gebhart/patrepeval huggingface dataset:
Computational Profiling of Bioactive Compounds Using a Target-Dependent Composite Workflow (2013)

Computational target fishing is a chemoinformatic method aimed at determining main and secondary targets of bioactive compounds in order to explain their mechanism of action, anticipate potential side effects, or repurpose existing drugs for novel therapeutic indications. Many existing successes in this area have been based on a use of a single computational method to estimate potentially new target-ligand associations. We herewith present an automated workflow using several methods to optimally browse target-ligand space according to existing knowledge on either ligand and target space under investigation. The protocol uses four ligand-based (SVM classification, SVR affinity prediction, nearest neighbors interpolation, shape similarity) and two structure-based approaches (docking, protein-ligand pharmacophore match) in series, according to well-defined ligand and target property checks. The workflow was remarkably accurate (72%) in identifying the main target of 189 clinical candidates and proposed two novel off-targets which could be experimentally validated. Rolofylline, an adenosine A1 receptor antagonist, was confirmed to inhibit phosphodiesterase 5 with a moderate affinity (IC50 = 13.8 μM). More interestingly, we describe a strong binding (IC50 = 142 nM) of a claimed selective phosphodiesterase 10 A inhibitor (PF-2545920) with the cysteinyl leukotriene type 1 G protein-coupled receptor.
Calcium-Mediated Reduction of Ionic Currents: A Biophysical Memory Trace (1984)

Learning behavior similar to vertebrate classical conditioning was demonstrated for the mollusc Hermissenda crassicornis. Postsynaptic membrane changes within well-defined neural systems that mediate the learning play a casual role in recording the learned association for later recall. Specific ionic currents in neural tissue undergo transformations lasting days after associative training with physiologic stimuli. During acquisition the intracellular calcium increases; this increase is accompanied by specific potassium current reduction that lasts for days after conditioning. The increase of calcium enhances calmodulin-dependent phosphorylation of proteins that either regulate or are part of ion channels. These currents and the conditions that precede their transformation occur in many types of vertebrate neurons, and hence this biophysical basis of Hermissenda learning could have relevance for species other than the gastropod studied.
Enrichment of eicosenoic and docosadienoic acids fromLimnanthes oil (1977)

Abstract and summary The long chain (&gt;C 18 ) monoene and diene acids of Limnanthes oil are useful in synthesizing diene and tetraene wax ester intermediates for prospective lubricant additives and PVC plasticizers. Low‐temperature crystallization of the L. alba acids (61% eicosenoic, 19% docosadienoic, and 20% others) in acetone (initial concentration=0.05 g/ml) at −50 C enriches eicosenoic acid (74%) in the precipitated fraction while concentrating docosadienoic (70%) in the supernatant fraction. This simple and efficient process is well suited for large‐scale laboratory separations.
Prospects of generating power with laser-driven fusion (1976)

The present status of the prospects for electric power generation with laser-driven fusion as the primary energy source is reviewed. The fundamentals of laser-fusion reactor design and attendant means of utilizing the thermonuclear energy for commercial electric power generation are discussed. Theoretical fusion-pellet microexplosion energy release characteristics and the requirements for high-energy short-pulse leasers are described. The results of analyses to assess the engineering feasibility of reactor cavities, for which protection of cavity components is provided either by suitable ablative materials, or by diversion of plasmas by magnetic fields, are presented. Two conceptual laser-fusion electric generating stations, based on different laserfusion reactor concepts, are described. Also the environmental and safety aspects of laser fusion energy systems and alternative means of fusion energy utilization, other than electric power via the conventional heat engine cycle, are briefly reviewed.
Gesture select: (2011)

When working at a large wall display, even if partially utilized, many targets are likely to be distant from the user, requiring walking, which is slow, and interrupts workflow. We propose a novel technique for selecting remote targets called Gesture Select, in which users draw an initial mark, in a target's direction; rectilinear gestures represented as icons are dynamically overlaid on targets within a region of interest; the user then continues by drawing the continuation mark corresponding to the target, to select it. Extensions to this technique to support working with remote content for an extended period, and learning gesture shortcuts are presented. A formal experiment indicates Gesture Select significantly outperformed direct selection for mid/far targets. Further analysis suggests Gesture Select performance is principally affected by the extent to which users can read the gestures, influenced by distance and perspective warping, and the gesture complexity in the ROI. The results of a second 2-D experiment with labeled targets indicate Gesture Select significantly outperformed direct selection and an existing technique.
Cointegration, Exogeneity, and Policy Analysis: An Overview (1991)

This overview describes the concepts of cointegration and exogeneity, focusing on analytical structure, statistical inference, and implications for policy analysis. Examples help clarify the concepts. The remainder of the overview summarizes the articles in a special issue of the Journal of Policy Modeling entitled Cointegration, Exogeneity, and Policy Analysis.
Efficient deletion mutagenesis by PCR (1992)

Journal Article Efficient deletion mutagenesis by PCR Get access Zumrut B. Ogel, Zumrut B. Ogel Department of Biochemistry and Molecular Biology, University of LeedsLeeds LS2 9JT, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael J. McPherson Michael J. McPherson 1 Department of Biochemistry and Molecular Biology, University of LeedsLeeds LS2 9JT, UK 1To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Protein Engineering, Design and Selection, Volume 5, Issue 5, July 1992, Pages 467–468, https://doi.org/10.1093/protein/5.5.467 Published: 01 July 1992 Article history Received: 02 December 1991 Revision received: 13 May 1992 Accepted: 13 May 1992 Published: 01 July 1992
Branched Polyamines Cure Prion-Infected Neuroblastoma Cells (2001)

Branched polyamines, including polyamidoamine and polypropyleneimine (PPI) dendrimers, are able to purge PrP(Sc), the disease-causing isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture (S. Supattapone, H.-O. B. Nguyen, F. E. Cohen, S. B. Prusiner, and M. R. Scott, Proc. Natl. Acad. Sci. USA 96:14529-14534, 1999). We now demonstrate that exposure of ScN2a cells to 3 microg of PPI generation 4.0/ml for 4 weeks not only reduced PrP(Sc) to a level undetectable by Western blot but also eradicated prion infectivity as determined by a bioassay in mice. Exposure of purified RML prions to branched polyamines in vitro disaggregated the prion rods, reduced the beta-sheet content of PrP 27-30, and rendered PrP 27-30 susceptible to proteolysis. The susceptibility of PrP(Sc) to proteolytic digestion induced by branched polyamines in vitro was strain dependent. Notably, PrP(Sc) from bovine spongiform encephalopathy-infected brain was susceptible to PPI-mediated denaturation in vitro, whereas PrP(Sc) from natural sheep scrapie-infected brain was resistant. Fluorescein-labeled PPI accumulated specifically in lysosomes, suggesting that branched polyamines act within this acidic compartment to mediate PrP(Sc) clearance. Branched polyamines are the first class of compounds shown to cure prion infection in living cells and may prove useful as therapeutic, disinfecting, and strain-typing reagents for prion diseases.
Acoustic Emission Monitoring of Fracture Tests (2018)

Identification of defect(s) where crack initiation is possible and prediction of crack propagation are of great importance in materials engineering. The current chapter analyzes the application of the acoustic emission (AE) technique for fracture monitoring in the line pipe steel during single-edge-notched tension (SENT) test and Charpy V-notch (CVN) impact test. It was found that the AE activity starts before the yield point, due to the stress concentration at the crack tip, and increases suddenly before the peak load is reached, due to the fracture initiation. Toward the end of the test, the AE hit density increases again, following intensive crack propagation. The AE analysis conducted in the present chapter showed a strong evidence of AE hit density increasing before the peak load is reached, the moment corresponding to fracture initiation.
Development of Early Porcine Embryos In Vitro and In Vivo1 (1998)

In vitro development of early porcine embryos under different culture conditions was evaluated and compared to in vivo development. First, one- and two-cell embryos were collected and cultured individually in 20- microl drops under 5% CO2 in air for 4 days. Embryos from one oviduct were cultured in NCSU-23, and those from the contralateral oviduct were cultured in KSOM/AA. The embryos developed in NCSU-23 had a higher mean number of inner cell mass (ICM) nuclei compared to those developed in KSOM/AA (p = 0.025). They also had higher trophectoderm (TE) and total nuclear number (p = 0.001), while there was no difference in the average ratio of ICM to TE nuclei (p = 0.731). When the effect of different gas atmospheres was tested, the numbers of TE and total nuclei were higher (p < 0.01 and p < 0.025, respectively) in embryos cultured in an atmosphere with 5% CO2 in air than in those developed under 5% CO2:5% O2:90% N2. Next the development of embryos cultured in NCSU-23 was compared to that of embryos incubated in vivo. By the end of the 4-day incubation, the cultured embryos had higher nuclear numbers and a higher ratio of ICM to TE nuclei than those developed in vivo (p < 0.001). Finally, the embryos that developed in NCSU-23 or in vivo were transferred into recipients. By Day 40 of pregnancy, 37.1 +/- 15.3% of the in vitro- and 53.8 +/- 15.3% of the in vivo-incubated embryos formed conceptuses. These results indicate that despite the lower nuclear numbers caused by in vitro conditions, the cultured embryos were developmentally competent.
Isolation of a high molecular weight polyphosphate from Neisseria gonorrhoeae. (1983)

Neisseria gonorrhoeae, as well as other Neisseriae, produce polyphosphate. This polyphosphate exists in two forms. Approximately half of it is loosely associated with the cells and can be recovered by washing in neutral buffers under conditions in which no significant lysis of the cells is observed. The other half is either intracellular or tightly associated, because it requires digestion of the cells with perchloric acid or sodium hypochlorite. Polyphosphate obtained by both methods was purified by column chromatography and chemically characterized. In contrast to other organisms, gonococci do not respond with increased polyphosphate synthesis when shifted from phosphate starvation to a phosphate-rich medium. In addition, gonococcal polyphosphate does not serve as a depletable phosphate source during phosphate starvation. All strains of Neisseriae examined produce substantial amounts of polyphosphate.
Predicting antibody hypervariable loop conformation. I. Ensembles of random conformations for ringlike structures (1987)

Abstract One approach to finding the conformation of minimum energy for a complicated molecule is to perform energy minimization, perhaps coupled to more exhaustive search procedures such as dynamics or Monte Carlo sampling, from many starting conformation. Where there are geometric constraints on the conformations, as in a ring molecule, or a variable loop starting and ending in known constant regions of one of a series of homologous proteins, rapidly generating many such starting conformations, all satisfying the constraints, has been a problem in the past. We have devised an algorithm, which we call random tweak , which performs this task in the context of a torsional description of a molecule, and have used it to model the backbones of the six CDRs (complementarity determining regions) of the immunoglobulin MCPC603. These range in size from 5 to 19 residues, and have from 8 to 36 variable dihedral angles. Ensembles of 100 properly closed backbone structures for each CDR were generated under several conditions of van der Waals screening internally and against the rest of the molecule, and ensembles of 1000 were generated for selected CDRs. These structure “libraries” reveal how the geometry at the base of a CDR and the topography of the surrounding protein surface restrict the region of space that a given CDR can occupy. In accord with simple notions of chain molecule statistics, the more highly extended a CDR at its base, the more similar the possible structures and the fewer that are necessary to span the conformational space. Energy minimization and molecular dynamics studies (reported elsewhere) using these libraries to furnish starting conformations show that, as the number of residues in a CDR goes from five to nine, the number of randomly generated structures necessary to ensure that low‐lying energetic minima, such as the native conformation, will be found several times goes from a few tens to a few hundred. Some of the spatial features of an ensemble of random conformations are implicit in the histogram of the rms atomic displacements calculated for all the pairs in the ensemble. The random tweak method is carried out by setting each dihederal angle on the main chain of the variable fragment to a random value, then using an iterated linearized Lagrange multiplier technique to enforce the geometric constraints with the minimal conformational perturbation. The time required for the algorithm is linear in fragment length, and the resulting ability of the method to handle large loops makes it especially applicable to the modeling of homologous proteins. In most cases, hundreds of acceptable structures could be generated in a few hours on a VAX 11/780. Where van der Waals screening against fixed atoms need not be performed, as for isolated ring molecules, generation times go down by an order of magnitude or more.
From broadcasting to narrowcasting: television as a language of possibility for community development in a learning society (1997)

The field of adult education is currently experiencing more than its usual degree of internal fractionality about the fundamental nature and purpose of adult education. This paper challenges narrow formulations of adult education in the instrumentalist mode by focusing on the implications of mass media, particularly television, technology and globalization as central issues for adult educators now and in the twenty‐first century. This paper takes the position that learning as is a by‐product of encounters with everyday cultural phenomenon, such as television, is the ground against which other learning activities are figures. While this is the case for all consumers and users of mass media, the ‘hidden curriculum’ of television has special relevance for the learning and development of marginalized groups in society. Thus, television's ‘curriculum’ is of great significance to progressive adult educators whose social justice agenda allies their practice with marginalized peoples. The paper returns to an example of the largely declasse mode of adult education known as community development, arguing the utility of examining the issues of mass media in the context of this specific and situated form of learning because community offers a manageable micro‐setting for the analysis of learning in a natural societal setting. The learning of a specific community in rural Canada which faced economic devastation is examined to ascertain the influence of both broadcast television and locally created narrowcast television on the community's conception of capacity to envision, develop, create and manage their own alternative economic future. The sharp insights of residents about being objects and non‐objects of network television and the discernable difference of being self‐directed subjects of locally‐created community television offer compelling evidence as to how marginality and its pernicious suppression of agency are learned and reinforced through mass media. Their direct words deserve attention from critical adult educators.
Changes in membrane trafficking and actin dynamics during axon formation in cultured hippocampal neurons (2000)

Neurons begin to polarize when one of the neurites becomes the axon. Hippocampal neurons in cell culture have a sharp transition between their unpolarized and polarized stage revealed by the rapid growth of the future axon. Recent progress shows that both a cytoplasmic membrane flow and actin dynamics govern axon formation, and thereby initial neuronal polarization. We here review these mechanisms, evaluate their physiological role, and show similarities to the transient polarization of migrating fibroblasts. Finally, we present a model how actin dynamics and vectorial membrane flow may interact to achieve axon formation.
Effects of anxiety on the long-term course of depressive disorders (2011)

The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.
Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis (2005)

Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that pancreatic acinar cells produce the chemokine monocyte chemotactic protein (MCP)-1 in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Blocking chemokine production or action is a major target for pharmacological intervention in a variety of inflammatory diseases, such as acute pancreatitis. 2-Methyl-2-[[1-(phenylmethyl)-1H-indazol-3yl]methoxy]propanoic acid (bindarit) has been shown to preferentially inhibit MCP-1 production in vitro in monocytes and in vivo without affecting the production of the cytokines IL-1, IL-6, or the chemokines IL-8, protein macrophage inflammatory-1alpha, and RANTES. The present study aimed to define the role of MCP-1 in acute pancreatitis with the use of bindarit. In a model of acute pancreatitis induced by caerulein hyperstimulation, prophylactic as well as therapeutic treatment with bindarit significantly reduced MCP-1 levels in the pancreas. Also, this treatment significantly protected mice against acute pancreatitis as evident by attenuated hyperamylasemia neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections.
Lipopolysaccharide (LPS)-Binding Protein Mediates LPS Detoxification by Chylomicrons (2003)

Chylomicrons have been shown to protect against endotoxin-induced lethality. LPS-binding protein (LBP) is involved in the inactivation of bacterial toxin by lipoproteins. The current study examined the interaction among LBP, chylomicrons, and bacterial toxin. LBP was demonstrated to associate with chylomicrons and enhance the amount of LPS binding to chylomicrons in a dose-dependent fashion. In addition, LBP accelerated LPS binding to chylomicrons. This LBP-induced interaction of LPS with chylomicrons prevented endotoxin toxicity, as demonstrated by reduced cytokine secretion by PBMC. When postprandial circulating concentrations of chylomicrons were compared with circulating levels of low density lipoprotein, very low density lipoprotein, and high density lipoprotein, chylomicrons exceeded the other lipoproteins in LPS-inactivating capacity. Furthermore, highly purified lipoteichoic acid, an immunostimulatory component of Gram-positive bacteria, was detoxified by incubation with LBP and chylomicrons. In conclusion, our results indicate that LBP associates with chylomicrons and enables chylomicrons to rapidly bind bacterial toxin, thereby preventing cell activation. Besides a role in the detoxification of bacterial toxin present in the circulation, we believe that LBP-chylomicron complexes may be part of a local defense mechanism of the intestine against translocated bacterial toxin.
Sensitivity Comparison of Mx and Frequency-Modulated Bell–Bloom Cs Magnetometers in a Microfabricated Cell (2009)

We compare the sensitivity performance of two optically pumped atomic magnetometers based on the Mx and frequency-modulated bell-bloom configurations. The Cs magnetometers are implemented using a millimeter-scale microfabricated vapor cell. It is found that the Bell-Bloom magnetometer yields sensitivities similar to those of the Mx magnetometer when operated under equally optimized conditions. The Bell-Bloom approach offers several attractive features over the Mx approach for chip-scale magnetometer instrumentation.
Steps Following Attainment of Remission (2001)

Depressive disorders require long-term treatment with antidepressants, psychotherapy, or both. The goal of antidepressant therapy is complete remission of symptoms and return to normal daily functioning. Studies have shown that achieving remission and continuing antidepressant therapy long after the acute symptoms remit can protect against the relapse or recurrence of the psychiatric episode. Many patients, however, inadvertently or intentionally skip doses of their antidepressant, and even discontinue it, if their symptoms improve or if they experience side effects. Antidepressant discontinuation may increase the risk of relapse or precipitate certain distressing symptoms such as gastrointestinal complaints, dizziness, flu-like symptoms, equilibrium disturbances, and sleep disorders. Documented with all classes of antidepressants, these reactions may emerge within a couple of days, or even hours, after the abrupt discontinuation of an antidepressant with a short half-life. These distressing responses may be mistaken for a relapse or recurrence. It is important to recognize the potential for these sequelae and educate patients about the need to take all antidepressants at the doses prescribed, warning them of the symptoms that may occur if they skip doses or stop their medication too quickly. Antidepressants should be tapered slowly over a period of days, weeks, or even months, depending on the dose, duration of treatment, and pharmacologic properties of the agent, as well as the patient's individual response. This article reviews the risks and reactions associated with discontinuation of antidepressants. It offers guidelines for distinguishing relapse and recurrence from discontinuation responses as well as for prevention and management of the antidepressant discontinuation syndrome.