gebhart/patrepeval huggingface dataset:
The ECVAM International Validation Study on In Vitro Embryotoxicity Tests: Results of the Definitive Phase and Evaluation of Prediction Models (2002)

From 1996 to 2000, ZEBET (Centre for Documentation and Evaluation of Alternative Methods to Animal Experiments at the BgVV, Berlin, Germany) coordinated the European Centre for the Validation of Alternative Methods (ECVAM) prevalidation and validation study on three embryotoxicity tests: a) a test employing embryonic stem cell lines (EST); b) the micromass (MM) test; and c) the postimplantation rat whole-embryo culture assay (WEC test). The main objectives of the study were to assess the performance of these three in vitro tests in discriminating between non- embryotoxic, weakly embryotoxic and strongly embryotoxic compounds. Phase I of the study (1997) was designed as a prevalidation phase, for test protocol optimisation, and for the establishment of a comprehensive database of in vivo and in vitro data on embryotoxic compounds. Phase II (1998-2000) involved a formal validation trial, conducted under blind conditions on 20 test compounds selected from the database, which were coded and distributed to the participating laboratories. In the preliminary phase of the validation study, six chemicals out of the 20, which showed embryotoxic potential, were tested. These results were used to define new biostatistically based prediction models (PMs) for the MM and WEC tests, and to evaluate those developed previously for the EST. As a next step, the PMs were evaluated by using the results for the remaining 14 chemicals of the definitive phase of the validation study. The three in vitro embryotoxicity tests proved to be applicable to testing a diverse group of chemicals with different embryotoxic potentials (non-embryotoxic, weakly embryotoxic, and strongly embryotoxic). The reproducibility of the three in vitro embryotoxicity tests were acceptable according to the acceptance criteria defined by the Management Team. The concordances between the embryotoxic potentials derived from the in vitro data and from the in vivo data were good for the EST and the WEC (PM2) test, and sufficient for the MM test and the WEC (PM1) tests according to the performance criteria defined by the Management Team before the formal validation study. When applying the PM of the EST to the in vitro data obtained in the definitive phase of the formal validation study, chemicals were classified correctly in 78% of the experiments. For the MM and the WEC tests, the PMs provided 70% and 80% (PM2) correct classifications, respectively. And, very importantly, an excellent predictivity (100%, except for PM1 of the WEC test, with 79%, considered as good) was obtained with strong embryotoxic chemicals in each of the three in vitro tests.
Characterization of the P2‘ and P3‘ Specificities of Thrombin Using Fluorescence-Quenched Substrates and Mapping of the Subsites by Mutagenesis, (1996)

The importance of substrate residues P2' and P3' on thrombin catalysis has been investigated by comparing the hydrolysis of a series of fluorescence-quenched substrates. Each consisted of a 10-residue peptide, carrying a 2-aminobenzoyl (Abz) group at the N-terminus, and a penultimate 2,4-dinitrophenyl (Dnp) derivatized lysine. Cleavage of such a peptide relieves the intramolecularly-quenched fluorescence, allowing determination of the kinetic parameters. The nature of the P2' residue was found to have a major influence on the rate of cleavage: the Kcat/Km value for the hydrolysis of the Arg-Ser bond in Abz-Val-Gly-Pro-Arg-Ser-Phe-Leu-Leu-Lys(Dnp)-Asp-OH was nearly 3 orders of magnitude higher than that for the hydrolysis of the same substrate with aspartate instead of phenylalanine at the P2' position. Comparatively, the P3' side chain was less important: the kcat/Km value for the substrate with the least effective residue (aspartate) was only 33 times lower than that of the substrate with the most favorable amino acid (lysine). The role of thrombin residues Arg35, Lys36, Glu39 and Lys60f in the putative P2' and P3' binding sites was also examined. Replacement of Lys60f by glutamine improved the rate of cleavage for peptides with P2' lysine or leucine. Compared with thrombin, mutants E39K and E39Q hydrolyzed faster substrates with an acidic residue in P2' or P3', but slightly slower those with a lysine at either position. Mutations R35Q and K36Q only improved the hydrolysis of substrates with an acidic P2' residue. Overall, thrombin prefers bulky hydrophobic side chains in subsite S2' and positively charged residues in S3', whereas acidic residues are markedly antagonistic to both subsites.
Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death (1998)

Increased LV mass and hypertrophy are associated with increased risk for sudden death after accounting for known risk factors.
Self‐Powered Cardiac Pacemaker Enabled by Flexible Single Crystalline PMN‐PT Piezoelectric Energy Harvester (2014)

A flexible single-crystalline PMN-PT piezoelectric energy harvester is demonstrated to achieve a self-powered artificial cardiac pacemaker. The energy-harvesting device generates a short-circuit current of 0.223 mA and an open-circuit voltage of 8.2 V, which are enough not only to meet the standard for charging commercial batteries but also for stimulating the heart without an external power source.
Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation (2008)

Most testicular germ cell tumors are curable using cisplatin-based chemotherapy, and cell lines from these tumors are unusually sensitive to cisplatin and other DNA-damaging agents. It has been suggested that this might be caused by a lower-than normal nucleotide excision repair (NER) activity. Previous studies found that cell lines from testicular germ cell tumors have on average about one-third the level of the NER protein XPA in comparison to cell lines from other tumors. We asked whether over-expression of XPA protein would alleviate the cellular sensitivity and increase the DNA repair capacity of a testis tumor cell line. Increasing XPA levels in 833K cells by 10-fold did not increase resistance to UV irradiation. XPA was localized to the cell nucleus in all cell lines, before and after exposure to UV-radiation. 833K cells were proficient in removing UV radiation-induced photoproducts from the genome and increased XPA did not enhance the rate of removal. Further, over-expressing functional XPA protein did not correlate with increased resistance of 833K testis tumor cells to cisplatin. Thus, although the amount of XPA in this testis tumor cell line is lower than normal, it is sufficient for NER in vivo. The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells.
Fatigue crack detection in metallic structures with Lamb waves and 3D laser vibrometry (2007)

The paper presents the application of ultrasonic guided waves for fatigue crack detection in metallic structures. The study involves a simple fatigue test performed to introduce a crack into an aluminium plate. Lamb waves generated by a low-profile, surface-bonded piezoceramic transducer are sensed using a tri-axis, multi-position scanning laser vibrometer. The results demonstrate the potential of laser vibrometry for simple, rapid and robust detection of fatigue cracks in metallic structures. The method could be used in quality inspection and in-service maintenance of metallic structures in aerospace, civil and mechanical engineering industries.
A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis (2001)

Stearoyl-CoA desaturase (SCD) catalyzes the de novo biosynthesis of oleate and palmitoleate, which are the major fatty acids found in triglycerides, cholesteryl esters, and phospholipids. A high carbohydrate (lipogenic) diet induces lipogenic gene expression by sterol regulatory element binding protein 1 (SREBP-1c)-mediated gene transcription, leading to an increase in the synthesis of triglycerides. The lipogenic diet fed to mice with a null mutation in the SCD1 gene (SCD-/-) fails to induce the synthesis of triglycerides in liver, despite the induction of expression of SREBP-1 and its target genes, fatty acid synthase and glycerol-3-phosphate acyltransferase. The lipogenic diet led to a decrease in the levels of triglyceride, but an increase in the level of cholesteryl esters of saturated fatty acids. Feeding a lipogenic diet supplemented with high levels of oleate to the SCD-/- mice resulted in incorporation of oleate in the liver of SCD-/- mice, but failed to restore triglycerides to the levels in the normal mouse. Triglyceride synthesis, as measured by the incorporation of [(3)H]glycerol, was dramatically reduced in the liver of SCD-/- mouse fed a lipogenic diet compared with the normal mouse. These observations demonstrate that induction of triglyceride synthesis is highly dependent on SCD1 gene expression.
Human Growth Hormone-regulated HOXA1 Is a Human Mammary Epithelial Oncogene (2003)

Increased mammary epithelial expression of the human growth hormone (hGH) gene is associated with the acquisition of pathological proliferation. We report here that autocrine hGH production by human mammary carcinoma cells increased the expression and transcriptional activity of the homeobox domain containing protein HOXA1. Forced expression of HOXA1 in human mammary carcinoma cells resulted in increased total cell number primarily by the promotion of cell survival mediated by the transcriptional up-regulation of Bcl-2. HOXA1 also abrogated the apoptotic response of mammary carcinoma cells to doxorubicin. Forced expression of HOXA1 in mammary carcinoma cells, in a Bcl-2-dependent manner, resulted in dramatic enhancement of anchorage-independent proliferation and colony formation in soft agar. Finally, forced expression of HOXA1 was sufficient to result in the oncogenic transformation of immortalized human mammary epithelial cells with aggressive in vivo tumor formation. Herein, we have therefore provided a molecular mechanism by which autocrine hGH stimulation of human mammary epithelial cells may result in oncogenic transformation.
A new type of transporter with a new type of cellular function: l‐lysine export from Corynebacterium glutamicum (1996)

We discovered that after deregulation of the L-lysine biosynthesis in Corynebacterium glutamicum, L-lysine accumulated in the cytosol and the efflux properties of this amino acid in mutants used for L-lysine production were altered. In this study we describe the cloning and molecular identification of lysE, which encodes the translocator specifically exporting L-lysine from the cell. The lysE gene product does not display homology to any known transporter. It is only 236 amino acids in size, with the potential to span the membrane six times. The LysE protein was oversynthesized to confirm its deduced M(r) of 25425 Da. A probable regulatory gene, lysG, is localized immediately adjacent to lysE and displays all the typical structural features of an autoregulatory transcriptional regulator of the LysR-type family. L-Lysine export is correlated with lysE expression. A null mutant is unable to excrete L-lysine, whereas with overexpressed lysE, L-lysine is exported at a rate of 3.76 nmol min-1 mg-1 dry weight, which is five times the rate that was obtained with the wild type. A deletion mutant was constructed to search for a natural function of this unique carrier. Surprisingly, growth of this mutant is abolished on a salt medium in the presence of the dipeptide Lys-Ala. The quantification of the intracellular L-lysine concentrations revealed that, in response to peptide addition, there was an accumulation of the exceptionally high concentration of more than 1100 mM L-lysine. These results distinguish LysE as an exporter, which: (i) structurally represents a new type of translocator; (ii) demonstrates that exporters are also present for primary metabolites such as amino acids; and (iii) serves in one physiological function to link import with export activity.
Thermodynamic contribution of nucleoside modifications to yeast tRNA(Phe) anticodon stem loop analogs. (1999)

The determination of the structural and functional contributions of natural modified nucleosides to tRNA has been limited by lack of an approach that can systematically incorporate the modified units. We have produced a number of oligonucleotide analogs, of the anticodon of yeast tRNA(Phe) by, combining standard automated synthesis for the major nucleosides with specialty chemistries for the modified nucleosides. In this study, both naturally occurring and unnatural modified nucleotides were placed in native contexts. Each oligonucleotide was purified and the nucleoside composition determined to validate the chemistry. The RNAs were denatured and analyzed to determine the van't Hoff thermodynamic parameters. Here, we report the individual thermodynamic contributions for Cm, Gm, m1G, m5C, psi. In addition m5m6U, m1psi, and m3psi, were introduced to gain additional understanding of the physicochemical contribution of psi and m5C at an atomic level. These oligonucleotides demonstrate that modifications have measurable thermodynamic contributions and that loop modifications have global contributions.
Induction of Fetal Globin in β‐Thalassemia: Cellular Obstacles and Molecular Progress (2005)

Accelerated apoptosis of erythroid progenitors in beta-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with beta+-thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one beta 0-globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.
Spectroscopic characterization of heterochiral DNAs. (1993)

We have synthesized heterochiral dodecadeoxynucleotides having an unnatural L-nucleotide residue, and have investigated their structures by ultraviolet (UV) absorption, circular dichroism (CD) measurements and nuclear magnetic resonance (NMR) spectroscopy. It was clearly shown that the overall structures of the heterochiral 12-mers are a right-handed B-conformation and the unnatural L-nucleotide residue in the heterochiral 12-mer (L-4) forms stable Watson-Crick type base-pairing with the natural complementary residue. In this double helix (L-4), the unnatural G4 residue has an S-type sugar conformer and a low-anti glycosidic torsion angle. From the properties of an enantiomer, natural nucleotides may possibly form a low-anti left-handed B-form duplex with the aid of certain factors.
Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing ofPseudomonas aeruginosaand Attenuates ChronicP. aeruginosaLung Infection inCftr−/−Mice (2007)

The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.
Giant Spin Hall Effect and Switching Induced by Spin-Transfer Torque in aW/Co40Fe40B20/MgOStructure with Perpendicular Magnetic Anisotropy (2015)

Tomorrow's spintronic MRAM and logic processors could exploit the physics of the spin Hall effect for switching bits, but the materials engineering is challenging. The authors have realized robust perpendicular magnetic anisotropy (PMA) in a layered structure combining the elusive, metastable $\ensuremath{\beta}$ phase of tungsten and a ferromagnetic thin film. The large spin-orbit coupling in $\ensuremath{\beta}$-W yields, after suitable annealing, a very low critical current density for magnetization switching. The authors' structures furthermore are easily fabricated, making them even more technologically promising.
Nanoimprint lithography at the 6 in. wafer scale (2000)

We demonstrate the nanoimprint lithography (NIL) technique with sub 100 nm resolution, on 6 in. Si substrates. The pattern transfer is performed using a specially designed NIL machine optimized to achieve a very high degree of parallelism between stamp and substrate. The stamp is made with the help of electron beam lithography and Ni electroplating achieving features below 100 nm in size. The nanoimprint process is done in a single layer as well as in a multilayer resist scheme with subsequent O2-plasma etching and metal lift-off.
Synthesis and physicochemical characterization of silicon oxynitride thin films prepared by rf magnetron sputtering (1997)

SiO(x)N(y) thin films deposited by rf magnetron sputtering to realize low-loss optical multilayers have been studied. We have analyzed the variations of the optical and physicochemical properties of oxynitride layers according to the deposition parameters: the gas partial pressures, the rf power, and the target composition. A linear variation of the layer refractive index as a function of the oxygen partial pressure was observed as well as a strict substitution of O atoms by N atoms. Thanks to IR spectrophotometric analyses, a model of the oxynitride amorphous structure was proposed and confirmed by Bruggeman and Gained approximation methods. Finally, the absorption level of the oxynitride layers was studied by photothermal deflection spectroscopy.
Escherichia coli Translocation at the Blood-Brain Barrier (2001)

The mortality and morbidity associated with bacterial meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. A major contributing factor is the incomplete understanding of the pathogenesis of this disease. For example, most cases of bacterial meningitis develop as a result of hematogenous spread, but it is unclear how circulating bacteria cross the blood-brain barrier (12, 25, 33, 46). Recent studies have shown that Escherichia coli K1, group B Streptococcus, Streptococcus pneumoniae, and Citrobacter spp., the important pathogens that cause meningitis, translocate from blood to the central nervous system (CNS) without altering the integrity of the blood-brain barrier (2, 23, 27, 36, 42). These studies of bacterial translocation from blood to the CNS have become possible because of the availability of both in vitro and in vivo models of the blood-brain barrier (1, 3, 4, 7, 11, 13, 17–20, 22, 26, 28, 32, 41, 43, 47). The in vitro model of the blood-brain barrier is composed of brain microvascular endothelial cells (BMEC), which exhibit transendothelial resistance of 200 to 600 Ω/cm2, a unique property of the brain microvascular endothelium monolayer compared to systemic vascular endothelium. The in vivo model of the blood-brain barrier utilizes experimental hematogenous meningitis in animals. In these experimental meningitis models, bacteria are injected via intravenous, intraperitoneal, subcutaneous, or intracardiac administration, resulting in bacteremia and subsequent entry into the CNS. At present, E. coli-BMEC interactions represent the most characterized system concerning how circulating bacteria cross the blood-brain barrier. This review summarizes our current understanding of the pathogenetic mechanisms involved in bacterial translocation of the blood-brain barrier, using E. coli as a paradigm.
Regulating speed and generating large speed transitions in a neuromuscular human walking model (2012)

Although current humanoid controllers can rely on inverse kinematics or dynamics of the full humanoid system, powered prosthetic legs or assistive devices cannot, because they do not have access to the full states of the human system. This limitation creates the need for alternative control strategies. One strategy is to embed fundamental knowledge about legged dynamics and control in local feedback. In a previous paper, we have developed a control model of human locomotion which relies mostly on local feedback. The model can robustly walk at normal walking speeds. Here we extend this model to adapt to a wide range of walking speeds and to generate corresponding speed transitions. We use optimization of the model's control parameters and find key parameters responsible for steady walking between 0.8ms <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> and 1.8ms <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> , covering the range of speed at which humans normally walk. Using these parameters, we demonstrate speed transitions between slow and fast walking. In addition, we discuss how the speed-dependent changes of the identified control parameters connect to biped walking dynamics, and suggest how these changes can be integrated in local feedback control.