gebhart/patrepeval huggingface dataset:
Sequence variation of a novel heptahelical leucocyte receptor through alternative transcript formation (1995)

Chemoattractants, including chemokines such as interleukin 8 (IL-8) and related proteins, activate leucocytes via seven-transmembrane-domain G-protein-coupled receptors. A cDNA for a novel receptor of this kind consisting of 327 amino acids was isolated from a human blood monocyte cDNA library. The polypeptide, termed monocyte-derived receptor 15 (MDR15), is an alternative form of the Burkitt's lymphoma receptor 1 (BLR1) encoded by a human Burkitt's lymphoma cDNA [Dobner, Wolf, Emrich and Lipp (1992) Eur. J. Immunol. 22, 2795-2799]. MDR15 and BLR1 cDNAs differ in the 5' region, where the open reading frame of MDR15 is shorter by 45 codons. Southern-blot analysis indicates that the two transcripts for MDR15 and BLR1 are encoded by the same gene. Northern-blot analysis using a probe that hybridizes with both mRNAs demonstrated high-level expression in chronic B-lymphoid leukaemia and non-Hodgkin's lymphoma cells and, to a lesser extent, peripheral blood monocytes and lymphocytes. Reverse transcription-PCR studies with MDR15- and BLR1-specific primers showed similar levels of transcripts for both receptors in RNA that was positive in Northern-blot analysis. MDR15 and BLR1 have high structural similarity to receptors for human IL-8 (about 40% amino acid identity) and other chemokines. However, none of a series of radiolabelled chemokines (IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-2, MCP-3, I-309, RANTES and MIP-1 alpha) and other ligands (C3a and leukotriene B4) bound to Jurkat transfectants that stably expressed either MDR15 or BLR1 mRNA. The fact that MDR15 and BLR1 are expressed on leucocytes and show marked sequence similarity to chemokine receptors suggests the existence of as yet unidentified chemokines. Alternative transcript formation affecting the 5'-terminal part of the coding region may be a way to modify ligand-binding selectivity.
Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric SarcomasIn vitroandIn vivo (2013)

The IL-6/JAK/STAT pathway is a key signal transduction pathway implicated in the pathogenesis of many human cancers, suggesting that kinase inhibitors targeting JAK/STAT3 may have a broad spectrum of antitumor activity. AZD1480, a pharmacological JAK1/2 inhibitor, exhibits anti-tumor potency in multiple adult malignancies. To evaluate the efficacy of inhibition of JAK/STAT3 signal transduction pathway we assessed the activity of AZD1480 in pediatric malignancies using preclinical models of three highly malignant pediatric solid tumors: neuroblastoma (NB), rhabdomyosarcoma (RMS) and the Ewing Sarcoma Family Tumors (ESFT). In this study, we employed panels of biomedical and biological experiments to evaluate the in vitro and in vivo activity of AZD1480 in NB, RMS and ESFT. Our data indicate that AZD1480 blocks endogenous as well as IL-6 induced STAT3 activation. AZD1480 decreases cell viability in 7/7NB, 7/7RMS and 2/2 ESFT cell lines (median EC50 is 1.5 μM, ranging from 0.36-5.37 μM). AZD1480 induces cell growth inhibition and caspase-dependent apoptosis in vitro and decreases expression of STAT3 target genes, including cell cycle regulators CyclinD1, 3 and CDC25A, anti-apoptotic genes Bcl-2 and survivin, the metastasis-related factor TIMP-1 and c-Myc. In vivo studies showed AZD1480 significantly decreased tumor growth and prolonged overall survival in tumor-bearing mice. Tumors from AZD1480-treated mice showed inhibition of activated STAT3 as well as decreased expression of STAT3 downstream targets. Our study provides strong evidence of the anti-tumor growth potency of JAK inhibitor AZD1480 in pediatric solid tumors, providing proof-of principle that inhibition of the JAK/STAT3 signal transduction could be a promising therapeutic target for high-risk pediatric solid tumors.
Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout (2003)

Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia.
Crack Arrest and Multiple Cracking in Glass Through the Use of Designed Residual Stress Profiles (1999)

A processing approach has been identified and reduced to practice in which a residual stress profile can be designed such that cracks in a brittle material are arrested or grow in a stable manner. In the approach, cracks in the body encounter an increase in the magnitude of residual compression as the crack propagates. If correctly designed, the process increases strength and significantly decreases strength variability. This approach was demonstrated for a silicate glass, and multiple cracking was observed as a forewarning of the final failure. Normally, such glasses would fail catastrophically with the propagation of a dominant crack.
Identification and Molecular Cloning of a Chondroitin Synthase from Pasteurella multocida Type F (2000)

Pasteurella multocida Type F, the minor fowl cholera pathogen, produces an extracellular polysaccharide capsule that is a putative virulence factor. It was reported that the capsule was removed by treating microbes with chondroitin AC lyase. We found by acid hydrolysis that the polysaccharide contained galactosamine and glucuronic acid. We molecularly cloned a Type F polysaccharide synthase and characterized its enzymatic activity. The 965-residue enzyme, called P. multocida chondroitin synthase (pmCS), is 87% identical at the nucleotide and the amino acid level to the hyaluronan synthase, pmHAS, from P. multocida Type A. A recombinant Escherichia coli-derived truncated, soluble version of pmCS (residues 1-704) was shown to catalyze the repetitive addition of sugars from UDP-GalNAc and UDP-GlcUA to chondroitin oligosaccharide acceptors in vitro. Other structurally related sugar nucleotide precursors did not substitute in the elongation reaction. Polymer molecules composed of approximately 10(3) sugar residues were produced, as measured by gel filtration chromatography. The polysaccharide synthesized in vitro was sensitive to the action of chondroitin AC lyase but resistant to the action of hyaluronan lyase. This is the first report identifying a glycosyltransferase that forms a polysaccharide composed of chondroitin disaccharide repeats, [beta(1,4)GlcUA-beta(1,3)GalNAc](n). In analogy to known hyaluronan synthases, a single polypeptide species, pmCS, possesses both transferase activities.
Transduction of a novel HLA-DRB1*04:05-restricted, WT1-specific TCR gene into human CD4+ T cells confers killing activity against human leukemia cells. (2015)

The novel TCR gene cloned here should be a promising tool to develop adoptive immunotherapy of WT1332-specific TCR-transduced CD4+ T-cells for the treatment of WT1-expressing cancer, such as leukemia.
Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds (2001)

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3+/-0.5 MPa and compressive strength at 1% yield of 0.11+/-0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.
Combination chemoradiotherapy with gemcitabine: potential applications. (2000)

Gemcitabine (Gemzar) is a novel deoxycitidine drug that has demonstrated promising single-agent activity in non-small-cell lung cancer and has been proven to be a potent radiosensitizer. Although the exact mechanism of the radiosensitizing effect is unknown, several studies have focused on the drug's effect on deoxyadenosine triphosphate (dATP) pool depletion or cell-cycle manipulation. A number of trials have evaluated this feature of gemcitabine by combining chemotherapy and radiation in various doses and schedules, and those studies are described in this article. Gemcitabine appears to be a promising agent to be combined with radiation therapy. However, further clinical trials are needed to define optimal doses, toxicity, and efficacy.
A Cell Surface Receptor Complex for Fibrillar β-Amyloid Mediates Microglial Activation (2003)

Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of β-amyloid (Aβ) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Aβ fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the α 6 β 1 -integrin. Antagonists of scavenger receptors, CD36, CD47, and α 6 β 1 inhibited the adhesion of THP-1 monocytes to Aβ fibrils. In addition, peptide competitors of Aβ fibril interactions with CD36, scavenger receptors, CD47, and the α 6 β 1 -integrin inhibited Aβ stimulation of Tyr kinase-based signaling cascades in both THP-1 monocytes and murine microglia as well as interleukin 1β production. A scavenger receptor antagonist and antibodies specific for CD36 and the β 1 -integrin subunit also inhibited the Aβ-stimulated generation of reactive oxygen species. Importantly, the principal components of this receptor complex are shared with those for other fibrillar proteins and thus represent general elements through which myeloid lineage cells recognize complex fibrillar proteins. Identification of the cell surface molecules that interact with Aβ fibrils and mediate their activation of intracellular signaling cascades represents a potential intervention point in the treatment of Alzheimer's disease.
Editing the Genome Without Double-Stranded DNA Breaks (2017)

Genome editing methods have commonly relied on the initial introduction of double-stranded DNA breaks (DSBs), resulting in stochastic insertions, deletions, and translocations at the target genomic locus. To achieve gene correction, these methods typically require the introduction of exogenous DNA repair templates and low-efficiency homologous recombination processes. In this review, we describe alternative, mechanistically motivated strategies to perform chemistry on the genome of unmodified cells without introducing DSBs. One such strategy, base editing, uses chemical and biological insights to directly and permanently convert one target base pair to another. Despite its recent introduction, base editing has already enabled a number of new capabilities and applications in the genome editing community. We summarize these advances here and discuss the new possibilities that this method has unveiled, concluding with a brief analysis of future prospects for genome and transcriptome editing without double-stranded DNA cleavage.
Improved method for the analysis of membrane proteins by mass spectrometry (2007)

Membrane-bound and membrane-associated proteins are difficult to analyze by mass spectrometry, since the association with lipids impedes the isolation and solubilization of the proteins in buffers suitable for mass spectrometry and the efficient generation of positively charged peptide ions by electrospray ionization. Current methods mostly utilize detergents for the isolation of proteins from membranes. In this study, we present an improved detergent-free method for the isolation and mass spectrometric identification of membrane-bound and membrane-associated proteins. We delipidate proteins from the membrane bilayer by chloroform extraction to overcome dissolution and ionization problems during analysis. Comparison of our results to results obtained by direct tryptic digestion of insoluble membrane pellets identifies an increased number of membrane proteins, and a higher quality of the resulting mass spectral data.
Structural basis for the fast self-cleavage reaction catalyzed by the twister ribozyme (2014)

Twister is a recently discovered RNA motif that is estimated to have one of the fastest known catalytic rates of any naturally occurring small self-cleaving ribozyme. We determined the 4.1-Å resolution crystal structure of a twister sequence from an organism that has not been cultured in isolation, and it shows an ordered scissile phosphate and nucleotide 5' to the cleavage site. A second crystal structure of twister from Orzyza sativa determined at 3.1-Å resolution exhibits a disordered scissile phosphate and nucleotide 5' to the cleavage site. The core of twister is stabilized by base pairing, a large network of stacking interactions, and two pseudoknots. We observe three nucleotides that appear to mediate catalysis: a guanosine that we propose deprotonates the 2'-hydroxyl of the nucleotide 5' to the cleavage site and a conserved adenosine. We suggest the adenosine neutralizes the negative charge on a nonbridging phosphate oxygen atom at the cleavage site. The active site also positions the labile linkage for in-line nucleophilic attack, and thus twister appears to simultaneously use three strategies proposed for small self-cleaving ribozymes. The twister crystal structures (i) show its global structure, (ii) demonstrate the significance of the double pseudoknot fold, (iii) provide a possible hypothesis for enhanced catalysis, and (iv) illuminate the roles of all 10 highly conserved nucleotides of twister that participate in the formation of its small and stable catalytic pocket.
The Protein Kinase Family: Conserved Features and Deduced Phylogeny of the Catalytic Domains (1988)

In recent years, members of the protein kinase family have been discovered at an accelerated pace. Most were first described, not through the traditional biochemical approach of protein purification and enzyme assay, but as putative protein kinase amino acid sequences deduced from the nucleotide sequences of molecularly cloned genes or complementary DNAs. Phylogenetic mapping of the conserved protein kinase catalytic domains can serve as a useful first step in the functional characterization of these newly identified family members.
Introduction of a novel dose saving acquisition mode for the PortalVision™ aS500 EPID to facilitate on‐line patient setup verification (2004)

In external beam radiotherapy, electronic portal imaging becomes more and more an indispensable tool for the verification of the patient setup. For the safe clinical introduction of high dose conformal radiotherapy like intensity modulated radiation therapy, on-line patient setup verification is a prerequisite to ensure that the planned dosimetric coverage of the tumor volume is actually realized in the patient. Since the direction of setup fields often deviates from the direction of the treatment beams, extra dose is delivered to the patient during the acquisition of these portal images which may reach clinical relevance. The aim of this work was to develop a new acquisition mode for the PortalVision aS500 electronic portal imaging device from Varian Medical Systems that allows one to take portal images with reduced dose while keeping good image quality. The new acquisition mode, called RadMode, selectively enables and disables beam pulses during image acquisition allowing one to stop wasting valuable dose during the initial acquisition of "reset frames." Images of excellent quality can be taken with 1 MU only. This low dose per image facilitates daily setup verification with considerably reduced extra dose.
Oxytocin, Vasopressin, and the Neurogenetics of Sociality (2008)

There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.
Full-Wavefield Inversion of Marine Streamer Data with the Encoded Simultaneous Source Method (2011)

Recent developments in simultaneous source techniques for full-wavefield inversion have shown promise in significantly reducing the computational cost. The key is in reducing the large number of individual shots with one or a few encoded shots, thereby providing computational savings for both forward simulation and gradient computation. However, the majority of the applications of this approach have focused on a fixed-receiver geometry, where each receiver records all shots in the survey. Although a fixed receiver geometry is a natural application of this method, few surveys (such as marine streamer) use this geometry. Moving receiver geometries are the common practice in marine and land surveys. Unfortunately, the simultaneous source method using an L2 objective function can not be easily extended to non-fixed (moving) receiver geometry in a straightforward manner. This is because the recorded data are deficient in traces compared to the simulated data generated from an encoded source. We develop a new approach to overcome this problem and propose the use of a cross-correlation objective function instead of the conventional L2 objective function to invert non-fixed spread simultaneous source data. We demonstrate our methodology using a marine streamer synthetic example.
Potent Delivery of Functional Proteins into Mammalian Cells in Vitro and in Vivo Using a Supercharged Protein (2010)

The inability of proteins to potently penetrate mammalian cells limits their usefulness as tools and therapeutics. When fused to superpositively charged GFP, proteins rapidly (within minutes) entered five different types of mammalian cells with potency up to approximately 100-fold greater than that of corresponding fusions with known protein transduction domains (PTDs) including Tat, oligoarginine, and penetratin. Ubiquitin-fused supercharged GFP when incubated with human cells was partially deubiquitinated, suggesting that proteins delivered with supercharged GFP can access the cytosol. Likewise, supercharged GFP delivered functional, nonendosomal recombinase enzyme with greater efficiencies than PTDs in vitro and also delivered functional recombinase enzyme to the retinae of mice when injected in vivo.
Changes in Phytochemical Stability and Food Functionality during Cooking and Processing (2006)

Research interest on functional food and phytochemicals has mainly focused on their health effects, mechanism of action and structure-activity relationship for the development of nutraceuticals. Considering the intake of phytochemicals via the normal diet, further information is required on changes in food functionality or individual phytochemicals that occur during the cooking or processing of foods, in order to increase the intake of these bioactive compounds, because many of the unit-operating procedures involved in cooking or food processing may result in physicochemical changes of food constituents. This study reviews the changes of selected phytochemicals, i.e. flavonoids, organosulfur compounds and carotenoids, or food functionality by major cooking or processing procedures such as heating, fermentation, and pH changes. In general, heating has a negative effect on food functionality, although in some cases, mild heating increases bioactive phytochemical contents. Some phytochemicals, including anthocyanins and catechins, are stabilized in lower pH conditions. The structures of phytochemicals, including isoflavones and catechins, are changed by fermentation. The loss of bioactive compounds may be decreased by recently developed cooking or processing methods such as microwave cooking or use of high hydrostatic pressure. However, the effects of cooking and processing procedures on food functionality and phytochemicals are so diverse and dependent on test conditions that further research efforts are needed to form accurate conclusions on the effects of cooking and processing of foods.
Sonogashira Coupling Reaction with Diminished Homocoupling (2003)

[reaction: see text] The side product from homocoupling reaction of two terminal acetylenes in the Sonogashira reaction can be reduced to about 2% using an atmosphere of hydrogen gas diluted with nitrogen or argon. Terminal arylethynes, diarylethynes, and a few new arylpyridylethynes with donor substituents have been synthesized in very good yields. Comparative control experiments suggest that the homocoupling yield is determined by concentration of both catalyst and oxygen.
Structure–activity relationships of neuropeptide Y analogues with respect to Y1 and Y2 receptors (1995)

Secondary structure investigations, affinities, and activities of neuropeptide Y analogues with respect to the Y1 and the Y2 receptor are reviewed. The results are discussed with respect to the different prerequisites for affinities to both receptor subtypes. The results from a systematic scanning of the hormone using L-alanine and from a large variety of discontinuous and cyclic analogs suggest that two different conformations of neuropeptide Y are adopted at the Y1 and Y2 receptors. Whereas a C-terminal turn structure is suggested for Y1 receptor affinity, an alpha-helical conformation of the C-terminus is afforded for good binding to the Y2 receptor.
Enabling Robust Grammatical Error Correction in New Domains: Data Sets, Metrics, and Analyses (2019)

Until now, grammatical error correction (GEC) has been primarily evaluated on text written by non-native English speakers, with a focus on student essays. This paper enables GEC development on text written by native speakers by providing a new data set and metric. We present a multiple-reference test corpus for GEC that includes 4,000 sentences in two new domains ( formal and informal writing by native English speakers) and 2,000 sentences from a diverse set of non-native student writing. We also collect human judgments of several GEC systems on this new test set and perform a meta-evaluation, assessing how reliable automatic metrics are across these domains. We find that commonly used GEC metrics have inconsistent performance across domains, and therefore we propose a new ensemble metric that is robust on all three domains of text.