gebhart/patrepeval huggingface dataset:
Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome (1999)

The dose-limiting toxicity of interleukin-2 (IL-2) and immunotoxin (IT) therapy in humans is vascular leak syndrome (VLS). VLS has a complex etiology involving damage to vascular endothelial cells (ECs), extravasation of fluids and proteins, interstitial edema, and organ failure. IL-2 and ITs prepared with the catalytic A chain of the plant toxin, ricin (RTA), and other toxins, damage human ECs in vitro and in vivo. Damage to ECs may initiate VLS; if this damage could be avoided without losing the efficacy of ITs or IL-2, larger doses could be administered. In this paper, we provide evidence that a three amino acid sequence motif, (x)D(y), in toxins and IL-2 damages ECs. Thus, when peptides from RTA or IL-2 containing this sequence motif are coupled to mouse IgG, they bind to and damage ECs both in vitro and, in the case of RTA, in vivo. In contrast, the same peptides with a deleted or mutated sequence do not. Furthermore, the peptide from RTA attached to mouse IgG can block the binding of intact RTA to ECs in vitro and vice versa. In addition, RTA, a fragment of Pseudomonas exotoxin A (PE38-lys), and fibronectin also block the binding of the mouse IgG-RTA peptide to ECs, suggesting that an (x)D(y) motif is exposed on all three molecules. Our results suggest that deletions or mutations in this sequence or the use of nondamaging blocking peptides may increase the therapeutic index of both IL-2, as well as ITs prepared with a variety of plant or bacterial toxins.
Elimination of the Truncated Message from the Herpes Simplex Virus Thymidine Kinase Suicide Gene (2001)

Introduction of the Herpes simplex virus thymidine kinase (HSV-tk) gene into target cells renders them susceptible to killing by ganciclovir (GCV). We are studying the use of HSV-tk-transduced T lymphocytes in the context of hematopoietic stem cell transplantation. We have previously shown, in vitro and in vivo, the occurrence of transduced cells resistant to GCV due to a deletion within HSV-tk. This deletion, a consequence of the presence of cryptic splice donor and acceptor sites, originates in the retroviral producer cell. Here we adopt two different methods that introduce third-base degenerate changes at the cryptic splice sites and so prevent splicing. Consequently, the HSV-tk protein is unaltered and the sensitivity of the target cells to GCV is preserved. The use of this mutated HSV-tk should reduce the likelihood of the development of resistant genetically modified cells during clinical trials.
A randomized, placebo‐controlled trial of infliximab plus methotrexate for the treatment of polyarticular‐course juvenile rheumatoid arthritis (2007)

While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA.
Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV‐1106, a Long‐Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects (2016)

TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median t<sub>max</sub> , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.
A convergent route to phthalideisoquinoline alkaloids via directed metalation of tertiary benzamides (1979)

Diastereomeric phthalideisoquinolines 8 and 9 have been synthesized by a route involving an amine-induced bromohomophthalic anhydride – phthalide-α-carboxamide rearrangement, 3 + 4 → 6, as the key step. This rearrangement has been applied to the synthesis of the methoxylated phthalide-α-carboxamide 18 which has been converted into the dehydrophthalide 19 thereby achieving a formal synthesis of the phthalideisoquinoline alkaloids cordrastine I (1a) and cordrastine II (1b). The key intermediate in this sequence, 3,4-dimethoxyhomophthalic acid (15), has been efficiently prepared in two steps via directed lithiation of 2,3-dimethoxy-N,N-diethylbenzamide (13).
Nutritional management of gut health in pigs around weaning (2007)

Early weaning of piglets is often accompanied by a severe growth check and diarrhoea. It is well established that this process is multi-factorial and that post-weaning anorexia and undernutrition are major aetiological factors. Gastrointestinal disturbances include alterations in small intestine architecture and enzyme activities. Recent data indicate transiently-increased mucosal permeability, disturbed absorptive-secretory electrolyte balance and altered local inflammatory cytokine patterns after weaning. These responses appear to operate according to two distinct temporal patterns, an acute response followed by a long-lasting adaptation response. Pigs coexist with a diverse and dense commensal microbiota in their gastrointestinal tract. Most of these microbes are beneficial, providing necessary nutrients or protection against harmful pathogens for the host. The microbial colonisation of the porcine intestine begins at birth and follows a rapid succession during the neonatal and weaning period. Following the withdrawal of sow's milk the young piglets are highly susceptible to enteric diseases partly as a result of the altered balance between developing beneficial microbiota and the establishment of intestinal bacterial pathogens. The intestinal immune system of the newborn piglet is poorly developed at birth and undergoes a rapid period of expansion and specialisation that is not achieved before early (commercial) weaning. Here, new insights on the interactions between feed components, the commensal microbiota and the physiology and immunology of the host gastrointestinal tract are highlighted, and some novel dietary strategies are outlined that are focused on improving gut health. Prebiotics and probiotics are clear nutritional options, while convincing evidence is still lacking for other bioactive substances of vegetable origin.
Erythroid cell differentiation: murine erythroleukemia cell variant with unique pattern of induction by polar compounds. (1976)

The murine-virus-infected erythroleukemia cell system provides an opportunity to examine regulatory mechanisms controlling cytodifferentiation. A cloned cell line (DR10c3) resistant to the erythropoiesis-inducing effect of dimethylsulfoxide (Me2SO) was isolated from the Me2SO-sensitive line DS19. DR10c3 is characterized as follows: (1) the uptake of [3H]Me2SO is similar to that in DS19; (2) cell growth with and without Me2SO is similar to that of DS19; (3) resistance is relatively stable; (4) the karyotype of DR10c3 reveals an average loss of five chromosomes per cell, but is otherwise similar to that of DS19; (5) total protein and globin synthesis by cells cultured 4 days with or without Me2SO is similar to these syntheses in DS19 cultured without Me2SO; (6) virtually no globin mRNA is detectable after 3 days in Me2SO, as assayed both by RNA-complementary DNA hybridization and by the heterologous cell-free protein-synthesizing system; (7) other polar compounds, N-methylpyrrolidinone, 1-methyl-2-piperidone, N, N-dimethylacetamide, and N-methylacetamide, induce erythroid differentiation in DR10c3, and the accumulation of alpha- and beta-globin chains is indistinguishable from that in DS19; and (8) the concentration optima for induction of differentiation by all these compounds are identical for DR10c3 and DS19.
Specific and Differential Activation of Mitogen-Activated Protein Kinase Cascades by Unfamiliar Taste in the Insular Cortex of the Behaving Rat (1998)

Rats were given to drink an unfamiliar taste solution under conditions that result in long-term memory of that taste. The insular cortex, which contains the taste cortex, was then removed and assayed for activation of mitogen-activated protein kinase (MAPK) cascades by using antibodies to the activated forms of various MAPKs. Extracellular responsive kinase 1-2 (ERK1-2) in the cortical homogenate was significantly activated within <30 min of drinking the taste solution, without alteration in the total level of the ERK1-2 proteins. The activity subsided to basal levels within <60 min. In contrast, ERK1-2 was not activated when the taste was made familiar. The effect of the unfamiliar taste was specific to the insular cortex. Jun N-terminal kinase 1-2 (JNK1-2) was activated by drinking the taste but with a delayed time course, whereas the activity of Akt kinase and p38MAPK remained unchanged. Elk-1, a member of the ternary complex factor and an ERK/JNK downstream substrate, was activated with a time course similar to that of ERK1-2. Microinjection of a reversible inhibitor of MAPK/ERK kinase into the insular cortex shortly before exposure to the novel taste in a conditioned taste aversion training paradigm attenuated long-term taste aversion memory without significantly affecting short-term memory or the sensory, motor, and motivational faculties required to express long-term taste aversion memory. It was concluded that ERK and JNK are specifically and differentially activated in the insular cortex after exposure to a novel taste, and that this activation is required for consolidation of long-term taste memory.
What is the Young's Modulus of Silicon? (2010)

The Young's modulus ( <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">E</i> ) of a material is a key parameter for mechanical engineering design. Silicon, the most common single material used in microelectromechanical systems (MEMS), is an anisotropic crystalline material whose material properties depend on orientation relative to the crystal lattice. This fact means that the correct value of <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">E</i> for analyzing two different designs in silicon may differ by up to 45%. However, perhaps, because of the perceived complexity of the subject, many researchers oversimplify silicon elastic behavior and use inaccurate values for design and analysis. This paper presents the best known elasticity data for silicon, both in depth and in a summary form, so that it may be readily accessible to MEMS designers.
Rational Combination of Parvovirus H1 With CTLA-4 and PD-1 Checkpoint Inhibitors Dampens the Tumor Induced Immune Silencing (2019)

The recent therapeutic success of immune checkpoint inhibitors in the treatment of advanced melanoma highlights the potential of cancer immunotherapy. Oncolytic virus-based therapies may further improve the outcome of these cancer patients. A human <i>ex vivo</i> melanoma model was used to investigate the oncolytic parvovirus H-1 (H-1PV) in combination with ipilimumab and/or nivolumab. The effect of this combination on activation of human T lymphocytes was demonstrated. Expression of CTLA-4, PD-1, and PD-L1 immune checkpoint proteins was upregulated in H-1PV-infected melanoma cells. Nevertheless, maturation of antigen presenting cells such as dendritic cells was triggered by H-1PV infected melanoma cells. Combining H-1PV with checkpoint inhibitors, ipilimumab enhanced TNFα release during maturation of dendritic cells; nivolumab increased the amount of IFNγ release. H-1PV mediated reduction of regulatory T cell activity was demonstrated by lower TGF-ß levels. The combination of ipilimumab and nivolumab resulted in a further decline of TGF-ß levels. Similar results were obtained regarding the activation of cytotoxic T cells. H-1PV infection alone and in combination with both checkpoint inhibitors caused strong activation of CTLs, which was reflected by an increased number of CD8<sup>+</sup>GranB<sup>+</sup> cells and increased release of granzyme B, IFNγ, and TNFα. Our data support the concept of a treatment benefit from combining oncolytic H-1PV with the checkpoint inhibitors ipilimumab and nivolumab, with nivolumab inducing stronger effects on cytotoxic T cells, and ipilimumab strengthening T lymphocyte activity.
Effects of Thermal History on Microdefect Formation in Czochralski Silicon Crystals (1985)

The mechanism of formation of microdefects in Czochralski silicon crystals is investigated, with particular attention to the effects of the thermal history in the growth process on the nucleation and growth of oxygen precipitates. The density and size of the nuclei of oxygen precipitates in the asgrown state of a crystal subjected to a special thermal history are analyzed in detail. The behaviors of the nuclei at various temperature ranges of the thermal history are then discussed on the basis of these analyses.
Mutations affecting stability and deadenylation of the yeast MFA2 transcript. (1992)

Decay rates of individual mRNAs in the yeast Saccharomyces cerevisiae can vary by 10- to 20-fold. To determine the basis for the rapid degradation of the mRNA encoded by the yeast MFA2 gene we have used a genetic screen to isolate mutations that increase the stability of this transcript. Analysis of point mutations obtained from this screen, and of additional lesions constructed in vitro, indicated that the MFA2 3'-untranslated region (UTR) contains sequences that specify rapid mRNA decay. Moreover, the lesions that affected mRNA decay rate also affected the process of mRNA deadenylation. Mutations in one region of the 3' UTR both decreased the rate of poly(A) shortening and increased the stability of an intermediate form in the decay pathway with an oligo(A) tail (approximately 10 nucleotides). Mutations in a second region primarily increased the stability of the oligo(A) form. These results suggest that the decay of the MFA2 mRNA initiates with the shortening of the poly(A) tail and there are specific sequences within the 3' UTR that stimulate poly(A) tail shortening as well as subsequent steps in the decay pathway. Given the similarity of this decay pathway to that seen for some mammalian mRNAs, these results suggest that mRNA deadenylation may be a common mechanism of mRNA turnover.
Optimized design of ring-based survivable networks (1995)

We describe an original method for the automated synthesis of transport network designs based on multiple SONET self-healing rings. A heuristic procedure is based on insights about the trade-off between capacity efficiency and traffic capture efficiency of ring sets to find a minimum-cost composite design. Test cases show designs that range from nearly optimal capacity efficiency to nearly optimal traffic capture, depending on the relative costs of transmission capacity and costs for ring-to-ring transition interfaces. The proposed approach may be used directly to produce complete multi-ring designs, or in an automated “ring proposer” context to be integrated with existing ring-planning tools. Results from a real-world long-haul network design involving a total of 141 self-healing rings are presented.
Clinical Skin Banking (1978)

A simplified procedure for the harvest and preservation of human allograft skin for burn treatment is outlined. In establishing a skin bank to serve the San Diego County Regional Burn Treatment Center, our primary goals were to deliver a low-cost product, monitored to be free of significant bacterial contamination. Our own innovations include the use of Falcon 2070 tubes as packaging material, and the use of microwave energy for the safe, rapid thawing of liquid nitrogen stored tissue.
Emerging gallium nitride based devices (1995)

Wide bandgap GaN has long been sought for its applications to blue and UV emitters and high temperature/high power electronic devices. Recent introduction of commercial blue and blue-green LED's have led to a plethora of activity in all three continents into the heterostructures based on GaN and its alloys with AlN and InN. In this review, the status and future prospects of emerging wide bandgap gallium nitride semiconductor devices are discussed. Recent successes in p-doping of GaN and its alloys with InN and AlN, and in n-doping with much reduced background concentrations have paved the way for the design, fabrication, and characterization of devices such as MESFET's, MISFET's, HBT's, LED's, and optically pumped lasers. We discuss the electrical properties of these devices and their drawbacks followed by future prospects. After a short elucidation of materials characteristics of the nitrides, we explore their electrical transport properties in detail. Recent progress in processing such as formation of low-resistance ohmic contacts and etching is also presented. The promising features of quarternaries and double heterostructures in relation to possible current injection lasers, LED's, and photodetectors are also elaborated on.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Pathogenicity Islands and the Evolution of Microbes (2000)

▪ Abstract Virulence factors of pathogenic bacteria (adhesins, toxins, invasins, protein secretion systems, iron uptake systems, and others) may be encoded by particular regions of the prokaryotic genome termed pathogenicity islands. Pathogenicity islands were first described in human pathogens of the species Escherichia coli, but have recently been found in the genomes of various pathogens of humans, animals, and plants. Pathogenicity islands comprise large genomic regions [10–200 kilobases (kb) in size] that are present on the genomes of pathogenic strains but absent from the genomes of nonpathogenic members of the same or related species. The finding that the G+C content of pathogenicity islands often differs from that of the rest of the genome, the presence of direct repeats at their ends, the association of pathogenicity islands with transfer RNA genes, the presence of integrase determinants and other mobility loci, and their genetic instability argue for the generation of pathogenicity islands by horizontal gene transfer, a process that is well known to contribute to microbial evolution. In this article we review these and other aspects of pathogenicity islands and discuss the concept that they represent a subclass of genomic islands. Genomic islands are present in the majority of genomes of pathogenic as well as nonpathogenic bacteria and may encode accessory functions which have been previously spread among bacterial populations.
Metformin Enhances Cisplatin Cytotoxicity by Suppressing Signal Transducer and Activator of Transcription–3 Activity Independently of the Liver Kinase B1–AMP-Activated Protein Kinase Pathway (2013)

Metformin has been used as first-line treatment in patients with type 2 diabetes, and is reported to reduce cancer risk and progression by activating the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Cisplatin remains the main drug for treating advanced non-small-cell lung cancer. However, drug resistance often develops through several mechanisms during the treatment course, including one mechanism mediated by the activation of the IL-6/signal transducer and activator of transcription (STAT)-3 pathway, related to the generation of reactive oxygen species (ROS). This study demonstrated a correlation between STAT3 phosphorylation and cisplatin cytotoxicity, using AS2 (PC14PE6/AS2)-derived cell lines (AS2/S3C) that contained constitutively active STAT3 plasmids as a model. A STAT3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 cells, whereas metformin inhibited STAT3 phosphorylation and enhanced cisplatin cytotoxicity. By contrast, another AMPK activator (5-aminoimidazole-4-carboxamide-riboside) failed to produce these effects. LKB1-AMPK silencing by small, interfering RNA or mammalian target of rapamycin (mTOR) inhibition by rapamycin or pp242 did not alter the effect of metformin on STAT3 activity suppression, suggesting that metformin can modulate the STAT3 pathway through an LKB1-AMPK-independent and probably mTOR-independent mechanism. Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 secretion in AS2 cells. Both mechanisms contributed to the ability of metformin to suppress STAT3 activation in cancer cells, which resulted in the decreased secretion of vascular endothelial growth factor by cancer cells. The growth of subcutaneous tumor xenografts was significantly delayed by a combination of cisplatin and metformin. This is the first study to demonstrate that metformin suppresses STAT3 activation via LKB1-AMPK-mTOR-independent but ROS-related and autocrine IL-6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting STAT3.
A novel and inexpensive technique for creating superhydrophobic surfaces using Teflon and sandpaper (2010)

Considerable efforts have been spent over the last decade developing hydrophobic surfaces exhibiting very large contact angles with water. Many of these methods require complex and expensive fabrication techniques. We demonstrate that sanding Teflon can produce superhydrophobic surfaces with advancing contact angles of up to 151° and contact angle hysteresis of less than 4°. Furthermore, we show that a wide range of both advancing contact angles and contact angle hysteresis can be achieved by varying the grit size of the sandpaper, allowing for future hysteresis and contact angle studies. Scanning electron microscopy images of the roughened surfaces depict the range and amplitude of length scales imparted on the surface by the sandpaper, which leads to deeper understanding of the state of wetting on the surface.
Preparation of Soy‐Based Adhesive Enhanced by Waterborne Polyurethane: Optimization by Response Surface Methodology (2018)

Response surface methodology was used to optimize the preparation conditions of soy‐based adhesives (SBAs) in this work. The parameters such as the effects and interactions of waterborne polyurethane (WPU) addition level ( X 1 ), temperature ( X 2 ), and time ( X 3 ) on wet shear strength ( Y ) were investigated. The regression model for SBA preparation was significant ( p = 0.0034 &lt; 0.05). The coefficient of determination ( R 2 ) of this model was to be 0.9256. According to the results, WPU addition level ( X 1 ) had a significant influence on the wet shear strength, whereas reaction temperature ( X 2 ) and reaction time ( X 3 ) were not significant. The optimal preparation conditions of SBA were 12 wt.% WPU addition level for 101 min at 76°C. Under the optimal conditions, the wet shear strength was 1.07 ± 0.08 MPa, which was in good agreement with the model predicted value. An analysis of FTIR spectra of WPU, soy flour, and soy‐based adhesive further confirmed the validity of the model.