gebhart/patrepeval huggingface dataset:
Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischaemia (1988)

Arrhythmia scores have been used in recent years to facilitate the analysis of arrhythmias, particularly in relation to regional myocardial ischaemia. The recent Lambeth Conventions recommended caution in the use of arrhythmia scores since their use may be misleading. In the present study seven scoring systems were examined in an attempt to validate the use of arrhythmia scores. A strong positive correlation was present between all seven scores. Furthermore, the scores all correlated with the incidences of ventricular fibrillation, ventricular tachycardia, and ventricular premature beats in early myocardial ischaemia. All seven scores successfully detected statistically significant reductions in the incidence of ventricular fibrillation resulting from the administration of two drugs. Some of the scores occasionally showed statistically significant reductions when effects on the raw arrhythmia data were not statistically significant. In this respect, parametric statistical analysis of arrhythmia scores may be a more sensitive method of quantifying arrhythmias than non-parametric analysis of binomially distributed raw data such as the incidence of ventricular fibrillation (in accordance with the power of such tests) indicating that the scores have precision. However, none of the scores incorrectly showed a statistically significant reduction when the raw data expressed a statistically significant or non-significant increase, indicating that the scores have accuracy. In conclusion, it is possible to design many arrhythmia scores that show changes in arrhythmia severity when more conventional analyses show only non-statistically significant trends. When used in conjunction with raw arrhythmia data, comprehensive drug dose ranges, and appropriate parametric statistical tests, arrhythmia scores facilitate the quantification of arrhythmias. It is recommended that arrhythmia scores should be used only for quantifying group data and model building and not for prognostic purposes in individuals.
Defective thrombus formation in mice lacking coagulation factor XII (2005)

Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)-mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.
The Action of Isobutylmagnesium Bromide on 3,4,5-Trimethoxybenzonitrile (1939)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Action of Isobutylmagnesium Bromide on 3,4,5-TrimethoxybenzonitrileH. L. Haller and P. S. SchafferCite this: J. Am. Chem. Soc. 1939, 61, 8, 2175–2177Publication Date (Print):August 1, 1939Publication History Published online1 May 2002Published inissue 1 August 1939https://pubs.acs.org/doi/10.1021/ja01877a057https://doi.org/10.1021/ja01877a057research-articleACS PublicationsRequest reuse permissionsArticle Views49Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Engineering the substrate and inhibitor specificities of human coagulation Factor VIIa (2007)

The remarkably high specificity of the coagulation proteases towards macromolecular substrates is provided by numerous interactions involving the catalytic groove and remote exosites. For FVIIa [activated FVII (Factor VII)], the principal initiator of coagulation via the extrinsic pathway, several exosites have been identified, whereas only little is known about the specificity dictated by the active-site architecture. In the present study, we have profiled the primary P4-P1 substrate specificity of FVIIa using positional scanning substrate combinatorial libraries and evaluated the role of the selective active site in defining specificity. Being a trypsin-like serine protease, FVIIa had P1 specificity exclusively towards arginine and lysine residues. In the S2 pocket, threonine, leucine, phenylalanine and valine residues were the most preferred amino acids. Both S3 and S4 appeared to be rather promiscuous, however, with some preference for aromatic amino acids at both positions. Interestingly, a significant degree of interdependence between the S3 and S4 was observed and, as a consequence, the optimal substrate for FVIIa could not be derived directly from a subsite-directed specificity screen. To evaluate the role of the active-site residues in defining specificity, a series of mutants of FVIIa were prepared at position 239 (position 99 in chymotrypsin), which is considered to be one of the most important residues for determining P2 specificity of the trypsin family members. This was confirmed for FVIIa by marked changes in primary substrate specificity and decreased rates of antithrombin III inhibition. Interestingly, these changes do not necessarily coincide with an altered ability to activate Factor X, demonstrating that inhibitor and macromolecular substrate selectivity may be engineered separately.
SYNTHESIS ROUTES FOR LARGE VOLUMES OF NANOPARTICLES (2004)

▪ Abstract This review focuses on the preparation of capped nanoparticles of inorganic materials, classified by composition. The materials described include elemental metals and metalloids (semiconductors), chalcogenide II–VI and IV–VI semiconductors, III–V semiconductors, and oxides (both of simple- and multitransition metal). Although particular emphasis is placed on methods that yield large volumes of nanoparticles, recent novel methods that may not necessarily be scalable are also reviewed. The review makes apparent the richness of chemistry that has become routine to practitioners in the field; diverse inorganic systems with distinct chemistry require distinct methods of preparation.
Structural and Spectroscopic Analysis of the F393H Mutant of Flavocytochrome P450 BM3 (2001)

In the preceding paper in this issue [Ost, T. W. B., Miles, C. S., Munro, A. W., Murdoch, J., Reid, G. A., and Chapman, S. K. (2001) Biochemistry 40, 13421-13429], we have established that the primary role of the phylogenetically conserved phenylalanine in flavocytochrome P450 BM3 (F393) is to control the thermodynamic properties of the heme iron, so as to optimize electron-transfer both to the iron (from the flavin redox partner) and onto molecular oxygen. In this paper, we report a detailed study of the F393H mutant enzyme, designed to probe the structural, spectroscopic, and metabolic profile of the enzyme in an attempt to identify the factors responsible for causing the changes. The heme domain structure of the F393H mutant has been solved to 2.0 A resolution and demonstrates that the histidine replaces the phenylalanine in almost exactly the same conformation. A solvent water molecule is hydrogen bonded to the histidine, but there appears to be little other gross alteration in the environment of the heme. The F393H mutant displays an identical ferric EPR spectrum to wild-type, implying that the degree of splitting of the iron d orbitals is unaffected by the substitution, however, the overall energy of the d-orbitals have changed relative to each other. Magnetic CD studies show that the near-IR transition, diagnostic of heme ligation state, is red-shifted by 40 nm in F393H relative to wild-type P450 BM3, probably reflecting alteration in the strength of the iron-cysteinate bond. Studies of the catalytic turnover of fatty acid (myristate) confirms NADPH oxidation is tightly coupled to fatty acid oxidation in F393H, with a product profile very similar to wild-type. The results indicate that gross conformational changes do not account for the perturbations in the electronic features of the P450 BM3 heme system and that the structural environment on the proximal side of the P450 heme must be conformationally conserved in order to optimize catalytic function.
Plant-Associated Methylobacteria as Co-Evolved Phytosymbionts (2007)

Due to their wall-associated pectin metabolism, growing plant cells emit significant amounts of the one-carbon alcohol methanol. Pink-pigmented microbes of the genus Methylobacterium that colonize the surfaces of leaves (epiphytes) are capable of growth on this volatile C1-compound as sole source of carbon and energy. In this article the results of experiments with germ-free (gnotobiotic) sporophytes of angiosperms (sunflower, maize) and gametophytes of bryophytes (a moss and two liverwort species) are summarized. The data show that methylobacteria do not stimulate the growth of these angiosperms, but organ development in moss protonemata and in thalli of liverworts is considerably enhanced. Since methylobacteria produce and secrete cytokinins and auxin, a model of plant-microbe-interaction (symbiosis) is proposed in which the methanol-consuming bacteria are viewed as coevolved partners of the gametophyte that determine its growth, survival and reproduction (fitness). This symbiosis is restricted to the haploid cells of moisture-dependent "living fossil" plants; it does not apply to the diploid sporophytes of higher embryophytes, which are fully adapted to life on land and apparently produce sufficient amounts of endogenous phytohormones.
Cross-SAGD (XSAGD)—An Accelerated Bitumen Recovery Alternative (2005)

Abstract Steam Assisted Gravity Drainage (SAGD)1 has become the preferred in-situ recovery concept for Athabasca bitumen. However, to maintain steam-trap control, rates are limited by the close vertical spacing between the parallel horizontal wells. In Cross-SAGD (XSAGD) the injection wells are perpendicular to the producing wells. Sections of the wells near the crossing points are either restricted from the start, or are later plugged, to achieve a significant rate and thermal efficiency advantage over SAGD, especially in cases where low pressure is required.
Determination of carbohydrate profiles of Bacillus anthracis and Bacillus cereus including identification of O-methyl methylpentoses by using gas chromatography-mass spectrometry (1993)

Bacillus anthracis and Bacillus cereus are closely related pathogenic organisms that are difficult to differentiate phenotypically or genotypically. It is well known that vegetative and spore forms of bacilli are quite distinct both morphologically and chemically, but spore-specific chemical markers allowing these species to be distinguished have not been previously described. By using gas chromatography-mass spectrometry, vegetative cells and spores of the two species were shown to exhibit distinct carbohydrate profiles. Profiles of vegetative B. anthracis typically contained high levels of galactose but did not contain galactosamine, whereas B. cereus contained galactosamine and generally low levels of galactose. Spore cultures exhibited unique carbohydrate profiles compared with those of vegetative cultures. B. anthracis spore profiles contained rhamnose alone, whereas B. cereus spore profiles contained rhamnose and fucose. Additionally, two spore-specific O-methylated methylpentoses were discovered. Both B. anthracis and B. cereus spores contained 3-O-methyl rhamnose, whereas B. cereus spores also contained 2-O-methyl rhamnose. Carbohydrate profiling is demonstrated to be a powerful tool for differentiating the two closely related species. Differentiation does not depend on whether organisms are in the vegetative or spore stage of growth.
Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis (1977)

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.
Cyclin dependent kinases in cancer (2012)

Cell cycle progression through each phase is regulated by heterodimers formed by cyclin-dependent kinases (CDKs) and their regulatory partner proteins, the cyclins. Together they coordinate the cellular events through cell cycle. De-regulation of cell-cycle control due to aberrant CDK activity is a common feature of most cancer types. Intensive research on small molecules that target cell cycle regulatory proteins has led to the identification of many candidate inhibitors that are able to arrest proliferation and induce apoptosis in neoplastic cells as a promising strategy to treat cancer. Interestingly, cyclin-dependent kinases (CDKs) have also been proposed as therapeutic targets for Multiple Myeloma (MM). Overexpression and aberrant expression of the cyclins, specifically the D cyclins is seen in the majority of MM underscoring the value of exploring CDK inhibition in MM which currently remains an incurable neoplastic plasma-cell disorder. It is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenviroment and associated organ dysfunction. Recent preclinical and early clinical data explore several CDK inhibitors in the context of MM. This review will provide an overview of the main classes of CDK inhibitors with a focus on their mechanism of action and discuss clinical and pharmacological implications of CDK inhibitors as possible therapeutic approaches for the treatment of cancer with specific consideration to MM.
Localization of two high‐threshold potassium channel subunits in the rat central auditory system (2001)

The firing pattern of auditory neurons is determined in part by the type of voltage-sensitive potassium channels expressed. The expression patterns for two high-threshold potassium channels, Kv3.1 and Kv3.3, that differ in inactivation properties were examined in the rat auditory system. The positive activation voltage and rapid deactivation kinetics of these channels provide rapid repolarization of action potentials with little effect on action potential threshold. In situ hybridization experiments showed that Kv3.3 mRNA was highly expressed in most auditory neurons in the rat brainstem, whereas Kv3.1 was expressed in a more limited population of auditory neurons. Notably, Kv3.1 mRNA was not expressed in neurons of the medial and lateral superior olive and a subpopulation of neurons in the ventral nucleus of the lateral lemniscus. These results suggest that Kv3.3 channels may be the dominant Kv3 subfamily member expressed in brainstem auditory neurons and that, in some auditory neurons, Kv3.1 and Kv3.3 may coassemble to form functional channels. The localization of Kv3.1 protein was examined immunohistochemically. The distribution of stained somata and neuropil varied across auditory nuclei and correlated with the distribution of Kv3.1 mRNA-expressing neurons and their terminal arborizations, respectively. The intensity of Kv3.1 immunoreactivity varied across the tonotopic map in the medial nucleus of the trapezoid body with neurons responding best to high-frequency tones most intensely labeled. Thus, auditory neurons may vary the types and amount of K(+) channel expression in response to synaptic input to subtly tune their firing properties.
Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir (2015)

Porcine endogenous retroviruses (PERVs) are present in the genomes of pig cells. The PERV-A/C recombinant virus can infect human cells and is a major risk of zoonotic disease in the case of xenotransplantation of pig organs to humans. Raltegravir (RAL) is a viral integrase (IN) inhibitor used in highly active antiretroviral treatment. In the present study, we explored the potential use of RAL against PERV-A/C. We report (i) a three-dimensional model of the PERV-A/C intasome complexed with RAL, (ii) the sensitivity of PERV-A/C IN to RAL in vitro and (iii) the sensitivity of a PERV-A/C-IRES-GFP recombinant virus to RAL in cellulo. We demonstrated that RAL is a potent inhibitor against PERV-A/C IN and PERV-A/C replication with IC50s in the nanomolar range. To date, the use of retroviral inhibitors remains the only way to control the risk of zoonotic PERV infection during pig-to-human xenotransplantation.
Subcellular distribution and some properties of N-ethylmaleimide-sensitive and-insensitive forms of glycerol phosphate acyltransferase in rat adipocytes (1980)

1. Glycerol phosphate acyltransferase (GPAT) activities were measured in subcellular fractions obtained from rat epididymal adipocytes. These contained both N-ethylmaleimide-sensitive and N-ethylmaleimide-insensitive forms of the enzyme. 2. As shown by parallel measurements of marker enzymes, N-ethylmaleimide-insensitive GPAT is most probably a mitochondrial activity, whereas N-ethylmaleimide-sensitive GPAT is the microsomal enzyme. 3. Subcellular distributions are also reported for dihydroxyacetone phosphate acyltransferase (DHAPAT) (assayed with and without N-ethylmaleimide), monoacylglycerol phosphate acyltransferase (MGPAT) and Mg2+-dependent and Mg2+-independent forms of phosphatidate phosphohydrolase (PPH).
Display of Information for Time-Critical Decision Making (2013)

We describe methods for managing the complexity of information displayed to people responsible for making high-stakes, time-critical decisions. The techniques provide tools for real-time control of the configuration and quantity of information displayed to a user, and a methodology for designing flexible human-computer interfaces for monitoring applications. After defining a prototypical set of display decision problems, we introduce the expected value of revealed information (EVRI) and the related measure of expected value of displayed information (EVDI). We describe how these measures can be used to enhance computer displays used for monitoring complex systems. We motivate the presentation by discussing our efforts to employ decision-theoretic control of displays for a time-critical monitoring application at the NASA Mission Control Center in Houston.
Transplantable Metastasizing Prostate Adenocarcinomas in Rats<xref ref-type="fn" rid="fn2">2</xref> (1975)

Three spontaneous prostate adenocarcinomas from aged, randombred, germfree Lobund Wistar rats were transplanted, without change, through several series of conventional Lobund Wistar rats. One tumor type differed histologically from the other two tumor types. Rats with subcutaneously transplanted tumors developed metastatic tumors in the lymph nodes and lungs. No microbial agent was detected in the tumor cells.
Listeria monocytogenes phosphatidylinositol-specific phospholipase C has evolved for virulence by greatly reduced activity on GPI anchors (2005)

Listeria monocytogenes phosphatidylinositol-specific phospholipase C (PI-PLC) plays a critical role in escape of this human pathogen from host cell vacuoles. Unlike classical bacterial PI-PLCs, the L. monocytogenes enzyme has very weak activity on glycosylphosphatidylinositol (GPI)-anchored proteins. Previous crystal structure analysis has revealed that a small beta-strand (Vb) is present in Bacillus cereus PI-PLC and is absent in the enzyme from L. monocytogenes. This Vb beta-strand in B. cereus PI-PLC forms contacts with the glycan linker of GPI anchors, which presumably increases its activity on GPI-anchored proteins. In this study, we show that, of all known bacterial PI-PLCs, those from listeriae are the only ones that lack the beta-strand. Expression by L. monocytogenes of B. cereus PI-PLC, which has strong activity on GPI-anchored proteins, inhibited bacterial escape from a vacuole and cell-to-cell spread, resulting in greatly reduced virulence in mice. Deletion of the Vb beta-strand from B. cereus PI-PLC abolished its ability to cleave GPI-anchored proteins, decreased its inhibitory effects, and increased its virulence in mice. These results strongly suggest that L. monocytogenes PI-PLC has evolved as an important determinant of L. monocytogenes pathogenesis by absence of the Vb beta-strand, thus leading to greatly reduced activity on GPI-anchored proteins.
Structure-activity relationship study of human interleukin-3. Identification of residues required for biological activity by site-directed mutagenesis (1991)

Recombinant human interleukin-3 (rhuIL-3) variants were generated by site-directed mutagenesis and expression in Escherichia coli. Amino acid deletions and substitutions were made in the previously identified epitopes of two huIL-3-specific neutralizing monoclonal antibodies (mAbs). The rhuIL-3 variants were analyzed for their ability to bind to the IL-3 receptor and to induce the proliferation of the human IL-3-dependent cell line M-O7. Several deletion mutants spanning the epitopes of these neutralizing mAbs indicated the importance of residues Pro33 and Leu34 for biological activity. Further, substitution of Pro33 with Asn (Asn33) showed an enhanced proliferative activity (4-fold) and a moderate increase in receptor binding (2-fold) compared to wild-type (wt) rhuIL-3. The most remarkable change, however, was seen with variant Gly33, which showed a 14-fold increase in promoting the growth of M-O7 cells without a significant modification in its receptor binding capacity. In contrast, substitution of Leu34 with Gly (Gly34) yielded an IL-3 variant that had a 25-fold decreased receptor binding capacity and proliferative activity, while Glu34 had properties similar to wild-type rhuIL-3. Analysis of the binding of these variants to different rhuIL-3-specific monoclonal antibodies suggested that no major modification had occurred in their conformations. These results indicate that both residues, Pro33 and Leu34, play a critical role in modulating the activity of rhuIL-3.