gebhart/patrepeval huggingface dataset:
Rainfall-runoff modelling in a catchment with a complex groundwater flow system: application of the Representative Elementary Watershed (REW) approach (2005)

Abstract. Based on the Representative Elementary Watershed (REW) approach, the modelling tool REWASH (Representative Elementary WAterShed Hydrology) has been developed and applied to the Geer river basin. REWASH is deterministic, semi-distributed, physically based and can be directly applied to the watershed scale. In applying REWASH, the river basin is divided into a number of sub-watersheds, so called REWs, according to the Strahler order of the river network. REWASH describes the dominant hydrological processes, i.e. subsurface flow in the unsaturated and saturated domains, and overland flow by the saturation-excess and infiltration-excess mechanisms. The coupling of surface and subsurface flow processes in the numerical model is realised by simultaneous computation of flux exchanges between surface and subsurface domains for each REW. REWASH is a parsimonious tool for modelling watershed hydrological response. However, it can be modified to include more components to simulate specific processes when applied to a specific river basin where such processes are observed or considered to be dominant. In this study, we have added a new component to simulate interception using a simple parametric approach. Interception plays an important role in the water balance of a watershed although it is often disregarded. In addition, a refinement for the transpiration in the unsaturated zone has been made. Finally, an improved approach for simulating saturation overland flow by relating the variable source area to both the topography and the groundwater level is presented. The model has been calibrated and verified using a 4-year data set, which has been split into two for calibration and validation. The model performance has been assessed by multi-criteria evaluation. This work represents a complete application of the REW approach to watershed rainfall-runoff modelling in a real watershed. The results demonstrate that the REW approach provides an alternative blueprint for physically based hydrological modelling.
Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation (2006)

We describe a double-transgenic mouse strain (opticospinal EAE [OSE] mouse) that spontaneously develops an EAE-like neurological syndrome closely resembling a human variant of multiple sclerosis, Devic disease (also called neuromyelitis optica). Like in Devic disease, the inflammatory, demyelinating lesions were located in the optic nerve and spinal cord, sparing brain and cerebellum, and the murine lesions showed histological similarity with their human correlates. OSE mice have recombination-competent immune cells expressing a TCR-alphabeta specific for myelin oligodendrocyte glycoprotein (MOG) aa 35-55 peptide in the context of I-Ab along with an Ig J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG. OSE mouse B cells bound even high dilutions of recombinant MOG, but not MOG peptide, and processed and presented it to autologous T cells. In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1.
Chimeric tumor necrosis factor-TrkA receptors reveal that ligand-dependent activation of the TrkA tyrosine kinase is sufficient for differentiation and survival of PC12 cells. (1993)

To elucidate the function of the two nerve growth factor (NGF) receptors, p75NGFR and p140trk, chimeric molecules were constructed of tumor necrosis factor (TNF) and NGF receptors. Rat PC12 pheochromocytoma cells transiently transfected with TNF-p140trk chimeras, which contain the extracellular domain of TNF receptor and the transmembrane and cytoplasmic domains of p140trk, showed TNF-dependent neuronal differentiation and cell survival. The activity of TNF-p140trk chimeras was completely blocked by the tyrosine kinase inhibitor K252a, and TNF was unable to induce neurite elongation in PC12 cells transfected with a tyrosine kinase-defective chimeric receptor. The TNF-p75NGFR chimeras, which contain the cytoplasmic domain of p75NGFR, were nonfunctional. Our results suggest that p140trk may function as ligand-activated homodimers and that ligand-mediated activation of the cytoplasmic domain of p140trk alone is sufficient for inducing a neuronal phenotype.
Biochemical effects and therapeutic potential of tunicamycin in murine L1210 leukemia. (1983)

Tunicamycin, an antibiotic which specifically inhibits the dolichol-mediated synthesis of glycoproteins, significantly decreased the incorporation of tritiated D-mannose and D-glucosamine into L1210 ascites leukemia cell glycoproteins at concentrations which affected the biosynthesis of proteins minimally. Mice receiving inoculations of L1210 cells pretreated with 10 microM tunicamycin in vitro survived nearly twice as long as did mice receiving implants of untreated tumor cells. A nonlethal dose of X-irradiation (350 rads) to mice 24 hr prior to receiving their inoculation of tunicamycin-treated L1210 cells prevented this increase in life span. Thirty-eight % of the long-term surviving mice which received 1 X 10(5) L1210 cells pretreated with 10 microM tunicamycin in vitro were then resistant to a subsequent challenge with 10(6) untreated L1210 ascites cells. Direct i.p. administration of tunicamycin to mice resulted in potent liver toxicity (50% lethal dose, 2.0 mg/kg) which obviated any therapeutic efficacy when administered to L1210 ascites tumor-bearing mice. The administration of nontoxic levels of D-mannose prior to the administration of tunicamycin decreased the toxicity of the antibiotic in vivo and, when combined with D-mannose in vitro, exhibited cytotoxic additivity in terms of the inhibition of L1210 leukemic cell growth. A therapeutic regimen incorporating a 24-hr infusion of the sugar prior to multiple administrations of tunicamycin gave evidence of a small therapeutic response in terms of the survival of tumor-bearing mice. These results suggest that tunicamycin, an inhibitor of glycoprotein biosynthesis, might be able to alter tumor cell growth and immunogenicity provided that host liver toxicity is diminished.
The Jun and Fos Protein Families Are Both Required for Cell Cycle Progression in Fibroblasts (1991)

The expression of different members of the Jun and Fos families of transcription factors is rapidly induced following serum stimulation of quiescent fibroblasts. To determine whether these proteins are required for cell cycle progression, we microinjected affinity-purified antibodies directed against c-Fos, FosB, Fra-1, c-Jun, JunB, and JunD, and antibodies that recognize either the Fos or the Jun family of proteins, into Swiss 3T3 cells and determined their effects in cell cycle progression by monitoring DNA synthesis. We found that microinjection of anti-Fos and anti-Jun family antibodies efficiently blocked the entrance to the S phase of serum-stimulated or asynchronously growing cells. However, the antibodies against single members of the Fos family only partially inhibited DNA synthesis. In contrast, all three Jun antibodies prevented DNA synthesis more effectively than did any of the anti-Fos antibodies.
Studies on prodrugs of cephalosporins. I. Synthesis and biological properties of glycyloxybenzoyloxymethyl and glycylaminobenzoyloxymethyl esters of 7.BETA.-(2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido)-3-methyl-3-cephem-4-carboxylic acid. (1984)

p-Glycyloxy-, o-glycylamino- and p-glycylaminobenzoyloxymethyl esters of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic acid (1) were synthesized as prodrugs designed to improve the oral absorption of the parent cephalosporin. The esters were found to possess the desired factors for an orally active prodrug, that is, appropriate solubility, lipophilicity and lability. As predicted from these factors, the esters when administered orally to mice were well absorbed from the gastrointestinal tract and gave high blood levels of the parent compound (1).
Racionalidade, ética e a construção de uma certa cidadania (1999)

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Expression of p53 protein in spermatogenesis is confined to the tetraploid pachytene primary spermatocytes. (1993)

The various steps of differentiation and maturation in spermatogenesis are well characterized and offer a convenient system to explore the possibility that p53 plays a role in cell differentiation in vivo. In situ hybridization experiments indicate that the p53 gene is expressed in tetraploid primary spermatocytes at the meiotic pachytene stage of the first round of spermatogenesis in young mice. An analysis of spermatogenic cells treated with anti-p53 antibodies reveals that the p53 protein is expressed in a discrete tetraploid cell population, with size and cellular structure parameters characteristic of midpachytene spermatocytes. The specific kinetics of p53 expression in the first round of spermatogenesis and its localization in adult testicular sections, coupled with the fact that the protein is expressed in the largest cells with lower DNA density, suggest that p53 expression is confined to the tetraploid primary spermatocytes of the meiotic pachytene phase. These observations identify p53 protein as a potential member of the meiosis control protein family.
Detection of low‐level mosaicism by array CGH in routine diagnostic specimens (2006)

Abstract The advent of microarray‐based comparative genomic hybridization (array CGH) promises to revolutionize clinical cytogenetics because of its ability to rapidly screen the genome at an unprecedented resolution. Yet, the ability of array CGH to detect and evaluate low‐level mosaicism is not known. Our laboratory has analyzed over 3,600 clinical cases with the SignatureChip® which we developed for the detection of microdeletions, microduplications, aneuploidy, unbalanced translocations, and subtelomeric and pericentromeric copy number alterations. Here, we report 18 cases of mosaicism detected by array CGH in a routine diagnostic setting, 14 of which were not known to us at the time of the analysis. These 14 cases represent ∼8% of all abnormal cases identified in our laboratory. For each case, fluorescence in situ hybridization (FISH) analysis was performed on PHA‐stimulated cultures after mosaic chromosome abnormalities were suspected by array CGH. In all cases, FISH confirmed the mosaic chromosome abnormalities which included a variety of marker chromosomes, autosomal trisomies, terminal and interstitial deletions, and derivative chromosomes. Interestingly, confirmatory FISH analyses on direct blood smears indicated that the percentage of abnormal cells in unstimulated cultures was in some cases different than that found in PHA‐stimulated cells. We also report the detection of a previously unsuspected case of an isochromosome 12p (associated with Pallister–Killian syndrome) by array CGH using genomic DNA extracted from peripheral blood. These results support a growing body of data that suggests that stimulated peripheral blood cultures likely distort the percentage of abnormal cells and may, for some chromosome abnormalities, make their detection unlikely by conventional analysis. Thus, array CGH, which is based on genomic DNA extracted directly from uncultured peripheral blood, may be more likely to detect low‐level mosaicism for unbalanced chromosome abnormalities than traditional cytogenetic techniques. © 2006 Wiley‐Liss, Inc.
Role of Aggregated Human Growth Hormone (hGH) in Development of Antibodies to hGH* (1980)

By measuring [125I]hGH binding in the plasma of human GH (hGH)-deficient children at 3- to 4-month intervals during hGH therapy with hGH prepared by Raben's method, we have defined three patterns of antibody formation. One group of patients developed antibodies by 3 months of therapy that persisted despite the length or type of hGH therapy. Their antibodies were characterized by a low affinity (1.49 × 109 M−1) and a high capacity (29 nmol/liter plasma). The development or presence of antibodies adversely affected the growth rate in only one patient in this group. This patient's antibodies were characterized by the highest capacity (1235 nmol/liter plasma) and lowest affinity (0.044 × 109 M−1). The capacity decreased to 134 nmol/liter plasma upon switching to a hGH preparation without aggregated hGH. The second group developed antibodies to hGH by 6–9 months of therapy, but [125I]hGH binding by the plasma returned to control levels by 20 months of therapy. The antibodies of this group were characterized by a higher affinity (12.7 × 109 M−1) and a lower capacity (0.9 nmol/liter plasma) than the group with antibodies. This group had received hGH with less than 5% aggregated hGH. The third group did not develop significant [125I]hGH binding in the plasma despite prolonged therapy with multiple hGH preparations. Several patients have been treated solely with recent hGH preparations from the National Pituitary Agency which contain less than 10% aggregated hGH compared to earlier preparations containing more than 20%. The incidence (44%) of significant [125I]hGH binding by these patients' plasmas was similar to that of patients receiving hGH with aggregated hGH; however, hGH binding by the plasma of most of these patients was characteristic of that of patients with transient antibodies. We conclude that 1) the development of antibodies to hGH during therapy is dependent on individual susceptibility and the presence of aggregated hGH in the hGH preparation, 2) the antibody response is more likely to be transient if the content of aggregated hGH is low, and 3) the eventual incidence of significant hGH binding in plasma of patients who receive hGH prepared by Raben's method without aggregated hGH will be the same as that observed in patients receiving hGH prepared by other methods.
Cartilage Oligomeric Matrix Protein Is a Calcium-binding Protein, and a Mutation in Its Type 3 Repeats Causes Conformational Changes (2000)

Mutations in residues in the type 3 calcium-binding repeats and COOH-terminal globular region of cartilage oligomeric matrix protein (COMP) lead to two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia. It has been hypothesized that these mutations cause COMP to misfold and to be retained in the endoplasmic reticulum. However, this hypothesis is not supported by previous reports that COMP, when purified in the presence of EDTA, shows no obvious difference in electron microscopic appearance in the presence or absence of calcium ions. Since this discrepancy may be due to the removal of calcium during purification, we have expressed wild-type COMP and the most common mutant form found in pseudoachondroplasia, MUT3, using a mammalian expression system and have purified both proteins in the presence of calcium. Both proteins are expressed as pentamers. Direct calcium binding experiments demonstrate that wild-type COMP, when purified in the presence of calcium, is a calcium-binding protein. Rotary shadowing electron microscopy and limited trypsin digestion at various calcium concentrations show that there are conformational changes associated with calcium binding to COMP. Whereas COMP exists in a more compact conformation in the presence of calcium, it shows a more extended conformation when calcium is removed. MUT3, with a single aspartic acid deletion in the type 3 repeats, binds less calcium and presents an intermediate conformation between the calcium-replete and calcium-depleted forms of COMP. In conclusion, we show that a single mutation in the type 3 repeats of COMP causes the mutant protein to misfold. Our data demonstrate the importance of calcium binding to the structure of COMP and provide a plausible explanation for the observation that mutations in the type 3 repeats and COOH-terminal globular region lead to pseudoachondroplasia.
Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity (2010)

Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint--whether disease persistence is BCR-ABL dependent or independent--has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.
Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. (1992)

We have determined the complete nucleotide and deduced amino acid sequence of the major protein core of the human heparan sulfate proteoglycan HSPG2/perlecan of basement membranes. Eighteen overlapping cDNA clones comprise 14.35 kilobase pairs (kb) of contiguous sequence with an open reading frame of 13.2 kb. The mature protein core, without the signal peptide of 21 amino acids, has a M(r) of 466,564. This large protein is composed of multiple modules homologous to the receptor of low density lipoprotein, laminin, neural cell adhesion molecules, and epidermal growth factor. Domain I, near the amino terminus, appears unique for the proteoglycan since it shares no significant homology with any other proteins. It contains three Ser-Gly-Asp sequences that could act as attachment sites for heparan sulfate glycosaminoglycans. Domain II is highly homologous to the LDL receptor and contains four repeats with perfect conservation of all 6 consecutive cysteines. Next is domain III which shares homology to the short arm of laminin A chain and contains four cysteine-rich regions intercalated among three globular domains. Domain IV, the largest module with greater than 2000 residues, contains 21 repeats of the immunoglobulin type as found in neural cell adhesion molecule. Near the beginning of this domain, there is a stretch of 29 hydrophobic amino acids which could allow the molecule to interact with the plasma membrane. Domain V, similar to the carboxyl-terminal globular G-domain of laminin A and to the related protein merosin, contains three globular regions and four EGF-like repeats. In situ hybridization and immunoenzymatic studies show a close association of this gene product with a variety of cells involved in the assembly of basement membranes, in addition to being localized within the stromal elements of various connective tissues. Our studies show that this proteoglycan is present in all vascularized tissues and suggest that this unique molecule has evolved from the utilization of modular structures with adhesive and growth regulatory properties.
Preclinical development of keliximab, a Primatized™ anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies (2000)

The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.
The cloning of CD70 and its identification as the ligand for CD27. (1994)

CD70 is a surface Ag found on activated but not resting T and B lymphocytes. The biologic activity of this Ab-defined cell surface molecule on lymphocytes has not been established. Therefore, in an effort to understand the function of the CD70 protein, a mAb defining the CD70 Ag was used to isolate by expression cloning the cDNA responsible for the CD70 molecule. The predicted protein product is a type II transmembrane protein. Bioassays demonstrated that the CD70 cDNA clone expressed in African green monkey kidney cells would induce the proliferation of PHA-costimulated T cells. Comparison with known sequences indicates identity with the CD27 ligand. Therefore the molecule defining the CD70 Ag is identical to the recently defined ligand for CD27.
Carbon Nanocapsules as Nanoreactors for Controllable Synthesis of Encapsulated Iron and Iron Oxides: Magnetic Properties and Reversible Lithium Storage (2011)

This paper reports the synthesis of carbon-encapsulated Fe3O4, γ-Fe2O3, and Fe nanostructures using FeOOH as a precursor and carbon nanocapsules (CNCs) as nanoreactors via controllable thermal transformation processes. The magnetic property investigation reveals that the as-synthesized Fe3O4-CNCs, γ-Fe2O3-CNCs, and Fe-C nanostructures all exhibit ferromagnetic behavior with quite high saturation magnetizations. Moreover, the Fe3O4-CNCs with a controlled carbon coating are prepared and their comparative lithium storage properties are investigated. It is found that optimized Fe3O4-CNCs exhibit high capacity and good cycling performance.
Prognosis of Non–Small Cell Lung Cancer Patients by Detecting Circulating Cancer Cells in the Peripheral Blood with Multiple Marker Genes (2005)

Circulating cancer cell detection by a panel of markers and the Lc scoring method can supplement the current tumor, node, metastasis staging method for improved prognosis and for rapid assessment of therapeutic response. Together, they may facilitate the design of better therapeutic strategies for the treatment of NSCLC patients.