gebhart/patrepeval huggingface dataset:
Hepatocytes as a Tool in Drug Metabolism, Transport and Safety Evaluations in Drug Discovery (2010)

The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of critical blood and biliary components. A number of liver-derived in vitro systems, such as slices, primary and immortalized hepatocytes, microsomes and S9 fractions are used to assess the metabolism and potential toxicity of new chemical entities. Over the past decade, primary hepatocytes have become a standard in vitro tool to evaluate hepatic drug metabolism, cytochrome P450 (P450) induction, and drug interactions affecting hepatic metabolism. While earlier, hepatocytes were used in suspension for metabolic stability evaluations, more recent studies have demonstrated the added value of using these over longer terms in primary culture. Primary hepatocyte cultures are particularly useful in the evaluation of low turn-over compounds. Hepatic transporter studies are recommended for drug candidates that are predominantly eliminated through the bile. An appropriate strategy is to use primary hepatocytes to assess uptake, followed by singly transfected cell lines to identify the specific transporter(s) involved. Primary hepatocytes can also be used to assess biliary clearance to enable improved hepatic clearance predictions. Newer technologies such as siRNA can be used to knock out specific transporters for more predictive evaluations of potential clinically-based drug-drug interactions. In vitro safety (toxicology) studies have historically been conducted using cell lines. There is increasing evidence that co-cultures of primary hepatocytes and Kupffer cells would be more predictive of the in vivo outcome, as this system provides the complete complement of drug metabolizing enzymes, transcription factors and cytokines necessary to get a more in vivo-like toxicological response. In this review, we will discuss standard and novel in vitro approaches for using primary hepatocytes to extrapolate clinical hepatic metabolism, transport and toxicity.
Interaction Proxies for Runtime Repair and Enhancement of Mobile Application Accessibility (2017)

We introduce interaction proxies as a strategy for runtime repair and enhancement of the accessibility of mobile applications. Conceptually, interaction proxies are inserted between an application's original interface and the manifest interface that a person uses to perceive and manipulate the application. This strategy allows third-party developers and researchers to modify an interaction without an application's source code, without rooting the phone, without otherwise modifying an application, while retaining all capabilities of the system (e.g., Android's full implementation of the TalkBack screen reader). This paper introduces interaction proxies, defines a design space of interaction re-mappings, identifies necessary implementation abstractions, presents details of implementing those abstractions in Android, and demonstrates a set of Android implementations of interaction proxies from throughout our design space. We then present a set of interviews with blind and low-vision people interacting with our prototype interaction proxies, using these interviews to explore the seamlessness of interaction, the perceived usefulness and potential of interaction proxies, and visions of how such enhancements could gain broad usage. By allowing third-party developers and researchers to improve an interaction, interaction proxies offer a new approach to personalizing mobile application accessibility and a new approach to catalyzing development, deployment, and evaluation of mobile accessibility enhancements.
Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation--United States, 2010-2012. (2013)

Arthritis is the most common cause of disability among U.S. adults and is particularly common among persons with multiple chronic conditions. In 2003, arthritis in the United States resulted in an estimated $128 billion in medical-care costs and lost earnings. To update previous U.S. estimates of the prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation (AAAL), CDC analyzed 2010-2012 data from the National Health Interview Survey (NHIS). This report summarizes the results of that analysis, which found that 52.5 million (22.7%) of adults aged ≥18 years had self-reported doctor-diagnosed arthritis, and 22.7 million (9.8%, or 43.2% of those with arthritis) reported AAAL, matching and exceeding previous projected increases, respectively. Among persons with heart disease, diabetes, and obesity, the prevalences of doctor-diagnosed arthritis were 49.0%, 47.3%, and 31.2%, respectively; the prevalences of AAAL among persons with these specific conditions were 26.8%, 25.7%, and 15.2%, respectively. Greater use of evidence-based interventions, such as chronic disease self-management education and physical activity interventions that have been proven to reduce pain and improve quality-of-life among adults with chronic diseases might help reduce the personal and societal burden of arthritis.
Gene therapy: The first two decades and the current state‐of‐the‐art (2007)

The concept of gene therapy was envisioned soon after the emergence of restriction endonucleases and subcloning of mammalian genes in phage and plasmids. Over the ensuing decades, vectors were developed, including nonviral methods, integrating virus vectors (gammaretrovirus and lentivirus), and non-integrating virus vectors (adenovirus, adeno-associated virus, and herpes simplex virus vectors). Preclinical data demonstrated potential efficacy in a broad range of animal models of human diseases, but clinical efficacy in humans remained elusive in most cases, even after decades of experience in over 1000 trials. Adverse effects from gene therapy have been observed in some cases, often because of viral vectors retaining some of the pathogenic potential of the viruses upon which they are based. Later generation vectors have been developed in which the safety and/or the efficiency of gene transfer has been improved. Most recently this work has involved alterations of vector envelope or capsid proteins either by insertion of ligands to target specific receptors or by directed evolution. The disease targets for gene therapy are multiple, but the most promising data have come from monogenic disorders. As the number of potential targets for gene therapy continues to increase, and a substantial number of trials continue with both the standard and the later generation vector systems, it is hoped that a therapeutic niche for gene therapy will emerge in the coming decades.
A Combinatorial Approach To Discover New Chelators for Optical Metal Ion Sensing (2000)

This paper reports the synthesis and characterization of metal-binding indicators with diverse optical responses on exposure to various heavy metal ions. A combinatorial approach, based on azo coupling of diazonium salts with either phenolic compounds or aromatic amines, generated a library of azo dyes. Each reaction mixture, containing the product(s) of azo coupling, was incubated with a series of solutions, each containing a different heavy metal ion. The absorbance and, in some cases, fluorescence spectra of the resulting complexes were recorded. The metal chelates showed extensive diversity in their UV-visible absorbance spectra upon binding to selected metal ions. Of the azo dyes prepared, the terdentate dyes were particularly useful, providing distinct spectral responses to three or more metal ions in a panel of seven.
Naturally occurring insect growth regulators. III. Echinolone, a highly active juvenile hormone mimic from Echinacea angustifolia roots. (1976)

A compound, C14H24O2, which induces strong juvenilizing effects in the yellow mealworm, Tenebrio molitor L., following topical application to the pupal stage, was isolated in pure form from the roots of Echinacea angustifolia DC and tentatively identified as dextrorotatory (E)-10-hydroxy-4,10-dimethyl-4,11-dodecadien-2-one. The compound has been named echinolone.
Cellular and molecular mechanisms of nicotine's pro‐angiogenesis activity and its potential impact on cancer (2005)

The present study examined the mechanisms of nicotine's effect on angiogenesis and its impact on tumor growth. Nicotine demonstrated significant (P<0.01) stimulation of the release of endothelial cell growth factor, basic fibroblast growth factor (b-FGF) but not vascular endothelial growth factor (VEGF). In a concentration-dependent manner, nicotine induced endothelial cell tube formation. Additionally, in the chick chorioallantoic membrane (CAM) model of angiogenesis, nicotine effectively induced the generation of new blood vessels (P<0.01), an effect that is mediated via b-FGF. The pro-angiogenesis effect of nicotine in the CAM model was maximally blocked by either anti-integrin alphavbeta3 or inhibitor of mitogen activated protein kinase (MAPK, ERK 1/2). In the CAM tumor implant model, nicotine doubled (P<0.01) the growth rate of breast, colon, and lung cancer. These data indicated that the pro-angiogenesis effect is mediated via b-FGF and induced through the nicotinic receptor, alphavbeta3 integrin, and MAPK.
EBF1: a computer simulation of the preburst behavior of electrically heated exploding foils (1976)

A computer code is presented for calculating the transient temperature and current distributions in electrically exploded foils. The model employed is applicable up until the time of burst. Calculations presented for aluminum, copper, and gold foils show good agreement with experimental current waveforms and burst times over a wide range of capacitor bank charging voltages and for varying foil cross sections. The two-dimensional nature of the calculation permits investigation of effects associated with nonuniform heating of the foil and gives an estimate of the simultaneity of burst.
MUC1 expressed in PanC1 cells decreases adhesion to type 1 collagen but increases contraction in collagen lattices. (1996)

A subline of human pancreatic cells (PanC1) that expresses low levels of cytokeratins 8 and 18 but not MUC1 mucin was transfected with both 3.5-kb and 3.9-kb full-length MUC1 cDNA. The MUC1-positive clone expressing the larger mucin was shown to express increased levels of cytokeratins 8 and 18 compared with the parental line or vector controls. Growth of these MUC1-transfected cells in type I collagen gels produced marked gel contraction that could be significantly reduced by the synthetic peptide SRGDTG or by growth in serum and fibronectin-depleted media. Cellular binding to type I collagen was found to be reduced by two- to four-fold in cells expressing the MUC1 mucin, for which the greatest inhibition was observed in cells expressing the larger form. No difference in cellular binding to fibronectin was observed. From these data we conclude that the human MUC1 mucin modifies the differentiated state of human pancreatic cells by altering cytokeratin expression and reducing adhesion to type I collagen but paradoxically enhancing the cellular contractile phenotype, effects that appear to be mediated by integrin expression and/or function.
Purification of papain-solubilized histocompatibility antigens from a cultured human lymphoblastoid line, RPMI 4265. (1975)

HL-A antigens having specificities HL-A2, HL-A7, HL-A12 have been solubilized by papain treatment of membrane preparations from the cultured human lymphoblastoid cell line RPMI 4265 and purified about 80-fold by chromatography on carboxymethylcellulose, Sephadex G-150, and diethylaminoethylcellulose columns. Separation of HL-A2 from a mixture of HL-A7 and HL-A12 was achieved on the final DEAE-cellulose column. The yield was about 1 mg of protein of each antigen preparation per 100 g of packed, frozen cells. On sodium dodecyl sulfate gel electrophoresis both preparations showed two polypeptide bands. The smaller subunit of 12,000 daltons is common to all HL-A preparations and has been shown to be identical with beta2-microglobulin. The larger subunit is a glycopeptide and in the HL-A7, 12 preparation was resolved into a duplex of 34,000 and 37,000 daltons. The HL-A2 preparation showed a single band at 34,000 daltons. On isoelectric focusing under nondenaturing conditions, the preparation showed multiple bands, all of which contained both subunits and retained antigenic activity. On isoelectric focusing in the presence of 6 M urea a single band for beta2-microglobulin and multiple bands for the larger subunit were seen. This charge heterogeneity of the larger subunit has been shown to be due to variable amounts of sialic acid. When HL-A antigen preparations were subjected to Sephadex G-100 chromatography in the presence of 3 M KCl, no separation of the two subunits was observed.
Evaluation of the Spacer Effect on Adamantane-Containing Vinyl Polymer Tg's (2000)

Two new adamantane-containing methacrylates having methylene and phenyl spacers between the adamantane and the methacrylate were synthesized: 1-adamantylmethyl methacrylate (AdMMA, 1) and 4-(1-adamantyl)phenyl methacrylate (AdPMA, 2). The homopolymer of 1 had a Tg of 201 °C while 2 showed a Tg of 253 °C. Copolymers of both monomers with styrene (St) showed significant Tg increases over PSt. The incremental increase obtained with AdPMA per adamantane unit is the highest of all vinyl monomers reported to date, to the best of our knowledge, with a value of 2.2 °C/mol %. Both sets of copolymers showed higher incorporation of adamantane monomers in the copolymer than the feed, with reactivity ratios calculated to be r1(St) = 0.22 and r2(AdPMA) = 1.52 and r1(St) = 0.94 and r2(AdMMA) = 1.54.
THE BIOLOGICAL FUNCTION OF VITAMIN A ACID (1960)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Nanoengineered Polymeric Thin Films by Sintering CNT‐Coated Polystyrene Spheres (2005)

Film developments: Multiwalled carbon nanotubes are flexible enough to coat polystyrene microspheres (see image). A monolayer of such spheres can be deposited onto a glass substrate and then coated with a polymeric thin film, which retains the conducting properties of the carbon nanotubes. Such nanoengineered materials are excellent candidates for future devices, including a variety of sensor applications.
Kinetics of isomerization of tetracyclic spiro oxindole alkaloids (1998)

The effects of temperature, pH and solvent polarity on the rate of isomerization and the equilibrium composition of the tetracyclic spiro oxindole alkaloids rhynchophylline, isorhynchophylline, corynoxeine and isocorynoxeine have been investigated.
Continuous microfluidic immunomagnetic cell separation (2004)

We present a continuous-flow microfluidic device that enables cell by cell separation of cells selectively tagged with magnetic nanoparticles. The cells flow over an array of microfabricated magnetic stripes, which create a series of high magnetic field gradients that trap the magnetically labeled cells and alter their flow direction. The process was observed in real time using a low power microscope. The device has been demonstrated by the separation of leukocytes from whole human blood.
Novelty Detection Classifiers in Weed Mapping: Silybum marianum Detection on UAV Multispectral Images (2017)

In the present study, the detection and mapping of <i>Silybum marianum (L.) Gaertn.</i> weed using novelty detection classifiers is reported. A multispectral camera (green-red-NIR) on board a fixed wing unmanned aerial vehicle (UAV) was employed for obtaining high-resolution images. Four novelty detection classifiers were used to identify <i>S. marianum</i> between other vegetation in a field. The classifiers were One Class Support Vector Machine (OC-SVM), One Class Self-Organizing Maps (OC-SOM), Autoencoders and One Class Principal Component Analysis (OC-PCA). As input features to the novelty detection classifiers, the three spectral bands and texture were used. The <i>S. marianum</i> identification accuracy using OC-SVM reached an overall accuracy of 96%. The results show the feasibility of effective <i>S. marianum</i> mapping by means of novelty detection classifiers acting on multispectral UAV imagery.
Dissection of c-myc domains involved in S phase induction of NIH3T3 fibroblasts. (1994)

The product of the c-myc proto-oncogene is an important regulator of cell proliferation and apoptosis in murine fibroblasts. Addition of the tumor promoter, phorbol myristate acetate (PMA), prevents apoptotic cell death induced by low serum concentrations in NIH3T3 cells that constitutively express and are transformed by v-myc. The protective effect of PMA allowed us to analyse the ability of normal c-Myc and Myc deletion mutants to induce serum starved, untransformed NIH3T3 cells to enter S phase. By microinjecting these quiescent cells with wild type and mutant human c-myc plasmids, we showed that full length c-myc is able to induce S phase entry in presence of PMA, but that c-Myc mutants that delete amino acids delta 7/91, delta 41/53, delta 56/103, delta 106/143, delta 265/317 and delta 414/433 are totally inactive. c-Myc did not shorten the period before entry into S phase, since Myc overexpressing cells entered S phase with the same kinetics as control cells when both were stimulated with 20% fetal calf serum (FCS). However, c-Myc overexpression did increase the percentage of cells entering S phase when these cells were stimulated with 2% fetal calf serum. Interestingly, this ability to enhance stimulation by a suboptimal concentration of FCS was retained to a significant degree by Myc mutants that delete amino acids delta 41/53, delta 56/103 or delta 265/317. Finally, Myc mutants that delete delta 106/143 or delta 414/433 exerted a dominant negative effect on S phase entry both in quiescent cells stimulated with 2% FCS and in unsynchronized, cycling cells.
Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome. (1975)

Serum glucocorticoid levels were determined in 20 mothers and 43 premature infants who received prenatal betamethasone therapy for prevention of respiratory distress syndrome (RDS). Maternal betamethasone peaked at 75 microg cortisol equivalents per 100 ml 1 h after injection of 12 mg steroid and declined to half by 6 h. Betamethasone in cord blood was 14.3 microg cortisol equivalents per 100 ml at 1 h, decreased to a level of 4.7 at 20 h, and was not detected 2 days after a second dose at 24 h. After the second dose, the mean level of cortisol in cord blood was 5.9 microg per 100 ml compared with 13.05 microg per 100 ml (p less than 0.001) in untreated premature infants. The unbound glucocorticoid activity in treated infants delivered 1-10 h after the second dose (mean, 8.4 microg per 100 ml) is similar to the unbound cortisol level after birth in untreated premature infants who develop RDS. These findings indicate that (a) serum glucocorticoid levels in the physiologic stress range can induce lung maturation in the human and (b) antenatal treatment with this dose of betamethasone does not expose the human fetus to potentially harmful pharmacologic levels of steroid.
Effect of poly(ethylene glycol) molecular weight on tensile and swelling properties of oligo(poly(ethylene glycol) fumarate) hydrogels for cartilage tissue engineering (2001)

This study was designed to determine the effect of changes in poly(ethylene glycol) (PEG) molecular weight on swelling and mechanical properties of hydrogels made from a novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF), recently developed in our laboratory. Properties of hydrogels made from OPF with initial PEG molecular weights of 860, 3900, and 9300 were examined. The PEG 3900 formulation had a tensile modulus of 23.1 +/- 12.4 kPa and percent elongation at fracture of 53.2 +/- 13.7%; the PEG 9300 formulation had similar tensile properties (modulus: 16.5 +/- 4.6 kPa, elongation: 76.0 +/- 26.4%). However, the PEG 860 gels had a significantly higher modulus (89.5 +/- 50.7 kPa) and a significantly smaller percent elongation at fracture (30.1 +/- 6.4%), when compared with other formulations. Additionally, there were significant differences in percent swelling between each of the formulations. Molecular weight between crosslinks (M(c)) and mesh size were calculated for each OPF formulation. M(c) increased from 2010 +/- 116 g/mol with PEG 860 to 6250 +/- 280 g/mol with PEG 9300. Mesh size calculations showed a similar trend (76 +/- 2 A for PEG 860 to 160 +/- 6 A for PEG 9300). It was also found that these hydrogels could be laminated if a second layer was added before the first had completely crosslinked. Mechanical testing of these laminated gels revealed that the presence of an interfacial area did not significantly alter their tensile properties. These results suggest that the material properties of OPF-based hydrogels can be altered by changing the molecular weight of PEG used in synthesis and that multilayered OPF hydrogel constructs can be produced, with each layer having distinct mechanical properties.
Deletion of the propeptide from human preproapolipoprotein A-II redirects cotranslational processing by signal peptidase. (1986)

The functions of NH2-terminal propeptides are not known. We have used apoA-II as a model to study prosegment structure/function relationships. The primary translation product of human apolipoprotein A-II mRNA contains an 18-amino acid signal peptide, a 5-amino acid propeptide, and the mature 77-amino acid plasma protein sequence. Its propeptide was deleted by site-directed mutagenesis of a cloned cDNA. The effects of this mutation on cotranslational translocation and proteolytic processing were assessed using an in vitro transcription/translation/microsomal membrane processing system. Deletion of the propeptide did not affect cotranslational translocation. However, without its propeptide, signal peptidase cleavage was redirected to a different site located between the 2nd and 3rd residues of the mature protein. Since the primary structure of the signal peptide was not altered in the mutant, these results suggest that sequences located downstream from the signal peptidase cleavage site (e.g. in propeptides) may modulate, or participate in defining, the correct site of cotranslational proteolytic processing.
Affimer proteins are versatile and renewable affinity reagents (2017)

Molecular recognition reagents are key tools for understanding biological processes and are used universally by scientists to study protein expression, localisation and interactions. Antibodies remain the most widely used of such reagents and many show excellent performance, although some are poorly characterised or have stability or batch variability issues, supporting the use of alternative binding proteins as complementary reagents for many applications. Here we report on the use of Affimer proteins as research reagents. We selected 12 diverse molecular targets for Affimer selection to exemplify their use in common molecular and cellular applications including the (a) selection against various target molecules; (b) modulation of protein function in vitro and in vivo; (c) labelling of tumour antigens in mouse models; and (d) use in affinity fluorescence and super-resolution microscopy. This work shows that Affimer proteins, as is the case for other alternative binding scaffolds, represent complementary affinity reagents to antibodies for various molecular and cell biology applications.
OptiType: precision HLA typing from next-generation sequencing data (2014)

We present OptiType, a novel HLA genotyping algorithm based on integer linear programming, capable of producing accurate predictions from NGS data not specifically enriched for the HLA cluster. We also present a comprehensive benchmark dataset consisting of RNA, exome and whole-genome sequencing data. OptiType significantly outperformed previously published in silico approaches with an overall accuracy of 97% enabling its use in a broad range of applications.