gebhart/patrepeval huggingface dataset:
Channel-type molecular structures. Part 4. Transmembrane transport of alkali-metal ions by ‘bouquet’ molecules (1995)

This report describes transport experiments with ‘bouquet’ molecules designed to act as artificial ion channels. The ‘bouquets’ are based on a central macrocycle which is either an 18-crown-6 (BM) or a cyclodextrin derivative (BCD) to which are attached polyethylene oxide [poly(oxyethylene)] chains (BMo and BCDo) or polyalkyl chains (BMc and BCDc) tipped with carboxylate endgroups. The ‘bouquets’ were studied in liposomes prepared from egg phosphatidylcholine (egg PC), dipalmitoyl phosphatidylcholine (DPPC) and a mixture of egg PC, stearylamine and cholesterol. Opposing gradients in Li+ and Na+ concentration were created and the transport of alkali-metal ions down their concentration gradients was followed directly by 7Li and 23Na NMR spectroscopy. ‘Bouquets’ were found to cause a one-for-one exchange of Na+ for Li+(antiport). In order to estimate transport rates, the extent of Na+ entry into liposomes was followed as a function of time. All ‘bouquets’ transported ions at similar rates in fluid membranes. Comparison of transport rates in fluid-(egg PC) and gel-state membranes (DPPC) was used to distinguish carrier and channel mechanisms. Control experiments demonstrated that a known carrier (monensin A) gave significantly lower transport rates in gel-state membranes. Two ‘bouquets’, BMc and BCDc, were found to transport Na+ at similar rates in fluid- and gel-state membranes; this suggests that ion passage occurs preferentially by the channel mechanism and not by the carrier mechanism. Variation of transport rate with ‘bouquet’ concentration was probed for BMo and BMc and the rates were found to increase with BMc concentration but not with BMo concentration. Since the transport rate is expected to be proportional to transporter concentration in both the carrier and channel mechanisms, this indicates that BMo uses neither a carrier nor a channel mechanism. The mechanism by which ‘bouquet’ molecules operate and the criteria which may be used to decide whether functioning channels have been created are discussed.
Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity. (1987)

Previous studies have established that the cytokine interleukin 1 (IL-1) is selectively cytotoxic for isolated human and rat pancreatic beta-cells. This observation raises the possibility that insulin-dependent diabetes mellitus is in part due to immunologically mediated mechanisms involving IL-1. However, other cytokines are produced during immunologic responses. To study possible modulatory effects of other cytokines on IL-1-mediated beta-cell cytotoxicity, we added human recombinant IL-1 alpha and beta (rIL-1 alpha, rIL-1 beta), tumor necrosis factor (rTNF), lymphotoxin (rLT), and interferon-gamma (rIFN-gamma) separately or in combinations to the culture medium of isolated rat islets of Langerhans. A half-maximal inhibition of glucose-stimulated insulin release after 7 days of culture was obtained with 100 pg/ml of rIL-1 beta, whereas 1000 pg/ml of rIL-1 alpha were necessary to obtain an equivalent effect. While ineffective in causing inhibition of beta-cell function or morphologic damage to islets alone 2.5 to 25 ng/ml of rTNF, but not 40 ng/ml of rLT, or 25 ng/ml of rIFN-gamma markedly potentiated the inhibition of beta-cell secretory response and dissolution of islet integrity caused by rIL-1 alpha and beta. The potentiating effect of rTNF was more pronounced if the rTNF was added after 60 min of preincubation of the islets with rIL-1 beta, than if rIL-1 beta was added after 60 min of preincubation with rTNF. rTNF did not interfere with the activity of rIL-1 alpha or beta on lymphocytes. Combinations of rIFN-gamma and rTNF or rLT did not affect beta-cell function. In conclusion, rTNF strongly potentiates the functional inhibition of beta-cells and the morphologic disintegration of islets caused by rIL-1 in vitro. These data, seen in context with previous observations of rIL-1-mediated beta-cell cytotoxicity, suggest that macrophages present in the intra-islet mononuclear cell infiltrate in insulin-dependent diabetes mellitus may secrete monokines that could be important effector molecules in beta-cell destruction.
Structure and energetics of ligand binding to proteins: Escherichia coli dihydrofolate reductase‐trimethoprim, a drug‐receptor system (1988)

A study of the binding of the antibacterial agent trimethoprim to Escherichia coli dihydrofolate reductase was carried out using energy minimization techniques with both a full, all-atom valence force field and a united atom force field. Convergence criteria ensured that no significant structural or energetic changes would occur with further minimization. Root-mean-square (RMS) deviations of both minimized structures with the experimental structure were calculated for selected regions of the protein. In the active site, the all-atom minimized structure fit the experimental structure much better than did the united atom structure. To ascertain what constitutes a good fit, the RMS deviations between crystal structures of the same enzyme either from different species or in different crystal environments were compared. The differences between the active site of the all-atom minimized structure and the experimental structure are similar to differences observed between crystal structures of the same protein. Finally, the energetics of ligand binding were analyzed for the all-atom minimized coordinates. Strain energy induced in the ligand, the corresponding entropy loss due to shifts in harmonic frequencies, and the role of specific residues in ligand binding were examined. Water molecules, even those not in direct contact with the ligand, were found to have significant interaction energies with the ligand. Thus, the inclusion of at least one shell of waters may be vital for accurate simulations of enzyme complexes.
Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 family (2011)

Positive and negative costimulation by members of the CD28 family is critical for the development of productive immune responses against foreign pathogens and their proper termination to prevent inflammation-induced tissue damage. In addition, costimulatory signals are critical for the establishment and maintenance of peripheral tolerance. This paradigm has been established in many animal models and has led to the development of immunotherapies targeting costimulation pathways for the treatment of cancer, autoimmune disease, and allograft rejection. During the last decade, the complexity of the biology of costimulatory pathways has greatly increased due to the realization that costimulation does not affect only effector T cells but also influences regulatory T cells and antigen-presenting cells. Thus, costimulation controls T-cell tolerance through both intrinsic and extrinsic pathways. In this review, we discuss the influence of costimulation on intrinsic and extrinsic pathways of peripheral tolerance, with emphasis on members of the CD28 family, CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1), as well as the downstream cytokine interleukin-1 (IL-2).
Site‐specific incorporation of unnatural amino acids into urate oxidase in Escherichia coli (2008)

Urate oxidase catalyzes the oxidation of uric acid with poor solubility to produce 5-hydroxyisourate and allantoin. Since allantoin is excreted in vivo, urate oxidase has the potential to be a therapeutic target for the treatment of gout. However, its severe immunogenicity limits its clinical application. Furthermore, studies on the structure-function relationships of urate oxidase have proven difficult. We developed a method for genetically incorporating p-azido-L-phenylalanine into target protein in Escherichia coli in a site-specific manner utilizing a tyrosyl suppressor tRNA/aminoacyl-tRNA synthetase system. We substituted p-azido-L-phenylalanine for Phe(170) or Phe(281) in urate oxidase. The products were purified and their enzyme activities were analyzed. In addition, we optimized the system by adding a "Shine-Dalgarno (SD) sequence" and tandem suppressor tRNA. This method has the benefit of site-specifically modifying urate oxidase with homogeneous glycosyl and PEG derivates, which can provide new insights into structure-function relationships and improve pharmacological properties of urate oxidase.
An edge-preserving image interpolation system for a digital camcorder (1996)

Conventional image interpolation techniques degrade the quality of the magnified image due to various artifacts, such as, blocking artifact and excessive smoothing. Those degradations become worse as the magnification ratio increases and there also exists a tradeoff between reducing the blocking artifact and excessive smoothness. An image interpolation system, which provides more naturally magnified images than the conventional ones, is proposed. The system preserves the original edge while not destroying the smoothness in the flat area. The hardware structure of the proposed system is also proposed.
Poly(Methyl Methacrylate) Nanoparticles As Vaccine Adjuvants (2003)

Nanoparticles are solid particles ranging in size from 1 to 1000 nm (1 μm). They consist of macromolecular materials and can be used therapeutically or prophylactically, for example, as adjuvants in vaccines or drug carriers, in which the active principle (drug or biologically active material) is dissolved, entrapped, or encapsulated, or to which the active principle is adsorbed or chemically attached (1–3). One of the first areas of application of nanoparticles was their employment as adjuvants for vaccines. The most frequent method for the preparation of nanoparticles for this purpose was, and still is, emulsion polymerization. The polymers that can be employed for this process include poly(methyl methacrylate) (4,6), polyacrylamide (7), and poly(alkyl cyanoacrylates) (8,9). Among these polymers, poly(methyl methacrylate) proved to be by far the most optimal and suitable material (10,11). Nanoparticles made from polyacrylamide or poly(alkyl cyanoacrylate) possess the disadvantage that they either require large amounts of organic solvents and surfactants for their production, followed by laborious cleaning procedures as in the case of polyacrylamide (7), or their adjuvant effects are very poor (8,9), as with the poly(alkyl cyanoacrylates).
Nanoscale Hydroxyl Radical Generation from Multiphoton Ionization of Tryptophan (2008)

Exposure of solutions containing both tryptophan and hydrogen peroxide to a pulsed ( approximately 180 fs) laser beam at 750 nm induces luminescence characteristic of 5-hydroxytryptophan. The results indicate that 3-photon excitation of tryptophan results in photoionization within the focal volume of the laser beam. The resulting hydrated electron is scavenged by hydrogen peroxide to produce the hydroxyl radical. The latter subsequently reacts with tryptophan to form 5-hydroxytryptophan. The involvement of hydroxyl radicals is confirmed by the use of ethanol and nitrous oxide as scavengers and their effects on the fluorescence yield in this system. It is postulated that such multiphoton ionization of tryptophanyl residues in cellular proteins may contribute to the photodamage observed during imaging of cells and tissues using multiphoton microscopy.
Design, Synthesis, and Biological Evaluation of a Series of Novel AXL Kinase Inhibitors (2011)

The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC(50) 19 nM) and strongly inhibited the growth of several pancreatic cell lines.
Gene walking by unpredictably primed PCR (1994)

Journal Article Gene walking by unpredictably primed PCR Get access Orlando Domínguez, Orlando Domínguez * 1Servicio de InmunologíaHCA, E-33006 Oviedo, Madrid, Spain *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Carlos López-Larrea Carlos López-Larrea 1Servicio de InmunologíaHCA, E-33006 Oviedo, Madrid, Spain2Departamento de InmunologíaUCM, Madrid, Spain Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 22, Issue 15, 11 August 1994, Pages 3247–3248, https://doi.org/10.1093/nar/22.15.3247 Published: 11 August 1994 Article history Received: 03 June 1994 Revision received: 01 July 1994 Accepted: 01 July 1994 Published: 11 August 1994
The Role of the Th2 CC Chemokine Ligand CCL17 in Pulmonary Fibrosis (2004)

Increasing evidence suggests that the development of pulmonary fibrosis is a Th2-mediated process. We hypothesized that the CC chemokines that are associated with a Th2 profile (CCL17 and CCL22) have an important role in the development of pulmonary fibrosis. We measured CCL17 and CCL22 during the pathogenesis of bleomycin-induced pulmonary fibrosis. We found that both CCL17 and CCL22 were significantly elevated through day 20 as compared with control mice. Peak expression of CCL22 preceded the peak levels of CCL17, as measured by real-time quantitative PCR. CCR4 is the receptor for CCL17 and CCL22 therefore, to further characterize the role of CCL17 and CCL22, we measured CCR4 mRNA in lung tissue of bleomycin-treated mice by real-time quantitative PCR. CCR4 was significantly elevated in bleomycin-treated mice as compared with control mice. Immunolocalization demonstrated that CCR4 was expressed predominantly on macrophages. Neutralization of CCL17, but not CCL22, led to a reduction in pulmonary fibrosis. Immunolocalization of bleomycin-treated lung tissue and human idiopathic pulmonary fibrosis tissue specimens showed that epithelial cells expressed CCL17. These findings demonstrate a central role for Th2 chemokines and the macrophage in the pathogenesis of pulmonary fibrosis and are further support for the role of a Th2 phenotype in the pathogenesis of pulmonary fibrosis.
The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model (1993)

We have studied the role of the accessory gene regulator (agr) of Staphylococcus aureus as a virulence determinant in the pathogenesis of septic arthritis. At least 15 genes coding for potential virulence factors in Staphylococcus aureus are regulated by a putative multicomponent signal transduction system encoded by the agr/hld locus. agr and hld mutants show a decreased synthesis of extracellular toxins and enzymes, such as alpha-, beta-, and delta-hemolysin, leucocidin, lipase, hyaluronate lyase, and proteases, and at the same time an increased synthesis of coagulase and protein A as compared with the wild-type counterpart. We have used a recently described murine model of S. aureus-induced arthritis to study the virulence of S. aureus 8325-4 and two agr/hld mutants derived from it. Sixty percent of the mice injected with the wild-type strain developed arthritis, whereas agrA and hld mutants displayed joint involvement in only 10 and 30%, respectively. In addition, 40% of the mice inoculated with the wild-type strain displayed an erosive arthropathy; such changes were not detectable at all in mice inoculated with the agrA mutant. Serum levels of interleukin-6, a potent B-cell differentiation factor, were significantly higher (P < 0.001) in the mice inoculated with the wild-type strain than in those inoculated with the agrA mutant counterpart. Overall, our results suggest that the agr system of S. aureus is an important virulence determinant in the induction and progression of septic arthritis in mice.
Molecular Cloning of SLP-76, a 76-kDa Tyrosine Phosphoprotein Associated with Grb2 in T Cells (1995)

The activation of protein tyrosine kinases is a critical event in T cell antigen receptor (TCR)-mediated signaling. One substrate of the TCR-activated protein tyrosine kinase pathway is a 76-kDa protein (pp76) that associates with the adaptor protein Grb2. In this report we describe the purification of pp76 and the molecular cloning of its cDNA, which encodes a novel 533-amino acid protein with a single carboxyl-terminal Src homology 2 (SH2) domain. Although no recognizable motifs related to tyrosine, serine/threonine, or lipid kinase domains are present in the predicted amino acid sequence, it contains several potential motifs recognized by SH2 and SH3 domains. A cDNA encoding the murine homologue of pp76 was also isolated and predicts a protein with 84% amino acid identity to human pp76. Northern analysis demonstrates that pp76 mRNA is expressed solely in peripheral blood leukocytes, thymus, and spleen; and in human T cell, B cell and monocytic cell lines. In vitro translation of pp76 cDNA gives rise to a single product of 76 kDa that associates with a GST/Grb2 fusion protein, demonstrating a direct association between these two molecules. Additionally, a GST fusion protein consisting of the predicted SH2 domain of pp76 precipitates two tyrosine phosphoproteins from Jurkat cell lysates, and antiserum directed against phospholipase C-gamma 1 coprecipitates a tyrosine phosphoprotein with an electrophoretic mobility identical to that of pp76. These results demonstrate that this novel protein, which we term SLP-76 (SH2 domain-containing Leukocyte Protein of 76 kDa), is likely to play an important role in TCR-mediated intracellular signal transduction.
Photoacoustic and photothermal detection of circulating tumor cells, bacteria and nanoparticles in cerebrospinal fluid in vivo and ex vivo (2013)

Abstract Circulating cells, bacteria, proteins, microparticles, and DNA in cerebrospinal fluid (CSF) are excellent biomarkers of many diseases, including cancer and infections. However, the sensitivity of existing methods is limited in their ability to detect rare CSF biomarkers at the treatable, early‐stage of diseases. Here, we introduce novel CSF tests based on in vivo photoacoustic flow cytometry (PAFC) and ex vivo photothermal scanning cytometry. In the CSF of tumor‐bearing mice, we molecularly detected in vivo circulating tumor cells (CTCs) before the development of breast cancer brain metastasis with 20‐times higher sensitivity than with current assays. For the first time, we demonstrated assessing three pathways (i.e., blood, lymphatic, and CSF) of CTC dissemination, tracking nanoparticles in CSF in vivo and their imaging ex vivo . In label‐free CSF samples, we counted leukocytes, erythrocytes, melanoma cells, and bacteria and imaged intracellular cytochromes, hemoglobin, melanin, and carotenoids, respectively. Taking into account the safety of PAFC, its translation for use in humans is expected to improve disease diagnosis beyond conventional detection limits. (© 2013 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Computational Analysis of Kilohertz Frequency Spinal Cord Stimulation for Chronic Pain Management (2015)

These results suggest that clinical KHFSCS may not function through direct activation or conduction block of dorsal column or dorsal root fibers. Although these results should be validated with further studies, the authors propose that additional concepts and/or alternative hypotheses should be considered when examining the pain relief mechanisms of KHFSCS.
Tissue-specific NK cell populations and their origin (2014)

Tissue-specific NK cell subpopulations are found in adult gut, liver, and endometrium, as well as other sites in the body. Some differ phenotypically and functionally from pbNK cells, and their origin is disputed. In this review, we discuss tissue-specific NK cells and suggest that subpopulations differentiate in situ from tissue-resident hematopoietic progenitor cells. The understanding of the origins and maturation requirements of tissue-specific NK cells could lead to new classes of immunotherapy for organ-specific pathologies of infectious and malignant origin.
Tunable narrow-band light source using two optical circulators (1997)

We report a tunable narrow-band light source with a spectral width of 0.26/spl plusmn/0.04 nm, a 0-dBm output power, and a reduced background spectrum in the 1.5-μm band, which we have developed for optical low coherence reflectometry. The Rayleigh backscatter signal fluctuations were reduced to within /spl plusmn/0.4 dB by using this source. The source will also be used in a system for measuring optical waveguide circuits. This is because the coherence length is about 1 cm and, by using a fiber-optic depolarizer, the degree of polarization is less than 0.016.
p53 Abnormalities in B-Cell Prolymphocytic Leukemia (1997)

B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of mature B cells with distinct clinical and pathologic features. To determine the incidence of abnormalities of p53, we analyzed 19 cases of B-PLL by DNA blot to assess loss of heterozygosity (LOH) at 17p13.3, by immunocytochemistry to assess p53 expression, and by direct DNA sequencing of polymerase chain reaction-amplified exons 5 to 9 of the p53 gene. LOH was detected in 10 of 19 (53%) cases, p53 expression was detected in 8 of 17 (47%), and p53 mutations were detected in 10 of 19 (53%) cases. The pattern of mutations was distinct from that observed in other B-cell malignancies. Six cases exhibited missense mutations; 4 were transversions and 2 were transitions. The G:C --> A:T transition at cathepsin G dinucleotides commonly reported in p53 mutations in chronic lymphocytic leukemia (CLL) and other hematologic malignancies was observed in only 1 case of B-PLL. Three cases exhibited deletions (ranging from 3 to 35 bp in length) and one case exhibited a 2-bp insertion. In 1 case, a 27-bp deletion resulted in the expression of a p53 protein lacking 9 amino acids from the DNA binding region. All samples with p53 mutation showed loss of germline p53 sequences. However, 3 of 10 showed no LOH by Southern blot, indicating a localized deletion around the p53 locus at 17p13.1. Five of the 10 cases with p53 mutation exhibited detectable p53 expression, including 4 cases with p53 missense mutation and 1 case with deletion. Two of 7 cases with no detectable mutation of p53 nevertheless overexpressed p53. Therefore, there was no correlation between protein expression and p53 mutation in B-PLL. Our data indicate that the overall abnormalities of p53 occurred in 14 of 19 (75%) cases of B-PLL. The frequency of p53 mutation (53%) in B-PLL is the highest reported in B-cell malignancies and may be responsible for the frequent resistance to therapy of this disease. In addition, the pattern of p53 mutation was different from that observed in CLL and other hematologic malignancies and may indicate that a distinct pathogenic mechanism operates in B-PLL.
Reduction Of Errors Of Microphotographic Reproductions By Optimal Corrections Of Original Masks (1981)

Using image restoration techniques, we report on an algorithm for determining the optimum correction of original masks, which are to be reduced by a given microphotographic system, in order to compensate for the system's distortion. The film is assumed highly nonlinear. As an example, we compute the profile of serifs that should be added to corners to compensate for distortion in a diffraction-limited imaging system.