gebhart/patrepeval huggingface dataset:
Blood Coagulation Factor IX Residues Glu78 and Arg94 Provide a Link between Both Epidermal Growth Factor-like Domains That Is Crucial in the Interaction with Factor VIII Light Chain (1998)

Recently, we established that mutations at calcium-binding sites within the first epidermal growth factor (EGF)-like domain of activated factor IX affect its interaction with factor VIIIa (Lenting, P. J., Christophe, O. D., ter Maat, H., Rees, D. J. G., and Mertens, K. (1996) J. Biol. Chem. 271, 25332-25337). In the present study, we have investigated the functional role of residue Glu78, which is not involved in calcium binding. Glu78 is also located in the first EGF-like domain and, when mutated to Lys, is associated with severe hemophilia B. Because Glu78 is conserved in related vitamin K-dependent proteins, it is difficult to understand how a mutation at this position is associated with factor IX-specific function. In this study, we addressed the hypothesis that Glu78 exerts its biological activity by interacting with another residue. One candidate was found to be the second EGF-like domain residue, Arg94, which is also associated with severe hemophilia B when mutated. We constructed a series of mutants that included mutations at position 78 alone (Glu78 to Lys/Glu78 to Asp) or at both positions 78 and 94 (Glu78 to Lys and Arg94 to Asp). The functional parameters of immunopurified and activated mutants were compared with normal activated factor IX. Mutants were indistinguishable from normal factor IXa in cleaving the synthetic substrate CH3SO2-Leu-Gly-Arg-p-nitroanilide or activating factor X in the absence of factor VIIIa. In contrast, in the presence of factor VIIIa, factor IXa Glu78 to Asp and factor IXa Glu78 to Lys/Arg94 to Asp were stimulated to the same extent as normal factor IXa, whereas factor IXa Glu78 to Lys was markedly less stimulated (140-fold versus 2,000-fold). This suggests that residues 78 and 94 should carry an opposite charge for a normal interaction of factor IXa to factor VIIIa. This hypothesis was confirmed in inhibition studies employing synthetic peptides comprising the factor IXa-binding motifs of factor VIII heavy (Ser558-Gln565) or light chain (Glu1811-Lys1818) and in direct binding studies. We propose that residues 78 and 94 link both EGF-like domains and thereby maintain the integrity of the factor VIII light chain binding site.
Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity (2000)

Abstract A group of 4,5‐diphenylisoxazoles ( 11a–p ), 3,4‐diphenyl‐5‐trifluoromethylisoxazoles ( 15, 21 ), and 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) possessing a variety of substituents (H, F, MeS, MeSO, MeSO 2 ) at the para ‐position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX‐2 inhibitory antiinflammatory (AI), agents. Although the 4,5‐diphenylisoxazole group of compounds (11a–p) exhibited potent analgesic and AI activities, those compounds evaluated ( 11a, 11b, 11m ) were more selective inhibitors of COX‐1 than COX‐2, with the exception of 4‐(4‐methylsulphonylphenyl)‐5‐phenylisoxazole ( 11n ) that showed a modest COX‐2 selectivity index (SI) of 2.1. In contrast, 3‐(4‐methylsulphonylphenyl)‐4‐phenyl‐5‐trifluoromethylisoxazole ( 15 ), which retained good analgesic and AI activities, was a highly potent and selective COX‐2 inhibitor (COX‐1 IC 50 &gt; 500 μM; COX‐2 IC 50 &lt; 0.001 μM) with a COX‐2 SI of &gt; 500,000, relative to the reference drug celecoxib (COX‐1 IC 50 = 22.9 μM; COX‐2 IC 50 = 0.0567 μM) with a COX‐2 SI of 404. The 3‐phenyl‐4‐(4‐methylsulphonylphenyl) regioisomer ( 21 ) was a less potent inhibitor (COX‐1 IC 50 = 252 μM; COX‐2 IC 50 = 0.2236 μM) with a COX‐2 SI of 1122, relative to the regioisomer ( 15 ). The related compound 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) exhibited similar (to 21 ) potency and COX‐2 selectivity (COX‐1 IC 50 &gt; 200 μM; COX‐2 IC 50 = 0.226 μM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX‐2 inhibitor (15) in the active site of the human COX‐2 enzyme showed the C‐5 CF 3 substituent is positioned 3.37 Å from the phenolic O H of Tyr 355 , and 6.91 Å from the Ser 530 O H. The S‐atom of the MeSO 2 substituent is positioned deep (7.40 Å from the entrance) inside the COX‐2 secondary pocket (Val 523 ). These studies indicate a C‐5 CF 3 ( 15, 21 ), or C‐3 NHSO 2 Me ( 23 ), central isoxazole ring substituent is crucial to selective inhibition of COX‐2 for this class of compounds. Drug Dev. Res. 51:273–286, 2000. © 2001 Wiley‐Liss, Inc.
Effectiveness of Intranasal Zolmitriptan in Acute Cluster Headache (2006)

Five-milligram and 10-mg doses of zolmitriptan intranasal spray are effective within 30 minutes and well tolerated in the treatment of acute cluster headache. Trial Registration controlled-trials.com Identifier ISCRTN27362692.
The limited role of interferon‐γ in systemic juvenile idiopathic arthritis cannot be explained by cellular hyporesponsiveness (2012)

Monocytes in patients with active systemic JIA retain the ability to respond to IFNγ, suggesting that the lack of an IFN-induced gene signature in patients with active disease reflects a limited in vivo exposure to IFNγ. In patients with inactive systemic JIA who received treatment with anti-IL-1β, hyperresponsiveness to IFNγ was observed.
The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. (1993)

Mutations in the p53 tumor suppressor gene are the most commonly observed genetic alterations in human cancer. The majority of these mutations occur in the conserved central portion of the gene, but there has been little information about the function of this region. Using proteolytic digestion of the 393-amino-acid human p53 protein, we have identified a 191-amino-acid protease-resistant fragment (residues 102-292) that corresponds to the central portion of p53, and we show that this core fragment is the sequence-specific DNA-binding domain of the protein. DNA binding is inhibited by metal chelating agents, and we find that the core domain contains zinc. Proteolytic digests also reveal a 53-amino-acid carboxy-terminal domain which we show to be the tetramerization domain of p53.
Impurities in New Drug Substances and New Drug Products (2017)

This chapter aims to address the general flow of impurity management in new drug substances and new drug products, tying in all aspects that have been covered by other International Conference on Harmonisation (ICH) guidelines. It also examines other aspects not covered by current guidelines. Reporting and identification are important within the context of impurity classification, qualification, and listing of impurities in specifications. The guideline provides clear guidance in respect to a number of factors that relate to the reporting of data, including number of decimal places, data rounding, and naming/labeling of impurities. The most important aspect of the ICH Q3A and Q3B guidelines is the sections relating to qualification. Q3A and Q3B apply specifically to the marketing phase and not during clinical development; the result is that during the development phase, a modified approach, usually company specific, is applied. This generally is based on an empirical modification of the limits defined in the guidelines.
Functional and Structural Characterization of a Synthetic Peptide Representing the N-Terminal Domain of Prokaryotic Pyruvate Dehydrogenase (2002)

A synthetic peptide (Nterm-E1p) is used to characterize the structure and function of the N-terminal region (amino acid residues 4-45) of the pyruvate dehydrogenase component (E1p) from the pyruvate dehydrogenase multienzyme complex (PDHC) from Azotobacter vinelandii. Activity and binding studies established that Nterm-E1p specifically competes with E1p for binding to the dihydrolipoyl transacetylase component (E2p) of PDHC. Moreover, the experiments show that the N-terminal region of E1p forms an independent folding domain that functions as a binding domain. CD measurements, two-dimensional (2D) (1)H NMR analysis, and secondary structure prediction all indicate that Nterm-E1p has a high alpha-helical content. Here a structural model of the N-terminal domain is proposed. The peptide is present in two conformations, the population of which depends on the sample conditions. The conformations are designated "unfolded" at pH > or =6 and "folded" at pH <5. The 2D (1)H TOCSY spectrum of a mixture of folded and unfolded Nterm-E1p shows exchange cross-peaks that "link" the folded and unfolded state of Nterm-E1p. The rate of exchange between the two species is in the range of 0.5-5 s(-1). Sharp resonances in the NMR spectra of wild-type E1p demonstrate that this 200 kDa enzyme contains highly flexible regions. The observed dynamic character of E1p and of Nterm-E1p is likely required for the binding of the E1p dimer to the two different binding sites on E2p. Moreover, the flexibility might be essential in sustaining the allosteric properties of the enzyme bound in the complex.
Ascorbate is an outstanding antioxidant in human blood plasma. (1989)

We have shown recently that the temporal order of antioxidant consumption in human blood plasma exposed to a constant flux of aqueous peroxyl radicals is ascorbate = protein thiols greater than bilirubin greater than urate greater than alpha-tocopherol and that detectable lipid peroxidation starts only after ascorbate has been consumed completely. In this paper, we show that it is indeed ascorbate that completely protects plasma lipids against detectable peroxidative damage induced by aqueous peroxyl radicals and that ascorbate is the only plasma antioxidant that can do so. Plasma devoid of ascorbate, but no other endogenous antioxidant, is extremely vulnerable to oxidant stress and susceptible to peroxidative damage to lipids. The plasma proteins' thiols, although they become oxidized immediately upon exposure to aqueous peroxyl radicals, are inefficient radical scavengers and appear to be consumed mainly by autoxidation. Our data demonstrate that ascorbate is the most effective aqueous-phase antioxidant in human blood plasma and suggest that in humans ascorbate is a physiological antioxidant of major importance for protection against diseases and degenerative processes caused by oxidant stress.
Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. (1996)

Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.
Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits. (1991)

Bolus intravenous administration of Bat-PA would facilitate prompt initiation of thrombolytic therapy, and the avoidance of plasminemia could result in fewer and less severe bleeding complications.
Models for the Specific Adhesion of Cells to Cells (1978)

A theoretical framework is proposed for the analysis of adhesion between cells or of cells to surfaces when the adhesion is mediated by reversible bonds between specific molecules such as antigen and antibody, lectin and carbohydrate, or enzyme and substrate. From a knowledge of the reaction rates for reactants in solution and of their diffusion constants both in solution and on membranes, it is possible to estimate reaction rates for membrane-bound reactants. Two models are developed for predicting the rate of bond formation between cells and are compared with experiments. The force required to separate two cells is shown to be greater than the expected electrical forces between cells, and of the same order of magnitude as the forces required to pull gangliosides and perhaps some integral membrane proteins out of the cell membrane.
The Data Mining Advisor: Meta-learning at the Service of Practitioners (2006)

In order to make machine learning algorithms more usable, our community must be able to design robust systems that offer support to practitioners. In the context of classification, this amounts to developing assistants, which deal with the increasing number of models and techniques, and give advice dynamically on such issues as model selection and method combination. This paper briefly reviews the potential of meta-learning in this context and reports on the early success of a Web-based data mining assistant.
Intratympanic gentamicin treatment for unilateral Ménière's disease: long-term follow up of a proven regime (2012)

Fixed-dose intratympanic gentamicin controlled symptomatic unilateral Ménière's disease in both the short and long term.
Efficiency of DNA replication in the polymerase chain reaction (1996)

A detailed quantitative kinetic model for the polymerase chain reaction (PCR) is developed, which allows us to predict the probability of replication of a DNA molecule in terms of the physical parameters involved in the system. The important issue of the determination of the number of PCR cycles during which this probability can be considered to be a constant is solved within the framework of the model. New phenomena of multimodality and scaling behavior in the distribution of the number of molecules after a given number of PCR cycles are presented. The relevance of the model for quantitative PCR is discussed, and a novel quantitative PCR technique is proposed.
Salt Dependence of Ion Transport and DNA Translocation through Solid-State Nanopores (2005)

We report experimental measurements of the salt dependence of ion transport and DNA translocation through solid-state nanopores. The ionic conductance shows a three-order-of-magnitude decrease with decreasing salt concentrations from 1 M to 1 muM, strongly deviating from bulk linear behavior. The data are described by a model that accounts for a salt-dependent surface charge of the pore. Subsequently, we measure translocation of 16.5-mum-long dsDNA for 50 mM to 1 M salt concentrations. DNA translocation is shown to result in either a decrease ([KCl] > 0.4 M) or increase of the ionic current ([KCl] < 0.4 M). The data are described by a model where current decreases result from the partial blocking of the pore and current increases are attributed to motion of the counterions that screen the charge of the DNA backbone. We demonstrate that the two competing effects cancel at a KCl concentration of 370 +/- 40 mM.
Characterization of a cDNA-encoding rabbit brain heme oxygenase-2 and identification of a conserved domain among mammalian heme oxygenase isozymes: Possible heme-binding site? (1991)

A 1.3-kb rat testis cDNA clone for heme oxygenase-2 (HO-2) was used as a Northern blot hybridization probe, and a single homologous mRNA species, of approximately 1.3 kb in rabbit brain and testis was detected. This contrasted with the observation made with rat brain in which two HO-2 transcripts of approximately 1.3 and 1.9 kb were detected. Use of the same rat HO-2 probe to screen a rabbit brain cDNA library in lambda gt11 resulted in the recovery of a single 1.2-kb cDNA clone. This cDNA exhibits 84% overall nucleotide sequence homology with rat HO-2 and encodes a protein of 35,352 Da, displaying 88% amino acid sequence homology with rat testis HO-2. Furthermore, when expressed in Escherichia coli, the rabbit cDNA-encoded protein displays heme oxygenase activity and cross-reactivity with antibody to rat HO-2. Based on findings obtained through Western immunoblot analysis of partially purified HO-2 protein prepared from rabbit testis and brain, the 35- to 36-kDa molecular form appears to be the major HO-2 form detected in the brain, whereas a 42-kDa species is the predominant form observed in rabbit testis. Having deduced the amino acid sequence of rabbit brain HO-2, we provide a comparison of this sequence with those of rat, mouse, and human HO-1 and rat HO-2, and thereby identify a 24-amino-acid-long peptide region which, except for one residue, is identical in all five species of HO-1 and HO-2 compared (96% similarity), and exhibits 100% similarity in predicted secondary structure (for this region) in all five proteins. We propose that this peptide may be important to the heme binding and isomer-specific tetrapyrrole cleavage activities of the heme oxygenase isozymes.
Lattice-Based Improvements for Voice Triggering Using Graph Neural Networks (2020)

Voice-triggered smart assistants often rely on detection of a trigger-phrase before they start listening for the user request. Mitigation of false triggers is an important aspect of building a privacy-centric non-intrusive smart assistant. In this paper, we address the task of false trigger mitigation (FTM) using a novel approach based on analyzing automatic speech recognition (ASR) lattices using graph neural networks (GNN). The proposed approach uses the fact that decoding lattice of a falsely triggered audio exhibits uncertainties in terms of many alternative paths and unexpected words on the lattice arcs as compared to the lattice of a correctly triggered audio. A pure trigger-phrase detector model doesn't fully utilize the intent of the user speech whereas by using the complete decoding lattice of user audio, we can effectively mitigate speech not intended for the smart assistant. We deploy two variants of GNNs in this paper based on 1) graph convolution layers and 2) self-attention mechanism respectively. Our experiments demonstrate that GNNs are highly accurate in FTM task by mitigating ~87% of false triggers at 99% true positive rate (TPR). Furthermore, the proposed models are fast to train and efficient in parameter requirements.
The mechanism of optic nerve damage in experimental acute intraocular pressure elevation. (1980)

We produced intraocular pressure (IOP) elevations in 32 primate eyes and studied retinal ganglion cell rapid axonal transport with autoradiography and electron microscopy. Animals breathing room air at sea level pressure were compared to animals breathing 100% oxygen at 3 atm pressure in a hyperbaric chamber. Despite major increases in arterial oxygen levels in the hyperbarically oxygenated animals, both groups had axonal transport blockade at the optic nerve head. Anoxia appears not to be the most important cause of acute axonal damage induced by elevated IOP. The pattern of axonal abnormality within individual fiber bundles at the optic nerve head provides support for mechanical compression as a more likely alternative cause for induced neural damage.
Temperature dependent spectral response measurements for III-V multi-junction solar cells (2003)

Temperature coefficients for the integrated current of all three subcells in a production InGaP/InGaAs/Ge solar cell structure have been measured at temperatures ranging from 5/spl deg/C to 100/spl deg/C. The InGaP, InGaAs, and germanium temperature coefficients are 0.011, 0.009, and 0.044 mA/cm/sup 2///spl deg/C, respectively. This data can be used to design multi-junction solar cells for optimum performance at any specified operating temperature in this range. The predicted current mismatch for a similar triple junction operating at 100/spl deg/C but designed to be current matched at 28/spl deg/C is approximately 3%.
Long-Acting Peptidomimergic Control of Gigantism Caused by Pituitary Acidophilic Stem Cell Adenoma* (2000)

Gigantism is caused by GH hypersecretion occurring before epiphyseal long bone closure and usually is associated with pituitary adenoma. A 15-yr-old female patient presented with accelerated growth due to a large pituitary tumor that was surgically resected to relieve pressure effects. Second surgery to remove residual tumor tissue was followed by administration of octreotide LAR, a long-acting depot somatostatin analog, together with long-acting cabergoline. Height was over the 95th percentile, with evidence of a recent growth spurt. Serum GH levels were more than 60 ng/mL (normal, <10 ng/mL) with no suppression to 75 g oral glucose, and serum PRL (>8,000 ng/mL; normal, <23 ng/mL) and insulin-like growth factor I levels (845 ng/mL; age-matched normal, 242-660 ng/mL) were elevated. Histology, immunostaining, and electron microscopy demonstrated a pituitary acidophil stem cell adenoma. Tumor tissue expressed both somatostatin receptor type 2 and dopamine receptor type 2. The Gs alpha subunit, GHRH receptor, and MEN1 genes were intact, and tumor tissue abundantly expressed pituitary tumor transforming gene (PTTG). Serum GH and PRL levels were controlled after two surgeries, and with continued cabergoline and octreotide LAR GH, PRL, and insulin-like growth factor I levels were normalized. In conclusion, administration of long-acting somatostatin analog every 4 weeks in combination with a long-acting dopamine agonist biweekly controlled biochemical parameters and accelerated growth in a patient with gigantism caused by a rare pituitary acidophil stem cell adenoma.
A shuttle mutagenesis system for tagging genes in the yeast Yarrowia lipolytica (1998)

A shuttle mutagenesis system was developed for the dimorphic yeast Yarrowia lipolytica. This system combines transposon insertions generated in Escherichia coli with the transformation of yeast with the Tn-mutagenized DNA. The mini-transposon mTn-3xHA/GFP, used in Saccharomyces cerevisiae for producing stable insertions, was adapted for use in the yeast Y. lipolytica. The mTnYl1 transposon (for mini-Tn of Y. lipolytica) confers resistance to tetracycline in E. coli. It also contains the Y. lipolytica URA3 gene for selection of yeast transformants, and the coding sequence for the S65T mutant form of GFP. The rare cutter endonuclease, I-SceI, restriction site, which enables identification of the chromosomal localization of mutagenized genes, was also incorporated. mTnYl1 was first tested on the ACO1 gene, which encodes an Acyl CoA oxidase isozyme. The mutagenesis system was further validated on a Y. lipolytica genomic DNA library constructed in a pHSS6 derivative vector. Mutants with a particular morphology or defective for alkane, fatty acids and oil degradation were obtained.