoptosis, was examined by agarose gel electrophoresis. The distribution of cells among various phases of cell cycle was determined by DNA flow cytometry. Expression of p53 protein was measured by the Western blotting technique. DNA fragmentation was detectable in cells treated with > or = 160 microM nickel(II) and its intensity increased with increasing nickel(II) concentration. The proportion of cells at S phase declined in a nickel(II) concentration-dependent manner. The decline was accompanied by an increase of cell proportion in G2/M phase and the increase became statistically significant in cells exposed to at least 480 microM nickel(II). Expression of p53 protein was not different from that in the control among samples treated with < or = 480 microM nickel(II). However, an extra fraction that migrated close to the p53 protein fraction was detected in cells treated with 640 microM nickel(II). Our findings suggest that nickel(II) modulates cellular response through effectors involved in both G2/M arrest and apoptosis regulatory pathways. The proportion of cells arrested at G2/M phase or undergoing apoptosis depends directly on nickel(II) concentration. High concentration of nickel(II) appears to up-regulate protein(s) other than the common form of p53 protein.
Integration of an Arabic transliteration module into a statistical machine translation system (2007)

We provide an in-depth analysis of the integration of an Arabic-to-English transliteration system into a general-purpose phrase-based statistical machine translation system. We study the integration from different aspects and evaluate the improvement that can be attributed to the integration using the BLEU metric. Our experiments show that a transliteration module can help significantly in the situation where the test data is rich with previously unseen named entities. We obtain 70% and 53% of the theoretical maximum improvement we could achieve, as measured by an oracle on development and test sets respectively for OOV words (out of vocabulary source words not appearing in the phrase table).
Discrepant INR values: a comparison between Manchester and Thrombotest reagents using capillary and venous samples (1989)

The International Sensitivity Index (ISI) for different thromboplastin reagents is obtained by calibration against WHO reference preparations. It is hoped that calculation of the International Normalized Ratio (INR) from the ISI will permit accuracy and conformity in reporting laboratory assays of warfarin effect even across a range of different techniques. We have examined the INR values of 128 warfarin patients obtained by four different techniques in common use, namely venous and capillary Thrombotest and venous and capillary Manchester reagent. Discrepant INR values were obtained. The mean Manchester venous INR values were lower than those obtained by the other three methods (P less than 0.0001). This suggests that patients dosed by reference to Manchester venous INR are liable to receive more warfarin than those dosed by the other methods.
Membrane Protein Expression in Lactococcus lactis (2009)

Membrane proteins play key roles in cellular physiology, and they are important drug targets. Approximately 25% of all genes identified in sequenced genomes are known to encode membrane proteins; however, the majority have no assigned function. Although the resolution of soluble protein structure has entered the high-throughput stage, only 100 high-resolution structures of membrane proteins have been described until now. Lactococcus lactis is a gram-positive lactic bacterium that has been used traditionally in food fermentations, but it is now used widely in biotechnology for large-scale overproduction of heterologously expressed proteins. Various expression vectors based on either constitutive or inducible promoters exist. The nisin-inducible controlled gene expression (NICE) system is the most suitable for recombinant membrane protein expression allowing for fine control of gene expression based on the autoregulation mechanism of the bacteriocin nisin. Recombinant membrane proteins can be produced with affinity tags for efficient detection and purification from crude membrane protein extracts. The purpose of this chapter is to provide a detailed protocol for the expression of membrane proteins and their detection using the Strep-tag II affinity tag in L. lactis.
Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597) (2006)

In the present article, we review the pharmacological properties of KDS-4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS-4103 inhibits FAAH activity with median inhibitory concentrations (IC(50)) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS-4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID(50)) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid-related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS-4103 elicits significant, anxiolytic-like, antidepressant-like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS-4103 does not evoke classical cannabinoid-like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC). These findings suggest that KDS-4103 acts by enhancing the tonic actions of anandamide on a subset of CB(1) receptors, which may normally be engaged in controlling emotions and pain. KDS-4103 is orally available in rats and cynomolgus monkeys. Sub-chronic repeated dose studies (1,500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS-4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1,500 mg/kg. The results suggest that KDS-4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.
Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase (2001)

We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T(max) = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.
Purification and characterization of thiol-reagent-sensitive glycerol-3-phosphate acyltransferase from the membrane fraction of an oleaginous fungus (2001)

Glycerol-3-phosphate acyltransferase (GPAT), responsible for the first committed, rate-limiting, step of glycerolipid synthesis, was purified to homogeneity from the membrane fraction of an oleaginous fungus, Mortierella ramanniana var. angulispora. The enzyme was solubilized from the membrane fraction by pretreatment with 0.05% Triton X-100 and treatment of the resulting pellet with 0.3% Triton X-100. The enzyme was subsequently purified by column chromatography on heparin-Sepharose, Yellow 86 agarose, a second heparin-Sepharose column, Superdex-200 and hydroxylapatite Bio-Gel. Enzyme activity was finally enriched 1308-fold over that of the starting membrane fraction. SDS/PAGE of the purified fraction revealed a single band with a molecular mass of 45kDa. Native PAGE showed a major band that corresponded to GPAT activity. Enzyme activity was inhibited by thiol reagents, suggesting that it originated from microsomes rather than mitochondria. Purified GPAT depended on exogenous oleoyl-CoA and sn-glycerol-3-phosphate, with the highest activity at approx. 50 and 250µM, respectively, and preferred oleoyl-CoA 5.4-fold over palmitoyl-CoA as an acyl donor. Anionic phospholipids, such as phosphatidic acid and phosphatidylserine, were absolutely required for activity of the purified enzyme, and their ability to activate GPAT was influenced by the purity of the GPAT preparation. Bivalent cations, such as Mg2+ and Ca2+, inhibited purified GPAT activity, whereas 5mM Mn2+ elevated activity approx. 2-fold. These results provide new insights into the molecular characterization of microsomal GPAT, which has not been well characterized compared with mitochondrial and plastidic GPAT.
Ocean-bottom seismograph (1965)

In one program of Project VELA UNIFORM, the Air Force Cambridge Research Laboratories and Texas Instruments developed the ocean-bottom seismograph as a research tool for the study of acoustical wave energy at the solid earth-water interface generated either by earthquakes or by explosive sources. The seismograph described by this article is a third-generation unit having progressed through more than four years of development, design, and field experiments. The present configuration is spherical, 40 inches in diameter. It has been tested successfully in various locations to a depth of 24 000 feet. The primary components, in addition to the three-component seismometer system, contained within the seismograph are a digital clock having a 40-day capacity, with 0.1 second accuracy, seismic amplifiers capable of detecting noise level of 0.1 microvolt or less, a magnetic tape transport having a 30-day recording capacity for signals of less than 10 c/s frequency, and internal battery power supply for all components. In operation, the seismograph descends to the desired depth free fall, remains unattended and untethered, and is retrieved on sonar code command or preset time by decoupling the anchor base through a cocked spring mechanism, which is triggered by fusion of a small steel wire. Results to date have proved the feasibility of such an ocean-bottom data system, including the important capability to recall the package by sonar code command.
Fomes annosus Butt Rot of Sitka Spruce (1979)

Journal Article Fomes annosus Butt Rot of Sitka Spruce : III. Losses in Yield and Value of Timber in Diseased Trees and Stands Get access J.E. PRATT J.E. PRATT Forestry Commission Forest Research Station, Alice Holt Lodge, Wrecclesham, Farnham, Surrey GU10 4LH Search for other works by this author on: Oxford Academic Google Scholar Forestry: An International Journal of Forest Research, Volume 52, Issue 2, 1979, Pages 113–127, https://doi.org/10.1093/forestry/52.2.113 Published: 01 October 1979