gebhart/patrepeval huggingface dataset:
Non-binding site modulation of G protein-coupled receptor signalling (1999)

AbstractG protein-coupled receptors (GPCRs) are by far the most successful drug targets yet known, due to their key role in cellular communication. Historically, these drugs bind to the same site at which the endogenous agonist interacts. However, as the details of cell signalling are clarified, it is becoming apparent that there are many other sites at which GPCR signalling can be modulated. Furthermore, the emerging ability to block protein-protein interactions with small molecules means that these sites are now also viable therapeutic targets. Potential points of therapeutic intervention of GPCR signalling are at the level of the G protein, where the activities of both a and βγ subunits could be controlled; at multiple effectors such as the adenylyl cyclases, phospholipases and phosphodiesterases; at regulatory proteins such as the regulators of G protein signalling (RGS) proteins or receptor kinases; or at the mitogenic pathways, which offer many sites for intervention. By targeting these sites, perhaps just one arm of the multiple pathways through which a receptor works can be modified, thus providing a greater degree of therapeutic selectivity and specificity than can be attained using receptor agonists or antagonists.KeywordsG proteinG protein-coupled receptorsignal transduction
A Parallel Multiblock/Multidomain Approach for Reservoir Simulation (1999)

Abstract Our approach for parallel multiphysics and multiscale simulation uses two levels of domain decomposition: physical and computational. First, the physical domain is decomposed into subdomains or blocks according to the geometry, geology, and physics/chemistry/biology. Each subdomain represents a single physical system, on a reasonable range of scales, such as a black oil region, a compositional region, a region to one side of a fault, or a near-wellbore region. Second, the computations are decomposed on a parallel machine for efficiency. That is, we use a multiblock or macro-hybrid approach, in which we describe a domain as a union of regions or blocks, and employ an appropriate hierarchical model on each block. This approach allows one to define grids and computations independently on each block. This local grid structure has many advantages. It allows the most efficient and accurate discretization techniques to be employed in each block. The multiblock structure of the algebraic systems allows for the design and use of efficient domain decomposition solvers and preconditioners. Decomposition into independent blocks offers great flexibility in accommodating the shape of the external boundary, the presence of internal features such as faults and wells, and the need to refine a region of the domain in space or time (by treating it as a distinct block); interfacing structured and unstructured grids; and accommodating various models of multiscale and multiphysical phenomena. The resulting grid is not suited to direct application of discretization methods. We use mortar space techniques to impose physically meaningful, mass conservative, fluxmatching conditions on the interfaces between blocks. We present numerical simulations to illustrate several of these decomposition strategies, including the coupling of IMPES and fully implicit models and upscaling by varying the number of degrees of freedom on the block interfaces.
Abstract A173: Potent anti-tumor activity of entrectinib in patient-derived models harboring oncogenic gene rearrangements of NTRKs (2015)

Abstract The Trk family of kinases, which include TrkA, TrkB and TrkC, encoded by NTRK1, NTRK2 and NTRK3, respectively, are high affinity receptors for the neurotrophin family of nerve growth factors. Dysregulated kinase activity of Trk family members due to chromosome rearrangements has been shown to be an oncogenic driver in a number of cancer types, including lung, colorectal, salivary gland, papillary thyroid, glioblastoma, melanoma and other tumors. Although the prevalence of such events is relatively low in most tumor types (&amp;lt;2%), the number of new fusion partners and the list of tumor types that are found to harbor these driver fusions have been steadily increasing. The significant unmet medical need and the relatively low frequency of fusion incidents require an integrated therapeutic/diagnostic (Rx/Dx) approach to best serve the patients in need. Entrectinib (formerly RXDX-101) is an orally available, potent and selective ATP-competitive pan-Trk, ROS1 and ALK inhibitor, with comparable, low nanomolar potency against kinase activity of TrkA, TrkB and TrkC in biochemical and cell based assays. In engineered BaF3 cells expressing clinically identified Trk fusion proteins, with various partners, entrectinib demonstrated potent anti-proliferative activity in the range of 2-5 nM, accompanied by inhibition of Trk phosphorylation and concomitant inactivation of downstream effectors such as PLCγ1, AKT and ERK. The clinical relevance of targeting Trk fusions by entrectinib was further demonstrated by several in vitro and in vivo studies involving patient-derived tumor cells (PDCs) and patient-derived xenografts (PDXs) determined to harbor (by NGS and FISH) and express (by IHC) Trk rearrangements. In 2-dimensional and 3-dimensional proliferation assays, entrectinib effectively inhibited proliferation of PDCs from a CRC patient positive for TPM3-NTRK1 fusion. In another independent study, entrectinib, at exposures significantly lower than clinically achievable levels, caused tumor regression in a PDX derived from a CRC patient positive for LMNA-NTRK1 fusion. All the functional readouts were correlated with changes in target and pathway biomarkers. In conclusion, our preclinical data demonstrate the potential of entrectinib as an effective treatment for Trk-fusion driven tumors of multiple histologies, which is now being demonstrated in ongoing clinical trials. Citation Format: Gang Li, Seung Tae Kim, Kyoung-Mee Kim, Jeeyun Lee, Mariangela Russo, Sandra Misale, Alberto Bardelli, Roopal Patel, Nicholas Cam, Ge Wei, Aaron Boomer, Danielle Murphy, Jason Christiansen, Robert Shoemaker, Zachary Hornby, Robert Wild. Potent anti-tumor activity of entrectinib in patient-derived models harboring oncogenic gene rearrangements of NTRKs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A173.
The on-chip 3 MB subarray based 3rd level cache on an Itanium microprocessor (2003)

This 3 MB on-chip level-three cache employs subarray design style, and achieves 85% array efficiency. Characterized to operate up to 1.2 GHz, the cache allows a store and a load in every four core cycles, and provides a total bandwidth of 64 GB/s at 1.0 GHz.
Development of a biomimetic microfluidic oxygen transfer device (2016)

Blood oxygenators provide crucial life support for patients suffering from respiratory failure, but their use is severely limited by the complex nature of the blood circuit and by complications including bleeding and clotting. We have fabricated and tested a multilayer microfluidic blood oxygenation prototype designed to have a lower blood prime volume and improved blood circulation relative to current hollow fiber cartridge oxygenators. Here we address processes for scaling the device toward clinically relevant oxygen transfer rates while maintaining a low prime volume of blood in the device, which is required for clinical applications in cardiopulmonary support and ultimately for chronic use. Approaches for scaling the device toward clinically relevant gas transfer rates, both by expanding the active surface area of the network of blood microchannels in a planar layer and by increasing the number of microfluidic layers stacked together in a three-dimensional device are addressed. In addition to reducing prime volume and enhancing gas transfer efficiency, the geometric properties of the microchannel networks are designed to increase device safety by providing a biomimetic and physiologically realistic flow path for the blood. Safety and hemocompatibility are also influenced by blood-surface interactions within the device. In order to further enhance device safety and hemocompatibility, we have demonstrated successful coating of the blood flow pathways with human endothelial cells, in order to confer the ability of the endothelium to inhibit coagulation and thrombus formation. Blood testing results provide confirmation of fibrin clot formation in non-endothelialized devices, while negligible clot formation was documented in cell-coated devices. Gas transfer testing demonstrates that the endothelial lining does not reduce the transfer efficiency relative to acellular devices. This process of scaling the microfluidic architecture and utilizing autologous cells to line the channels and mitigate coagulation represents a promising avenue for therapy for patients suffering from a range of acute and chronic lung diseases.
Role of Junctional Adhesion Molecule-Like Protein in Mediating Monocyte Transendothelial Migration (2008)

Monocytic JAML plays a critical role in regulating monocyte TEM probably via binding to the endothelial CAR and other tight junction-associated adhesive molecules.
Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. (1992)

After cell infection by the human immunodeficiency virus type 1 (HIV-1), nascent viral DNA in the form of a high molecular weight nucleoprotein preintegration complex must be transported to the nucleus of the host cell prior to integration of viral DNA with the host genome. The mechanism used by retroviruses for nuclear targeting of preintegration complexes and dependence on cell division has not been established. Our studies show that, after infection, the preintegration complex of HIV-1 was rapidly transported to the nucleus of the host cell by a process that required ATP but was independent of cell division. Functional HIV-1 integrase, an essential component of the preintegration complex, was not required for nuclear import of these complexes. The ability of HIV-1 to use host cell active transport processes for nuclear import of the viral preintegration complex obviates the requirement for host cell division in establishment of the integrated provirus. These findings are pertinent to our understanding of early events in the life cycle of HIV-1 and to the mode of HIV-1 replication in terminally differentiated nondividing cells such as macrophages (monocytes, tissue macrophages, follicular dendritic cells, and microglial cells).
Structural immunochemistry of melatonin-BSA binding, model of amino and indole groups cross-linking. (1980)

The sites of fixation to bovine serum albumin of melatonin and of mono- and dimethylated melatonin identified by mass spectrometry and nuclear magnetic resonance, have been determined. The binding sites appear to be important in the conservation of the structural features necessary for the antigenicity of the molecule.
A microarray enzyme-linked immunosorbent assay for autoimmune diagnostics (2000)

In order to quantify autoantibodies in the sera of patients with autoimmune disease, we have created a microarray-based immunoassay that allows the simultaneous analysis of 18 known autoantigens. The microarrays contain serial dilutions of the various antigens, thereby allowing accurate determination of autoantibody titer using minimal amounts of serum. The assay is very sensitive and highly specific: as little as 40 fg of a known protein standard can be detected with little or no cross-reactivity to nonspecific proteins. The signal intensities observed from serial dilutions of immobilized antigen correlate well with serial dilutions of autoimmune sera. Miniaturized and highly parallelized immunoassays like these will reduce costs by decreasing reagent consumption and improve efficiency by greatly increasing the number of assays that can be performed with a single serum sample. This system will significantly facilitate and accelerate the diagnostics of autoimmune diseases and can be adapted easily to any other kind of immunoassay.
Molecular Mechanisms of Hepatitis B Virus-Associated Liver Cancer (2001)

Hepatitis B infection is associated with an increased risk of hepatocellular carcinoma development. Hepatitis B proteins, such as the hepatitis B x protein, the large hepatitis B surface protein, or truncated middle hepatitis B surface proteins, regulate transcription of many candidate genes for liver carcinogenesis by trans-mechanisms. They also alter mechanisms of apoptosis and interfere with nucleotide excision repair of damaged DNA. Together with an influence on cellular signaling, these mechanisms may favor the cell's clonal expansion.
A Robust Deep-Learning-Based Detector for Real-Time Tomato Plant Diseases and Pests Recognition (2017)

Plant Diseases and Pests are a major challenge in the agriculture sector. An accurate and a faster detection of diseases and pests in plants could help to develop an early treatment technique while substantially reducing economic losses. Recent developments in Deep Neural Networks have allowed researchers to drastically improve the accuracy of object detection and recognition systems. In this paper, we present a deep-learning-based approach to detect diseases and pests in tomato plants using images captured in-place by camera devices with various resolutions. Our goal is to find the more suitable deep-learning architecture for our task. Therefore, we consider three main families of detectors: Faster Region-based Convolutional Neural Network (Faster R-CNN), Region-based Fully Convolutional Network (R-FCN), and Single Shot Multibox Detector (SSD), which for the purpose of this work are called "deep learning meta-architectures". We combine each of these meta-architectures with "deep feature extractors" such as VGG net and Residual Network (ResNet). We demonstrate the performance of deep meta-architectures and feature extractors, and additionally propose a method for local and global class annotation and data augmentation to increase the accuracy and reduce the number of false positives during training. We train and test our systems end-to-end on our large Tomato Diseases and Pests Dataset, which contains challenging images with diseases and pests, including several inter- and extra-class variations, such as infection status and location in the plant. Experimental results show that our proposed system can effectively recognize nine different types of diseases and pests, with the ability to deal with complex scenarios from a plant's surrounding area.
.alpha.-Methoxy-.alpha.-trifluoromethylphenylacetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and amines (1969)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT.alpha.-Methoxy-.alpha.-trifluoromethylphenylacetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and aminesJames A. Dale, David L. Dull, and Harry S. MosherCite this: J. Org. Chem. 1969, 34, 9, 2543–2549Publication Date (Print):September 1, 1969Publication History Published online1 May 2002Published inissue 1 September 1969https://pubs.acs.org/doi/10.1021/jo01261a013https://doi.org/10.1021/jo01261a013research-articleACS PublicationsRequest reuse permissionsArticle Views9465Altmetric-Citations2350LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Modern multiphase catalysis: new developments in the separation of homogeneous catalysts (2009)

Homogeneous catalysts are powerful tools for the synthesis of fine chemicals, pharmaceuticals and materials, however their exploitation on an industrial scale is often held back due to the challenges of separating and recycling the catalyst. This perspective focuses on approaches to multiphase catalysis that have emerged in the last decade, highlighting methods that can address the separation issues and in some cases result in superior catalyst performance and environmental benefits.
A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains (2000)

Members of the double-stranded RNA- (dsRNA) specific adenosine deaminase gene family convert adenosine residues into inosines in dsRNA and are involved in A-to-I RNA editing of transcripts of glutamate receptor (GluR) subunits and serotonin receptor subtype 2C (5-HT(2C)R). We have isolated hADAR3, the third member of this class of human enzyme and investigated its editing site selectivity using in vitro RNA editing assay systems. As originally reported for rat ADAR3 or RED2, purified ADAR3 proteins could not edit GluR-B RNA at the "Q/R" site, the "R/G" site, and the intronic "hot spot" site. In addition, ADAR3 did not edit any of five sites discovered recently within the intracellular loop II region of 5-HT(2C)R RNAs, confirming its total lack of editing activity for currently known substrate RNAs. Filter-binding analyses revealed that ADAR3 is capable of binding not only to dsRNA but also to single-stranded RNA (ssRNA). Deletion mutagenesis identified a region rich in arginine residues located in the N-terminus that is responsible for binding of ADAR3 to ssRNA. The presence of this ssRNA-binding domain as well as its expression in restricted brain regions and postmitotic neurons make ADAR3 distinct from the other two ADAR gene family members, editing competent ADAR1 and ADAR2. ADAR3 inhibited in vitro the activities of RNA editing enzymes of the ADAR gene family, raising the possibility of a regulatory role in RNA editing.
Preparation and evaluation of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol as a highly selective radioligand for tissues containing estrogen receptors: concise communication. (1984)

The moxestrol analog 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol was prepared in 95% radiochemical yield from the corresponding 17 alpha-(tributylstannyl) vinyl compound and no-carrier-added sodium [125I]iodide. The new radioligand was evaluated in immature female rats to determine the uptake in and selectivity for tissues containing estrogen receptors. At 1, 2, and 6 hr after injection, the agent demonstrates both high selectivity (uterus to blood ratio) and a high concentration in the target tissue. These values are considerably better than those previously reported for IVE2 or for the 16 alpha-radiohalogenated estradiols. The compound's biologic properties and its ease of preparation suggest that it would be a likely candidate for clinical use as an estrogen-receptor-seeking radiopharmaceutical.
Identification of a guanosine triphosphate-binding site on guinea pig liver transglutaminase. Role of GTP and calcium ions in modulating activity. (1987)

Guanosine 5'-triphosphate (GTP) was found to inhibit guinea pig liver transglutaminase activity as measured by [3H]putrescine incorporation into casein. GDP and GTP-gamma-S also inhibited enzyme activity (GTP-gamma-S greater than GTP greater than GDP). Kinetic studies showed that GTP acted as a reversible, noncompetitive inhibitor and that CaCl2 partially reversed GTP inhibition. GTP also inhibited rat liver and adult bovine aortic endothelial cell transglutaminase, but did not inhibit Factor XIIIa activity. Guanosine monophosphate (GMP), cyclic GMP, and polyguanylic acid did not inhibit enzyme activity. Guinea pig liver transglutaminase adsorbed well to GTP-agarose affinity columns, but not to CTP-agarose columns, and the binding was inhibited by the presence of calcium ions. Specific binding of GTP to transglutaminase was demonstrated by photoaffinity labeling with 8-azidoguanosine 5'-[gamma-32P] triphosphate, which was inhibited by the presence of GTP or CaCl2. GTP inhibited trypsin proteolysis of guinea pig liver transglutaminase without affecting the trypsin proteolysis of chromogenic substrates. Proteolytic protection was reversed by the addition of calcium. This study demonstrates that GTP binds to transglutaminase and that both GTP and calcium ions function in concert to regulate transglutaminase structure and function.
Vibrio VopQ induces PI3‐kinase‐independent autophagy and antagonizes phagocytosis (2009)

Vibrio parahaemolyticus is a Gram-negative bacterium responsible for gastroenteritis acquired from the consumption of contaminated shellfish. This bacterium harbours two type III secretion systems, one on each chromosome. The type III secretion system on chromosome I induces cell death by a temporally controlled sequence of events that is caspase-independent and first involves induction of autophagy, followed by cellular rounding, and finally cellular lysis. VopQ is a type III secreted effector that is necessary for the induction of autophagy as mutant strains lacking VopQ are attenuated in their ability to induce autophagy during infection. VopQ is sufficient to induce rapid autophagy as demonstrated by microinjection of recombinant VopQ into GFP-LC3 HeLa cells. Our results demonstrate that VopQ is both necessary and sufficient for induction of autophagy during V. parahaemolyticus-mediated cell death and this effect is independent of phosphatidylinositol-3-kinases but requires Atg5. Furthermore, induction of VopQ-mediated autophagy prevents recruitment of the necessary cellular machinery required for phagocytosis of V. parahaemolyticus during infection. These data provide important insights into the mechanism used by V. parahaemolyticus to cause disease.
Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia (2003)

The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.