gebhart/patrepeval huggingface dataset:
Regulation of the epithelial sodium channel by accessory proteins (2003)

The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.
The characteristics of binding of human recombinant interferon-gamma to its receptor on human monocytes and human monocyte-like cell lines. (1985)

Interferon-gamma (IFN-gamma) induces many effector functions in macrophages, presumably through binding to cell surface receptors. Such receptors have been documented in murine macrophages. This report demonstrates that IFN-gamma interacts with a specific receptor on human monocytes and monocyte-like cell lines, U937 and HL60. Recombinant IFN-gamma (rIFN-gamma) was radioiodinated by using Bolton-Hunter reagent to high specific activity. 125I-rIFN-gamma bound in a specific and saturable manner. Saturation of binding sites occurred at 10(-9) M (300 U/ml); there were 4000 specific binding sites per cell for both monocytes and the cell lines. Purified lymphocyte-derived IFN-gamma as well as rIFN-gamma competed for binding sites with 125I-rIFN-gamma. There was no inhibition of binding of the 125I-rIFN-gamma by rIFN-alpha or rIFN-beta. The forward rate constant, k1, at 4 degrees C was about 8 X 10(5) M-1 sec-1 for each cell type studied. In the presence of excess ligand, the dissociation rate constant, k-1, was about 2 X 10(-4) sec-1. The Ka calculated from these constants (4 X 10(9) M-1) agreed closely with that calculated from experiments performed at equilibrium (8 X 10(9) M-1). Because the dissociation of rIFN-gamma from cells was enhanced in the presence of ligand, interactions between binding sites of a negative cooperative type could be operative. These studies demonstrate that rIFN-gamma binds in a specific and saturable manner and with high affinity to a receptor on human monocytes as well as monocyte-like cell lines.
Substance P and neurotensin in the control of gastrointestinal function. (1980)

Our experimental data show that neurotensin or a metabolite satisfies the rigid physiological criteria that should be met before a substance is classified as a true hormone with endocrine function. The gastrointestinal actions are produced by very small concentrations; the release into the blood is produced by a physiological stimulus (ingestion of food, especially fat); and the plasma concentrations of NTLI following the ingestion of food are comparable to those obtained by giving exogenous neurotensin at doses which produce effects in the gastrointestinal tract.
Criteria and markers for protein quality assessment – a review (2012)

Dietary proteins are found in animal products, plant products and single-cell organisms. Proteins are present in variable proportions in these different food sources and the different proteins also differ in their amino acid composition, dietary indispensable amino acid content and physico-chemical properties. Different criteria can be used to define dietary protein requirements and different markers can be used to assess nutritional protein quality according to the criteria used for protein requirement estimation. The current approach to determining protein requirements is related to nitrogen balance and the dietary indispensable amino acid score approach relates protein quality to the capacity of protein to allow reaching nitrogen balance by providing nitrogen and indispensable amino acids. A second approach considers more directly protein nitrogen utilization by the body and includes measurement of protein digestibility and of the efficiency of dietary nitrogen retention at maintenance or for protein deposition at the whole body level or in more specific body areas. Another approach is related to protein turnover and protein synthesis in relation to maintenance and/or efficiency for deposition or development (growth) at the whole body level or for different and more specific target tissues such as muscle or bone. Lastly, protein quality can also be evaluated from different markers used as risk factors for metabolic dysfunction and disorders related for instance to insulin resistance, diabetes and obesity or cardio-vascular disease. The accuracy and relevance of these different approaches is discussed regarding the capacity of the different protein sources (i.e. animal as meat, milk or eggs, legume as soya or pea, or cereal as wheat or rice) to satisfy protein requirements according to these different criteria and markers.
Oxidative stress: oxidants and antioxidants (1997)

An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.
Transplantation of Allogeneic Peripheral Blood Stem Cells Mobilized by Recombinant Human Granulocyte Colony Stimulating Factor (1996)

Recombinant G-CSF has been given to over 150 normal donors for the collection of allogeneic or syngeneic peripheral blood stem cells (PBSC). G-CSF was found to be well-tolerated with mild-moderate bone pain, edema and mild thrombocytopenia being the observed side effects. To date, approximately 90 unmodified primary PBSC transplants from HLA-identical related donors have been performed with engraftment that is, in general, considerably more rapid than marrow. Acute graft-versus-host-disease (GVHD), grades II-IV occurred in 47% of patients and grades III-IV in 17%. Despite the infusion of one to two logs more T cells, these results are not remarkably different than would be expected with marrow transplantation. There have also been successful reports of using G-CSF mobilized allogeneic PBSC following second transplants for graft rejection or relapse. Allogeneic PBSC have been infused without reconditioning for correction of graft failure and unmodified or CD34 selected PBSC have also been given with marrow to augment the dose of hematopoietic cells. Further studies are needed to define the role of allogeneic PBSC for transplantation, refine PBSC mobilization and collection techniques and to evaluate the long-term effects of cytokines in normal donors.
Cellular uptake and intracellular release are major obstacles to the therapeutic application of siRNA: novel options by phosphorothioate-stimulated delivery (2007)

The cellular uptake of oligomeric nucleic acid-based tools and drugs including small-interfering RNA (siRNA) represents a major technical hurdle for the biologic effectiveness and therapeutic success in vivo. Subsequent to cellular delivery it is crucial to direct siRNA to the cellular location where it enters the RNA interference pathway. Here the authors summarise evidence that functionally active siRNA represents a minor fraction in the order of 1% of total siRNA inside a given target cell. Exploiting possibilities of steering intracellular release or trafficking of siRNA bears the potential of substantially increasing the biological activity of siRNA. The recently described phosphorothioate stimulated cellular delivery of siRNA makes use of the caveolar system ending in the Golgi apparatus, which contrasts all other known delivery systems. Therefore, it represents an attractive alternative to study whether promoted intracellular release is related to increased target suppression and, thus, increased phenotypic biologic effectiveness.
Sound propagation in dilute suspensions of rigid particles (1998)

This paper considers sound propagation in suspensions of rigid particles, when both heat and momentum are exchanged between the particles and the host fluid. A theory is developed for small-amplitude, single-frequency oscillatory motions, on the assumption that the temperature of each particle is uniform. This theory applies to dilute suspensions that have arbitrary particle and fluid material densities, and yields the attenuation and the speed of sound in the suspension in terms of the particles’ velocity and temperature fluctuations. These quantities are not specified by the theory, but are available for some situations of interest which cover a very wide frequency range. In the particular case when the particle force and the heat transfer rate are not affected by the compressibility of the fluid, the particle’s velocity and temperature are given by closed-form results that are used to obtain explicit formulas for the attenuation and sound speed. For this case, the present theory reproduces all fundamental predictions available in the literature, and yields new basic results where none seem to exist. Results are also shown for the important case when the particle force includes compressibility effects in the fluid. These provide a unified description for the attenuation and the dispersions which covers the viscous and the scattering regions, as well as the transition region between them.
Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. (1987)

The cloning of the cDNA for the mdr1 gene, whose expression is associated with the development of multidrug-resistance in cultured cells, has made it possible to explore the mechanism of multidrug resistance in human tumors. We have found that normal human kidney, six of eight adenocarcinomas of the kidney, and four cell lines derived from kidney adenocarcinomas express high levels of mdr1 mRNA. Two criteria suggest that primary multidrug resistance in human adenocarcinomas of the kidney results, at least in part, from expression of the mdr1 gene: (1) mdr1 mRNA levels are elevated in four unselected kidney adenocarcinoma cell lines that show a multidrug-resistant phenotype; and (2) multidrug resistance in these kidney cancer cell lines is reversed by verapamil and quinidine, agents known to reverse mdr1-associated drug resistance in cell lines selected for multidrug resistance in vitro. These results suggest that appropriate pharmacological intervention to reverse multidrug resistance might make adenocarcinomas of the kidney more sensitive to chemotherapy with agents such as Adriamycin (Adria Laboratories, Columbus, OH) and the vinca alkaloids.
Rationalization and prediction of selective decoding of pseudouridine-modified nonsense and sense codons (2012)

A stop or nonsense codon is an in-frame triplet within a messenger RNA that signals the termination of translation. One common feature shared among all three nonsense codons (UAA, UAG, and UGA) is a uridine present at the first codon position. It has been recently shown that the conversion of this uridine into pseudouridine (Ψ) suppresses translation termination, both in vitro and in vivo. Furthermore, decoding of the pseudouridylated nonsense codons is accompanied by the incorporation of two specific amino acids in a nonsense codon-dependent fashion. Ψ differs from uridine by a single N¹H group at the C5 position; how Ψ suppresses termination and, more importantly, enables selective decoding is poorly understood. Here, we provide molecular rationales for how pseudouridylated stop codons are selectively decoded. Our analysis applies crystal structures of ribosomes in varying states of translation to consider weakened interaction of Ψ with release factor; thermodynamic and geometric considerations of the codon-anticodon base pairs to rank and to eliminate mRNA-tRNA pairs; the mechanism of fidelity check of the codon-anticodon pairing by the ribosome to evaluate noncanonical codon-anticodon base pairs and the role of water. We also consider certain tRNA modifications that interfere with the Ψ-coordinated water in the major groove of the codon-anticodon mini-helix. Our analysis of nonsense codons enables prediction of potential decoding properties for Ψ-modified sense codons, such as decoding ΨUU potentially as Cys and Tyr. Our results provide molecular rationale for the remarkable dynamics of ribosome decoding and insights on possible reprogramming of the genetic code using mRNA modifications.
WNTs in the Neonatal Mouse Uterus: Potential Regulation of Endometrial Gland Development (2010)

The WNTs are secreted proteins that control essential developmental processes, such as embryonic patterning, cell growth, migration, and differentiation. In mice, three members of the Wnt gene family (Wnt4, Wnt5a, and Wnt7a) have been studied extensively in the female reproductive tract. The present study determined effects of postnatal day and exposure to diethylstilbestrol (DES) on Wnt and Fzd gene expression in the mouse uterus as well as the biological role of Wnt11 in postnatal mouse uterine development and function. Wnt4, Wnt5a, Wnt7a, Wnt7b, Wnt11, Wnt16, Fzd6, and Fzd10 were detected by in situ hybridization in the neonatal mouse uterus. In situ hybridization analyses revealed that Wnt4, Wnt5a, and Wnt16 were localized in the endometrial stroma, whereas Wnt7a, Wnt7b, Wnt11, Fzd6, and Fzd10 were in the uterine epithelia of neonatal mice. Exposure of mice to estrogen or estrogen receptor agonists during critical development periods inhibits endometrial adenogenesis. In the present study, DES-induced disruption of endometrial gland development was associated with reduction or suppression of Wnt4, Wnt5a, Wnt7a, Wnt11, Wnt16, and Fzd10. Ablation of Wnt11, an epithelial-expressed, DES-regulated gene, in the neonatal uterus did not affect endometrial adenogenesis or expression of other Wnt genes. Interestingly, Wnt11-deleted uteri had more endometrial glands on Postnatal Day 10. Although CTNNB1 expression was not affected by ablation of Wnt11, Vangl2 was inhibited in the uteri of Wnt11(d/d) mice. These results support the idea that a number of different Wnt genes are potential regulators for uterine morphogenesis; however, Wnt11 does not have a direct effect on uterine development.
CTLA-4 blockade increases IFNγ-producing CD4 + ICOS hi cells to shift the ratio of effector to regulatory T cells in cancer patients (2008)

Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4(+)ICOS(hi) T cells produced IFN-gamma (IFNgamma) and could recognize the tumor antigen NY-ESO-1. Increase in CD4(+)ICOS(hi) cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.
The function and distinctive regulation of the integrin VLA-3 in cell adhesion, spreading, and homotypic cell aggregation. (1993)

To assess directly the functional role of the integrin VLA-3 (alpha 3 beta 1), we transfected human alpha 3 cDNA into erythroleukemia (K562) cells and rhabdomyosarcoma (RD) cells. The resulting transfectants (KA3 and RA3) expressed alpha 3 beta 1 on the cell surface as confirmed using a panel of nine anti-alpha 3 monoclonal antibodies. Neither of the transfected cells exhibited increased adhesion to the extracellular matrix proteins fibronectin, laminin, and collagen. However, the KA3 transfectants did bind strongly to the extracellular matrix deposited by epidermal and carcinoma cell lines, allowing the cells to attach and spread. Binding to this cell-deposited ligand, probably containing epiligrin/kalinin, was specific to VLA-3 and could be inhibited by anti-alpha 3 antibodies and by EDTA, but not by RGD peptides. In marked contrast to other integrins (VLA-2 and VLA-4), VLA-3 showed high constitutive activity in K562 cells, but was minimally active in RD cells. Also contrasting with other beta 1 integrins, VLA-3 was minimally stimulated by the anti-beta 1 monoclonal antibody TS/216 under normal conditions. VLA-3-mediated adhesive function was well supported by either Mg2+ or Mn2+, but was almost completely abolished by the presence of 1 mM Ca2+. Surprisingly, this negative Ca2+ effect was completely overcome by the addition of the stimulatory anti-beta 1 monoclonal antibody TS2/16. Together, these results point to markedly distinct regulation for VLA-3 function compared to other beta 1 integrins. Also, all anti-VLA-3 antibodies were able to induce temperature-dependent homotypic cell aggregation of KA3 cells, but not K562 cells. However, this aggregation did not appear to be directly mediated by VLA-3 since it was not inhibited by EDTA. In addition, no enhancement of heterotypic cell-cell adhesion was observed in alpha 3-transfected cells.
New Insights from the Structure-Function Analysis of the Catalytic Region of Human Platelet Phosphodiesterase 3A (2006)

Human phosphodiesterase 3A (PDE3A) degrades cAMP, the major inhibitor of platelet function, thus potentiating platelet function. Of the 11 human PDEs, only PDE3A and 3B have 44-amino acid inserts in the catalytic domain. Their function is not clear. Incubating Sp-adenosine-3',5'-cyclic-S-(4-bromo-2,3-di-oxobutyl) monophosphorothioate (Sp-cAMPS-BDB) with PDE3A irreversibly inactivates the enzyme. High pressure liquid chromatography (HPLC) analysis of a tryptic digest yielded an octapeptide within the insert of PDE3A ((K)T(806)YNVTDDK(813)), suggesting that a substrate-binding site exists within the insert. Because Sp-cAMPS-BDB reacts with nucleophilic residues, mutants Y807A, D811A, and D812A were produced. Sp-cAMPS-BDB inactivates D811A and D812A but not Y807A. A docking model showed that Tyr(807) is 3.3 angstroms from the reactive carbon, whereas Asp(811) and Asp(812) are >15 angstroms away from Sp-cAMPS-BDB. Y807A has an altered K(m) but no change in k(cat). Activity of wild type but not Y807A is inhibited by an anti-insert antibody. These data suggest that Tyr(807) is modified by Sp-cAMPS-BDB and involved in substrate binding. Because the homologous amino acid in PDE3B is Cys(792), we prepared the mutant Y807C and found that its K(m) and k(cat) were similar to the wild type. Moreover, Sp-cAMPS-BDB irreversibly inactivates Y807C with similar kinetics to wild type, suggesting that the tyrosine may, like the cysteine, serve as a H donor. Kinetic analyses of nine additional insert mutants reveal that H782A, T810A, Y814A, and C816S exhibit an altered k(cat) but not K(m), indicating that catalysis is modulated. We document a new functional role for the insert in which substrate binding may produce a conformational change. This change would allow the substrate to bind to Tyr(807) and other amino acids in the insert to interact with residues important for catalysis in the active site cleft.
Intracellular translocation and metabolism of a fluorescent phosphatidic acid analogue in cultured fibroblasts. (1983)

We have investigated the metabolism and intracellular translocation of a fluorescent derivative of phosphatidic acid, 1-acyl-2-[(N-4-nitrobenzo-2-oxa-1,3-diazole)aminocaproyl] phosphatidic acid (C6-NBD-PA), and its metabolites, in Chinese hamster fibroblasts. This derivative is rapidly transferred from phospholipid vesicles to cells at 2 degrees C, and results in fluorescent labeling of the mitochondria, endoplasmic reticulum, and nuclear membrane of intact cells during its metabolism predominantly to fluorescent diglyceride (Pagano, R. E., Longmuir, K. J., Martin, O. C., and Struck, D. K. (1981) J. Cell Biol. 91, 872-877). In the present study, we show that, upon warming to 37 degrees C, the fluorescence associated with the endoplasmic reticulum was greatly reduced, while cytoplasmic lipid droplets, which were initially nonfluorescent, became intensely labeled. This altered intracellular distribution of fluorescence was accompanied by further metabolism of the fluorescent lipids to NBD-triglyceride and NBD-phosphatidylcholine. Although NBD-fatty acid was also produced, it was not re-utilized in the synthesis of other cellular lipids. Subcellular fractionation experiments demonstrated that primarily NBD-labeled triglyceride was associated with the intracellular lipid droplets, although substantial amounts of NBD-labeled phosphatidic acid, phosphatidylcholine, and diglyceride were also present in the whole cell extracts. This finding was confirmed in a separate experiment in which the fluorescent lipids associated with the intracellular lipid droplets were selectively and irreversibly photobleached in situ. Extraction and analysis of the fluorescent lipids revealed that NBD-triglyceride was preferentially photobleached. These results indicate that "sorting" of the NBD-labeled lipids into various cytoplasmic compartments accompanied their metabolism.
HIV vaccine research in Thailand: lessons learned (2008)

Thailand is the only country that has conducted two Phase III efficacy trials and ten other Phase I/II studies using various HIV-1 vaccine constructs. This outstanding record is the result of strong efforts and commitment among various partners, including policy makers, regulators, researchers and foreign collaborators. Recently, it has become apparent that hardly any new HIV/AIDS candidate vaccines are in the pipeline reaching the stage of clinical testing, especially a candidate vaccine that is suitable for Thailand and the surrounding region. However, many lessons learned can be utilized or modified for other vaccine trials, particularly vaccines against other infectious diseases prevalent in developing countries.