gebhart/patrepeval huggingface dataset:
Gelsolin-Polyphosphoinositide Interaction (1989)

Calcium activates, and the polyphosphoinositides phosphatidylinositol 4-monophosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) inhibit the mechanical severing of actin filaments by gelsolin. Previous work indicated that the physical state of the two phospholipids is important for their effects in this system. This study correlates tests of gelsolin's severing function with quasielastic light scattering measurements of the size of mixed lipid particles and shows that the previously demonstrated diminution of the maximal effect of PIP2 in micellar form by aggregation of the micelles or mixing with other phospholipids is not the result of an absolute requirement for small lipid particles, but rather the masking of critical sites by aggregation, by sequestration in multilamellar vesicles, or by dilution of the polyphosphoinositides below a critical concentration. Large unilamellar vesicles of PIP and, importantly, PIP2 at low molar ratios (less than 3%) in mixed lipid vesicles of composition similar to plasma membranes are as active as PIP2 micelles. Aggregation or masking of polyphosphoinositide head groups by neomycin or profilin, respectively, blocked inhibition of gelsolin. Experiments with bilayer-forming phospholipids or with Triton X-100 indicate that a critical number of PIP2 molecules may be required for incipient effects on a gelsolin molecule. The actin and polyphosphoinositide binding protein profilin competed with gelsolin for binding PIP2 with a stoichiometry also suggesting binding to multiple PIP2 molecules. The membrane constituents sphingosine and cholesterol blocked the effect of PIP2 on gelsolin when added alone, but did not affect PIP2 when incorporated into mixed lipid bilayers containing phosphatidylinositol. The results suggest that profilin, small changes in membrane lipid composition, and, especially, membrane PIP2 concentration could have large effects on the modulation of gelsolin function in vivo.
Defective Presentation of Endogenous Antigen by a Cell Line Expressing Class I Molecules (1990)

Cytotoxic T lymphocytes (CTLs) recognize class I major histocompatibility complex (MHC) molecules associated with antigenic peptides derived from endogenously synthesized proteins. Binding to such peptides is a requirement for class I assembly in the endoplasmic reticulum (ER). A mutant human cell line, T2, assembles and transports to its surface some, but not all, class I MHC molecules. The class I molecules expressed on the surface of T2 do not present peptides derived from cytosolic antigens, although they can present exogenously added peptides to CTL. The transported class I molecules may interact weakly with an unknown retaining factor in the ER such that they can assemble despite the relative shortage of peptides.
Gradual Loss of T-Helper 1 Populations in Spleen of Mice During Progressive Tumor Growth (1995)

T cells from tumor-bearing mice lose the Th1 phenotype with progressive tumor growth.
An Actor-Critic Algorithm for Sequence Prediction (2016)

We present an approach to training neural networks to generate sequences using actor-critic methods from reinforcement learning (RL). Current log-likelihood training methods are limited by the discrepancy between their training and testing modes, as models must generate tokens conditioned on their previous guesses rather than the ground-truth tokens. We address this problem by introducing a \textit{critic} network that is trained to predict the value of an output token, given the policy of an \textit{actor} network. This results in a training procedure that is much closer to the test phase, and allows us to directly optimize for a task-specific score such as BLEU. Crucially, since we leverage these techniques in the supervised learning setting rather than the traditional RL setting, we condition the critic network on the ground-truth output. We show that our method leads to improved performance on both a synthetic task, and for German-English machine translation. Our analysis paves the way for such methods to be applied in natural language generation tasks, such as machine translation, caption generation, and dialogue modelling.
Data processing spheres of control (1978)

The designers of the semantics of applications are concerned mainly with spheres of control. Concern for performance is a strong second. It is not unusual to eliminate automation of an application if adequate performance can be achieved only by ignoring the spheres of control presented. The application is then done manually or not at all.
Cyclization of 1-alkylamino-3-halo 2-alkanols to 1-alkyl-3-azetidinols (1967)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCyclization of 1-alkylamino-3-halo 2-alkanols to 1-alkyl-3-azetidinolsVan R. GaertnerCite this: J. Org. Chem. 1967, 32, 10, 2972–2976Publication Date (Print):October 1, 1967Publication History Published online1 May 2002Published inissue 1 October 1967https://pubs.acs.org/doi/10.1021/jo01285a009https://doi.org/10.1021/jo01285a009research-articleACS PublicationsRequest reuse permissionsArticle Views566Altmetric-Citations49LEARN 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
CTL in mice immunized with human mucin 1 are MHC-restricted (1995)

CTLs that recognize tumor Ags have been described in mice and humans, particularly for melanoma. These CTLs are CD8+, which is MHC-restricted. In contrast, in human carcinomas of the breast, pancreas, or ovary, and in multiple myeloma, CD8+ CTLs have been described that lyse targets expressing human MUC1 in a non-MHC-restricted manner. On the basis of these observations, we immunized mice with conjugates of mannan-human fusion protein, human mucin 1 (MUC1), which produced CD8+ CTLs. In contrast to the human anti-MUC1 CTLs found in cancer patients, the murine anti-MUC1 CTLs were clearly MHC-restricted, e.g., in inbred mice of the H-2-b, d, k, s, or z haplotypes; the H-2 restriction was also confirmed in H-2 congenic strains. Tests of H-2 recombinant strains demonstrated that MUC1 peptides were able to associate with D or K class I molecules of the b, d, or k haplotypes. Mice lacking MHC-class I molecules made weak CTL responses that were H-2Db-restricted, and in the class I H-2Kbm1 mutant strain, CTL restriction was also shown. Finally, cold target inhibition studies demonstrated that Kb and Db are recognized similarly, but Kk is less well recognized. Thus, anti-MUC1 CTLs induced by immunization of mice are different from those obtained from patients. The immunization of cancer patients with MUC1 peptides is now undergoing clinical trials and it will be of interest to observe whether the CTLs induced are HLA-restricted, not restricted, or whether both types of CTLs are produced.
Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer (2018)

These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.
Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics (2007)

The conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of E1 have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive E1. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-kappaB activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to IkappaB kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of IkappaBalpha. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E1 inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation.
IL-17 in lung disease: friend or foe? (2013)

Interleukin 17 (IL-17) is a key proinflammatory cytokine in the T helper 17 pathway. While it is important in the clearance of certain pathogens, IL-17 has been shown to contribute to the pathogenesis of such inflammatory diseases as rheumatoid arthritis and psoriasis. In the lung, it has been postulated to be involved in the neutrophilic inflammation and airway remodelling of chronic respiratory conditions but the situation is increasingly complex. This review summarises the evidence for its role in several chronic inflammatory lung diseases: asthma, obliterative bronchiolitis, chronic obstructive pulmonary disease, sarcoidosis and cystic fibrosis.
Ethylene–vinyl acetate semi‐batch emulsion copolymerization: Use of factorial experiments for improved process understanding (1993)

Abstract A good working knowledge of the mechanism and an appreciation of the effects the process variables have on the properties of interest are required for optimization and control of polymerization processes. Despite the importance of ethylene‐vinyl acetate emulsion copolymers, limited kinetic information is available. Results from a series of factorial experiments are presented here which examine the emulsion polymerization of ethylene with vinyl acetate. Copolymers of up to 32 wt % ethylene have been produced at an ethylene pressure of 500 psig and a temperature of 20°C. The effects of the process variables on the rate of polymerization, copolymer composition, particle size and number, molecular weight averages, and gel content are discussed. The kinetic results obtained suggest process improvements for the production of homogeneous copolymer. Mechanistically, the locus of polymerization has been verified as the polymer particles and little water phase polymerization was observed. © 1993 John Wiley &amp; Sons, Inc.
Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects (2013)

Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings.
Windows NT Clustering Service (1998)

The Windows NT Clustering Service supports high-availability file servers, databases, and generic applications and services. A cluster is a collection of computer nodes-independent, self-contained computer systems-that work together to provide a more reliable and powerful system than a single node. In general, the goal of a cluster is to distribute a computing load over several systems, without users or system administrators being aware of the independent systems running the services. The Windows NT Clustering Service detects and restarts failed hardware or software components or migrates the failed component's functionality to another node if local restart is not possible. It also offers a much simpler user and programming interface. Microsoft Cluster Service for Windows NT has been shipping for about a year on Windows NT version 4.0. The upcoming Windows NT 5.0 release of Windows NT Clustering Service will improve ease of use through a wizard that guides the user through the creation of cluster resources.
Human gene therapy. (1993)

Current concepts in gene transfer and its application to the treatment of human genetic disorders, cancer, and other diseases are discussed. Gene therapy is a technique in which a functioning gene is inserted into a human cell to correct a genetic error or to introduce a new function to the cell. Many methods, including retroviral vectors, have been developed for ex vivo and in vivo gene insertion into cells. Some pharmacists have likened gene therapy to a sophisticated form of drug delivery and have envisioned an active role for the pharmacy profession. There are several safety and ethical issues related to manipulating the human genome that need to be understood. Current gene therapy efforts focus on gene insertion into somatic (nongerminal) cells only. Gene therapy has the potential to revolutionize the treatment of genetic disorders, diseases associated with a genetic component (e.g., cystic fibrosis), cancer, AIDS, and many other diseases. Gene transfer may also be used to better understand the biology of disease processes, such as the source of relapse in bone marrow transplant patients. The human genome project will undoubtedly lead to the identification, characterization, and understanding of genes that are responsible for many human diseases, and gene therapy trials are sure to expand accordingly. To date, over 40 clinical trials have been approved and more than 110 patients have been entered in gene therapy studies. There are still many technical obstacles to overcome before gene therapy can have widespread application. Injectable vectors need to be developed to simplify foreign gene administration. Perhaps the biggest problem to overcome will be engineering the target cells to be able to regulate gene expression according to physiologic needs. Pharmacists should become knowledgeable about gene transfer techniques and possible clinical applications of gene therapy to keep abreast of the newest trends in medicine.
On-Surface Formation of Metal Nanowire Transparent Top Electrodes on CdSe Nanowire Array-Based Photoconductive Devices (2012)

A simple wet chemical approach was developed for a unique on-surface synthesis of transparent conductive films consisting of ultrathin gold/silver nanowires directly grown on top of CdSe nanowire array photoconductive devices enclosed in polycarbonate membranes. The metal nanowire film formed an ohmic contact to the semiconductor nanowires without additional treatment. The sheet resistance and transparency of the metal nanowire arrays could be controlled by the number of metal nanowire layers deposited, ranging from ∼98-99% transmission through the visible range and several kOhm/sq sheet resistance for a single layer, to 80-85% transmission and ∼100 Ohm/sq sheet resistance for 4 layers.
Regulation of surface and intracellular expression of CTLA4 on mouse T cells (1996)

CTLA4 is a cell surface molecule that shares 30% homology with CD28 and binds B7 family members with high affinity. Analysis of surface expression on murine T cells revealed up-regulation after stimulation with anti-CD3 mAb in vitro and further augmentation after the addition of exogenous IL-2 or anti-CD28 mAb. The effects of IL-2 and anti-CD28 mAb were additive and in part independent, as anti-CD28 mAb increased anti-CD3 mAb-induced T cell CTLA4 expression in IL-2-deficient mice. In contrast, CTLA4 expression was only minimally augmented by the addition of IL-4, IL-6, IL-7, or IL-12. Expression of CTLA4 induced by anti-CD3 mAb was inhibited by anti-IL-2 plus anti-IL-2R mAbs. Inasmuch as these agents prevented T cell proliferation, the effects of cell cycle inhibitors also were examined. Drugs blocking at G1 (cyclosporin A, mimosine) or S (hydroxyurea) phase inhibited the up-regulation of CTLA4 induced by anti-CD3 mAb, suggesting that entry into the cell cycle was necessary to increase the expression of CTLA4. The kinetics of intracellular expression of CTLA4 after stimulation with anti-CD3 mAb paralleled those of surface expression, but surprisingly, much more CTLA4 was localized in the cytoplasm of T lymphocytes than on the cell surface at each time point. Importantly, surface CTLA4 was rapidly internalized intracellularly, which may explain the low levels of expression generally detected on the cell surface. We conclude that both CD28 and IL-2 play important roles in the up-regulation of CTLA4 expression. In addition, the cell surface accumulation of CTL4 appears to be primarily regulated by its rapid endocytosis.
Glycosylation of Nucleocytoplasmic Proteins: Signal Transduction and O-GlcNAc (2001)

The dynamic glycosylation of serine or threonine residues on nuclear and cytosolic proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) is abundant in all multicellular eukaryotes. On several proteins, O-GlcNAc and O-phosphate alternatively occupy the same or adjacent sites, leading to the hypothesis that one function of this saccharide is to transiently block phosphorylation. The diversity of proteins modified by O-GlcNAc implies its importance in many basic cellular and disease processes. Here we systematically examine the current data implicating O-GlcNAc as a regulatory modification important to signal transduction cascades.
Nonlinear Pharmacokinetics of 5-Fluorouracil in Rats (1997)

The effects of dose on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated following intravenous administration of 5-FU at 10, 50, and 100 mg/kg to adult male Sprague-Dawley rats. Six rats were studied at each dose level. The dose-normalized area under the curve (AUC) was significantly higher after administration of 100 mg/kg (1.14 +/- 0.55 mg.h/L/mg; mean +/- SD) than after 50 mg/kg (0.50 +/- 0.18 mg.h/L/mg) or 10 mg/kg (0.43 +/- 0.11 mg.h/L/mg), indicating nonlinear elimination of 5-FU in rats. Dose- and time-average pharmacokinetic parameters were calculated by area/moment analysis. The systemic clearance of 5-FU following administration of 100 mg/kg was significantly lower (1.1 +/- 0.49 L/h/kg) than after 50 mg/kg (2.2 +/- 0.72 L/h/kg) or 10 mg/kg (2.4 +/- 0.67 L/h/kg). There was no significant difference in renal clearance values between the three doses (0.47 +/- 0.26 L/h/kg). However, nonrenal clearance was significantly lower after the 100-mg/kg dose (0.77 +/- 0.2 L/h/kg) than after the 50-mg/kg (1.65 +/- 0.49 L/h/kg) and 10-mg/kg (1.87 +/- 0.75 L/h/kg) doses. There was no significant difference between the steady-state volume of distribution values (0.91 +/- 0.36 L/kg) at the three doses. The lower nonrenal clearance following the 100-mg/kg dose compared with that after the lower doses of 5-FU suggested nonlinear metabolism of 5-FU in rats. A two-compartment pharmacokinetic model with parallel first-order (renal excretion) and Michaelis-Menten elimination from the central compartment was simultaneously fit to mean plasma 5-FU concentration versus time data for the three doses. The maximum volume (Vmax) and Michaelis constant (Km) values averaged (mean +/- SE) 8.3 +/- 2.3 mg/h and 31.6 +/- 11.9 mg/L, respectively. The information obtained in this study will be valuable for the evaluation of prodrugs of 5-FU that are designed to reduce toxicities and to improve oral bioavailability of the anticancer agent.
Genetic analysis of Arabidopsis mutants impaired in plastid lipid import reveals a role of membrane lipids in chloroplast division (2011)

The biogenesis of photosynthetic membranes in plants relies largely on lipid import from the endoplasmic reticulum (ER) and this lipid transport process is mediated by TGD proteins in Arabidopsis. Such a dependency of chloroplast biogenesis on ER-to-plastid lipid transport was recently exemplified by analyzing double mutants between tgd1-1 or tgd4-3 and fad6 mutants. The fad6 mutants are defective in the desaturation of membrane lipids in chloroplasts and therefore dependent on import of polyunsaturated lipid precursors from the ER for constructing a competent thylakoid membrane system. In support of a critical role of TGD proteins in ER-to-plastid lipid trafficking, we showed that the introduction of the tgd mutations into fad6 mutant backgrounds led to drastic reductions in relative amounts of thylakoid lipids. Moreover, the tgd1-1 fad6 and tgd4-3 fad6 double mutants were deficient in polyunsaturated fatty acids in chloroplast membrane lipids, and severely compromised in the biogenesis of photosynthetic membrane systems. Here we report that these double mutants are severely impaired in chloroplast division. The possible role of membrane lipids in chloroplast division is discussed. :
Isolating recombinant antibodies against specific protein morphologies using atomic force microscopy and phage display technologies (2006)

Isolation of antibodies to antigens that are either unstable, exist in multiple morphologies or have very limited availability can be prohibitively difficult. Here we describe a novel technique combining the capabilities of phage display antibody technology and atomic force microscopy (AFM) that is used to isolate antibody fragments that bind to a specific morphology of the target antigen, alpha-synuclein. AFM imaging allows us to both visualize the presence and morphology of the target antigen as well as to monitor the efficiency of each step in the bio-panning process. We demonstrate that phage displayed antibodies specific to the target antigen morphology can be isolated after only two rounds of selection. The target antigen, alpha-synuclein, has been correlated with the Parkinson's disease (PD). Accumulation of alpha-synuclein fibrillar aggregates into Lewy body inclusions is a hallmark feature of PD. While alpha-synuclein can form several different aggregate morphologies including oligomers, protofibrils and fibrils, the role of these morphologies in the progression of PD is not known. The successful selection of the recombinant antibody described here can have potential therapeutic value since the single-chain fragment variable (scFv) can be expressed intracellularly to control folding and toxicity of the specific protein aggregates.