gebhart/patrepeval huggingface dataset:
Macropinosome quantitation assay (2014)

In contrast to phagocytosis, macropinocytosis is not directly initiated by interactions between cell surface receptors and cargo ligands, but is a result of constitutive membrane ruffling driven by dynamic remodelling of cortical actin cytoskeleton in response to stimulation of growth factor receptors. Wang et al. (2010) [13] developed a reliable assay that allows quantitative assessment of the efficiency and kinetics of macropinosome biogenesis and/or maturation in cells where the function of a targeted protein has been perturbed by pharmacological inhibitors or by knock-down or knock-out approaches. In this manuscript we describe a modified quantitative protocol to measure the rate and volume of fluid phase uptake in adherent cells. This assay:•uses fluorescent dextran, microscopy and semi-automated image analysis;•allows quantitation of macropinosomes within large numbers of individual cells;•can be applied also to non-homogenous cell populations including transiently transfected cell monolayers. We present the background necessary to consider when customising this protocol for application to new cell types or experimental variations.
Comparison of tests used to distinguish smokers from nonsmokers. (1987)

Questionnaire and biochemical measures of smoking were studied in 211 hospital outpatients. Eleven different tests of smoke intake were compared for their ability to categorize smokers and nonsmokers correctly. The concentration of cotinine, whether measured in plasma, saliva, or urine, was the best indicator of smoking, with sensitivity of 96-97 per cent and specificity of 99-100 per cent. Thiocyanate provided the poorest discrimination. Carbon monoxide measured as blood carboxyhaemoglobin or in expired air gave sensitivity and specificity of about 90 per cent. Sensitivities of the tests were little affected by the presence among the claimed nonsmokers of a group of 21 "deceivers" who concealed their smoking. It is concluded that cotinine is the measure of choice, but for most clinical applications carbon monoxide provides an acceptable degree of discrimination and is considerably cheaper and simpler to apply.
Toxicity studies with flutrimazole. (1992)

Studies with 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H- imidazole (flutrimazole, CAS 119006-77-8), a new topical imidazole antifungal agent, have been carried out to investigate the acute toxicity of the active substance in mice and rats, as well as the acute ocular and dermal irritation in rabbits, the dermal tolerance after repeated dose (21 days) applications in rabbits, and the sensitising, photoallergic and phototoxic potential in guinea pigs using 1% flutrimazole cream. LD50 values after oral or intraperitoneal administration were greater than or equal to 1000 mg/kg in both mice and rats, which reveal a very low acute toxicity of flutrimazole. No differences were found between the excipient and 1% flutrimazole cream in the acute ocular and dermal irritation studies in rabbits, the irritation indexes being indicative of no lesions due to flutrimazole. Cumulative dermal irritation studies in rabbits showed an improved local tolerance of a skin cream containing 1% flutrimazole as compared to a commercial skin cream containing 1% clotrimazole. The irritation indexes were 1.2 and 3.7, respectively (p less than 0.01). The corresponding histophatological findings confirmed the better local tolerance of 1% flutrimazole cream. Furthermore, it has been found that flutrimazole cream lacks sensitising potential (Magnusson and Kligman test), is also devoid of phototoxic potential and does not induce photoallergic reactions in guinea pigs, these data being confirmed by histopathological studies. These results, together with the very slight systemic absorption rate of flutrimazole from the 1% topical drug form, clearly show that no restrictions should be taken in the use of the cream for reasons of systemic toxicity or dermal tolerance.
Intensive Care for Extreme Prematurity — Moving beyond Gestational Age (2008)

The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 [ClinicalTrials.gov] and NCT00009633 [ClinicalTrials.gov].).
Impact of Genotypic Studies on Mycobacterial Taxonomy: the New Mycobacteria of the 1990s (2003)

The advancement of genetic techniques has greatly boosted taxonomic studies in recent years. Within the genus Mycobacterium, 42 new species have been detected since 1990, most of which were grown from clinical samples. Along with species for which relatively large numbers of strains have been reported, some of the new species of mycobacteria have been detected rarely or even only once. From the phenotypic point of view, among the new taxa, chromogens exceed nonchromogens while the numbers of slowly and rapidly growing species are equivalent. Whereas conventional identification tests were usually inconclusive, an important role was played by lipid analyses and in particular by high-performance liquid chromatography. Genotypic investigations based on sequencing of 16S rRNA gene have certainly made the most important contribution. The investigation of genetic relatedness led to the redistribution of the species previously included in the classically known categories of slow and rapid growers into new groupings. Within slow growers, the intermediate branch related to Mycobacterium simiae and the cluster of organisms related to Mycobacterium terrae have been differentiated; among rapid growers, the group of thermotolerant mycobacteria has emerged. The majority of species are resistant to isoniazid and, to a lesser extent, to rifampin. Many of the new species of mycobacteria are potentially pathogenic, and there are numerous reports of their involvement in diseases. Apart from disseminated and localized diseases in immunocompromised patients, the most frequent infections in immunocompetent people involve the lungs, skin, and, in children, cervical lymph nodes. The awareness of such new mycobacteria, far from being a merely speculative exercise, is therefore important for clinicians and microbiologists.
Mode of action of P2Y12 antagonists as inhibitors of platelet function (2010)

P2Y(12) receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y (12)receptors. However, some P2Y(12) receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y(12) antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y(12) receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y(12) antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y(12) antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y(12) antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y (12)antagonists enhanced VASP-phosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y(12)receptors and not through another G-protein-coupled receptor.
Drosophila P-element transposase is a novel site-specific endonuclease (1997)

We developed in vitro assays to study the first step of the P-element transposition reaction: donor DNA cleavage. We found that P-element transposase required both 5' and 3' P-element termini for efficient DNA cleavage to occur, suggesting that a synaptic complex forms prior to cleavage. Transposase made a staggered cleavage at the P-element termini that is novel for all known site-specific endonucleases: the 3' cleavage site is at the end of the P-element, whereas the 5' cleavage site is 17 bp within the P-element 31-bp inverted repeats. The P-element termini were protected from exonucleolytic degradation following the cleavage reaction, suggesting that a stable protein complex remains bound to the element termini after cleavage. These data are consistent with a cut-and-paste mechanism for P-element transposition and may explain why P elements predominantly excise imprecisely in vivo.
Prediction of Resistance to Small Molecule FLT3 Inhibitors (2004)

Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AML patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors.
Kinesiologic and biomechanical aspects of the normal gait (1985)

In this study the biomechanical and kinesiologic aspects of the normal gait have been reviewed by emphasizing the importance of the gait analysis. Also, the factors influencing the energy consumption have been described briefly.
Platelet thrombospondin forms a trimolecular complex with plasminogen and histidine-rich glycoprotein. (1985)

Thrombospondin (TSP), a multifunctional alpha-granule glycoprotein of human platelets binds fibrinogen, fibronectin, heparin, histidine-rich glycoprotein (HRGP), and plasminogen (Plg), and thus, may play an important role in regulating thrombotic influences at vessel surfaces. In this study we have demonstrated that purified human platelet TSP formed a trimolecular complex with human Plg and HRGP. Complex formation was detected by a specific binding enzyme-linked immunosorbent assay (ELISA) which demonstrated simultaneous binding of fluid-phase Plg and HRGP to TSP adsorbed to microtitration wells. While neither ligand inhibited complex formation of the other with TSP, 10 mM epsilon-amino-n-caproic acid selectively blocked incorporation of Plg into the complex, suggesting that TSP contains independent binding sites for Plg and HRGP. Comparable extent of trimolecular complex formation was also detected when TSP monomer was substituted for whole TSP in the ELISA. HRGP covalently cross-linked to Sepharose 4B simultaneously bound both 125I-TSP and 131I-Plg, confirming trimolecular complex formation. Rocket immunoelectrophoresis of mixtures of the purified radiolabeled proteins into anti-Plg containing agarose also confirmed trimolecular complex formation. The TSP-HRGP-Plg complex bound a similar amount of heparin as the TSP-HRGP complex, demonstrating that the HRGP within the trimolecular complex maintained functional capability. Similarly, using a fluorometric plasmin substrate, the trimolecular complex was shown to be an effective substrate for tissue plasminogen activator. Significant amounts of plasmin were generated from the TSP-HRGP-Plg complex (equivalent to that from the TSP-Plg complex), but the rate of plasmin generation from the trimolecular complex was greater than from the bimolecular complex, suggesting an important interaction of HRGP with Plg when both are complexed to TSP. The macromolecular assembly of these three proteins on cellular surfaces, such as the platelet, may serve important regulatory functions, both prothrombotic at sites of active fibrin deposition and proteolytic in nonfibrin-containing microenvironments.
Crimeware: Understanding New Attacks and Defenses (2008)

“This book is the most current and comprehensive analysis of the state of Internet security threats right now. The review of current issues and predictions about problems years away are critical for truly understanding crimeware. Every concerned person should have a copy and use it for reference.”i??Garth Bruen, Project KnujOn DesignerThere's a new breed of online predatorsi??serious criminals intent on stealing big bucks and top-secret informationi??and their weapons of choice are a dangerous array of tools called “crimeware.” With an ever-growing number of companies, organizations, and individuals turning to the Internet to get things done, there's an urgent need to understand and prevent these online threats.Crimeware: Understanding New Attacks and Defenses will help security professionals, technical managers, students, and researchers understand and prevent specific crimeware threats. This book guides you through the essential security principles, techniques, and countermeasures to keep you one step ahead of the criminals, regardless of evolving technology and tactics. Security experts Markus Jakobsson and Zulfikar Ramzan have brought together chapter contributors who are among the best and the brightest in the security industry. Together, they will help you understand how crimeware works, how to identify it, and how to prevent future attacks before your company's valuable information falls into the wrong hands. In self-contained chapters that go into varying degrees of depth, the book provides a thorough overview of crimeware, including not only concepts prevalent in the wild, but also ideas that so far have only been seen inside the laboratory.With this book, you willi? Understand current and emerging security threats including rootkits, bot networks, spyware, adware, and click fraud Recognize the interaction between various crimeware threats Gain awareness of the social, political, and legal implications of these threats Learn valuable countermeasures to stop crimeware in its tracks, now and in the future Acquire insight into future security trends and threats, and create an effective defense plan With contributions by Gary McGraw, Andrew Tannenbaum, Dave Cole, Oliver Friedrichs, Peter Ferrie, and others.
Evaluation of electrical aggregometry: comparison with optical aggregometry, secretion of ATP, and accumulation of radiolabeled platelets. (1983)

Platelet aggregation has been most commonly studied in vitro by measuring increases in light transmission as platelets aggregate in PRP. Recently, an electrical impedance method for measuring platelet aggregation has been introduced. This method can be used with either PRP or whole blood and measures an increase in impedance across electrodes placed in the blood samples as platelets accumulate on them. We have compared the results obtained by the two methods, using ADP and collagen as aggregating agents, and also have measured the secretion of platelet ATP simultaneously. Although the aggregometry results were similar, recordings obtained by the electrical method did not distinguish two waves of platelet aggregation or correlate with secretion as well as recordings obtained by the optical method. When PGI2 or PGE1 was added to the PRP, both the rate and extent of the increase in light transmittance were inhibited, but the main effect on the increase in impedance was a decrease in its rate and not in its extent. Increases in impedance and secretion of ATP were also measured in whole blood after the platelets had been labeled with a 125I-containing antibody specific for platelet surface glycoproteins. It appeared that the increases in impedance lagged several minutes behind the formation of platelet aggregates and the secretion of platelet ATP. It is suggested that there are advantages and disadvantages to both methods of measurement of platelet aggregation and that the parameters being measured must be clearly understood to properly interpret the results.
M.E.R.O.DE.: a model-driven entity-relationship object-oriented Development method (1994)

Object Orientation has as primary goal to improve the software construction process. Object Oriented analysis, design and software construction should yield software of a high quality: software that is reliable, maintainable, extensible, adaptable. However, delivering large OO software systems in a qualitative way is a significant challenge. Scaling up requires formal precision of the semantics of the modelling techniques and languages used by the development team. And when the target system contains an abundance of parallelism, the problem of validation becomes unfeasible if it is not supported by formal techniques. With the incorporation of formal techniques in the development process, we can expect significant benefits in terms of software quality.For this reason, one might expect a high level of formality in current OOAD methods [9]. Unfortunately, most current OOAD methods are characterised by a low level of formality. The M.E.R.O.DE. methodology addresses this void. By making use of algebra, the methodology has been provided with a formal basis at several levels with a significant improvement of the quality of the software development process as a result.Before presenting M.E.R.O.DE. to the reader in the second section, the first section motivates the development of still another OOA method. The final section demonstrates how exactly the formal definition of M.E.R.O.DE. results in a gain of quality at the software specification level.
Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis (2001)

IL-1beta is one of a family of proinflammatory cytokines thought to be involved in many acute and chronic diseases. Although it is considered to participate in wound repair, no major role has been attributed to IL-1beta in tissue fibrosis. We used adenoviral gene transfer to transiently overexpress IL-1beta in rat lungs after intratracheal administration. The high expression of IL-1beta in the first week after injection was accompanied by local increase of the proinflammatory cytokines IL-6 and TNF-alpha and a vigorous acute inflammatory tissue response with evidence of tissue injury. The profibrotic cytokines PDGF and TGF-beta1 were increased in lung fluid samples 1 week after peak expression of IL-1beta. Although PDGF returned to baseline in the third week, TGF-beta1 showed increased concentrations in bronchoalveolar lavage fluid for up to 60 days. This was associated with severe progressive tissue fibrosis in the lung, as shown by the presence of myofibroblasts, fibroblast foci, and significant extracellular accumulations of collagen and fibronectin. These data directly demonstrate how acute tissue injury in the lung, initiated by a highly proinflammatory cytokine, IL-1beta, converts to progressive fibrotic changes. IL-1beta should be considered a valid target for therapeutic intervention in diseases associated with fibrosis and tissue remodeling.
Protein Glucosylation and Its Role in Protein Folding (2000)

An unconventional mechanism for retaining improperly folded glycoproteins and facilitating acquisition of their native tertiary and quaternary structures operates in the endoplasmic reticulum. Recognition of folding glycoproteins by two resident lectins, membrane-bound calnexin and its soluble homolog, calreticulin, is mediated by protein-linked monoglucosylated oligosaccharides. These oligosaccharides contain glucose (Glc), mannose (Man), and N-acetylglucosamine (GlcNAc) in the general form Glc1Man7-9GlcNAc2. They are formed by glucosidase I- and II-catalyzed partial deglucosylation of the oligosaccharide transferred from dolichol diphosphate derivatives to Asn residues in nascent polypeptide chains (Glc3Man9GlcNAc2). Further deglucosylation of the oligosaccharides by glucosidase II liberates glycoproteins from their calnexin/calreticulin anchors. Monoglucosylated glycans are then recreated by the UDP-Glc:glycoprotein glucosyltransferase (GT), and thus recognized again by the lectins, only when linked to improperly folded protein moieties, as GT behaves as a sensor of glycoprotein conformations. The deglucosylation-reglucosylation cycle continues until proper folding is achieved. The lectin-monoglucosylated oligosaccharide interaction is one of the alternative ways by which cells retain improperly folded glycoproteins in the endoplasmic reticulum. Although it decreases the folding rate, it increases folding efficiency, prevents premature glycoprotein oligomerization and degradation, and suppresses formation of non-native disulfide bonds by hindering aggregation and thus allowing interaction of protein moieties of folding glycoproteins with classical chaperones and other proteins that assist in folding.
Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide: IUPHAR Review 1 (2012)

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs - PAC(1) , VPAC(1) and VPAC(2) - belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC(1) receptors are selective for PACAP, whereas VPAC(1) and VPAC(2) respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC(2) receptor in susceptibility to schizophrenia and the PAC(1) receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=67).