gebhart/patrepeval huggingface dataset:
Fetal alcohol syndrome prevention in Washington State: evidence of success (2004)

Fetal alcohol syndrome (FAS) is a permanent birth defect syndrome caused by maternal consumption of alcohol during pregnancy. It is characterised by growth deficiency, central nervous system damage/dysfunction, and a unique cluster of minor facial anomalies. To assess the effectiveness of fetal alcohol syndrome prevention efforts, one must be able to estimate accurately the prevalence of fetal alcohol syndrome over time in population-based samples. With the establishment of the Washington State Fetal Alcohol Syndrome Diagnostic and Prevention Network of clinics, the development of the Fetal Alcohol Syndrome Facial Photographic Analysis Software, the creation of the Fetal Alcohol Spectrum Disorders (FASD) 4-Digit Diagnostic Code, the establishment of the Foster Care Fetal Alcohol Syndrome Screening Program, and the collection of Pregnancy Risk Assessment Management System data on maternal use of alcohol during pregnancy, the tools, methods and infrastructure for assessing the effectiveness of fetal alcohol syndrome primary prevention efforts in Washington State are in place. A cross-sectional study was conducted to determine whether the prevalence of fetal alcohol syndrome among children in a foster care population, born between 1993 and 1998, decreased with the documented decrease in prevalence of maternal use of alcohol during pregnancy from 1993 and 1998 in Washington State. The prevalence of maternal drinking during pregnancy in Washington State declined significantly (P < 0.001) from 1993 to 1998 as did the prevalence of fetal alcohol syndrome among foster children born 1993-98 (P < 0.03). These observations support the likelihood that fetal alcohol syndrome prevention efforts in Washington State are working successfully.
A novel approach to insertional mutagenesis of Haemophilus influenzae (1991)

Insertional mutagenesis of the Haemophilus influenzae chromosome was accomplished by a novel method employing a 2.2-kbp element, TSTE. This element, consisting of the neo gene of Tn5 flanked by Haemophilus-specific uptake sequences, was ligated to circularized chromosomal fragments before transformation into the homologous strain. Eight mutants defective in the production of haemocin were detected. This strategy provides an efficient mechanism for the insertional mutagenesis of H. influenzae.
Self-Consistent Equations Including Exchange and Correlation Effects (1965)

From a theory of Hohenberg and Kohn, approximation methods for treating an inhomogeneous system of interacting electrons are developed. These methods are exact for systems of slowly varying or high density. For the ground state, they lead to self-consistent equations analogous to the Hartree and Hartree-Fock equations, respectively. In these equations the exchange and correlation portions of the chemical potential of a uniform electron gas appear as additional effective potentials. (The exchange portion of our effective potential differs from that due to Slater by a factor of $\frac{2}{3}$.) Electronic systems at finite temperatures and in magnetic fields are also treated by similar methods. An appendix deals with a further correction for systems with short-wavelength density oscillations.
Computational approach for identification and characterization of GPI‐anchored peptides in proteomics experiments (2007)

Genes that encode glycosylphosphatidylinositol anchored proteins (GPI-APs) constitute an estimated 1-2% of eukaryote genomes. Current computational methods for the prediction of GPI-APs are sensitive and specific; however, the analysis of the processing site (omega- or omega-site) of GPI-APs is still challenging. Only 10% of the proteins that are annotated as GPI-APs have the omega-site experimentally verified. We describe an integrated computational and experimental proteomics approach for the identification and characterization of GPI-APs that provides the means to identify GPI-APs and the derived GPI-anchored peptides in LC-MS/MS data sets. The method takes advantage of sequence features of GPI-APs and the known core structure of the GPI-anchor. The first stage of the analysis encompasses LC-MS/MS based protein identification. The second stage involves prediction of the processing sites of the identified GPI-APs and prediction of the corresponding terminal tryptic peptides. The third stage calculates possible GPI structures on the peptides from stage two. The fourth stage calculates the scores by comparing the theoretical spectra of the predicted GPI-peptides against the observed MS/MS spectra. Automated identification of C-terminal GPI-peptides from porcine membrane dipeptidase, folate receptor and CD59 in complex LC-MS/MS data sets demonstrates the sensitivity and specificity of this integrated computational and experimental approach.
DNA methylation and the promotion of flowering by vernalization (1998)

We have tested the hypothesis that the promotion of flowering by prolonged exposure to low temperatures (vernalization) is mediated by DNA demethylation [Burn, J. E., Bagnall, D. J., Metzger, J. M., Dennis, E. S. & Peacock, W. J. (1993) Proc. Natl. Acad. Sci. USA 90, 287-291]. Arabidopsis plants that have reduced levels of DNA methylation because of the presence of a methyltransferase (METI) antisense gene flowered earlier than untransformed control plants, without the need for a cold treatment. Decreased DNA methylation mutants (ddm1) also flowered earlier than the wild-type progenitor under conditions where they respond to vernalization. We conclude that demethylation of DNA is sufficient to cause early flowering, and we have found that the promotion of flowering is directly proportional to the decrease in methylation in METI antisense lines. The early-flowering phenotype was inherited in sexual progeny, even when the antisense transgene had been lost by segregation. Methyltransferase antisense plants with low DNA methylation levels responded to a low-temperature treatment by flowering even earlier than their untreated siblings indicating that the promotion of flowering by cold and by demethylation was additive when neither treatment saturated the early-flowering response. As in untransformed control plants, the cold-induced early-flowering signal was reset in progeny of METI antisense plants. These observations suggest that the demethylation brought about by a METI antisense can account for some properties of vernalization, but not for the need for revernalization in each generation.
3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy (2002)

Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, also known as statins, are lipid-lowering agents widely used in the prevention of coronary heart disease. Recent experimental and clinical data, however, indicate that the overall benefits of statin therapy may exceed its cholesterol-lowering properties. We postulate that statins may ameliorate the detrimental effects of high glucose (HG)-induced proliferation of mesangial cells (MCs), a feature of early stages of diabetic nephropathy, by preventing Rho isoprenylation. Rat MCs cultured in HG milieu were treated with and without simvastatin, an HMG-CoA reductase inhibitor. Simvastatin inhibited HG-induced MC proliferation as measured by [(3)H]thymidine incorporation. This inhibitory effect was reversed with geranylgeranyl pyrophosphate, an isoprenoid intermediate of the cholesterol biosynthetic pathway. At the cell-cycle level, the HG-induced proliferation of MCs was associated with a decrease in cyclin dependent kinase (CDK) inhibitor p21 protein expression accompanied by an increase in CDK4 and CDK2 kinase activities. Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities. Exposure of MCs to HG was associated with an increase in membrane-associated Ras and Rho GTPase protein expression. Cotreatment of MCs with simvastatin reversed HG-induced Ras and Rho membrane translocation. Immunofluorescence microscopy revealed that the overexpression of the dominant-negative RhoA led to a significant increase in p21 expression. Our data suggest that simvastatin represses the HG-induced Rho GTPase/p21 signaling in glomerular MCs. Thus, this study provides a molecular basis for the use of statins, independently of their cholesterol-lowering effect, in early stages of diabetic nephropathy.
Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) (1998)

We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.
Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals (1994)

Diabetes was induced in rats by an injection of streptozotocin (55 mg/kg). Endothelium-dependent relaxations in mesenteric resistance arteries (luminal diameter 210 +/- 20 microns) of control and diabetic rats were compared in myographs. Acetylcholine induced endothelium-dependent relaxations that were mediated by nitric oxide (EDNO). EDNO-mediated relaxations were impaired in diabetic arteries; concentrations of acetylcholine required to produce 50% relaxation (ED50) of activated arteries were 5 nM in control and 13.5 nM in arteries from diabetic rats studied after 6 wk (P < 0.05). The impairment in relaxation worsened with duration of the diabetes; ED50 for acetylcholine increased to 63 and 100 nM in diabetic arteries studied after 16 and 24 wk of diabetes, respectively. NG-nitro-L-arginine produced 5.5- and 16-fold decreases in sensitivity of control and diabetic arteries to acetylcholine. NG-nitro-L-arginine produced at least as much inhibition of acetylcholine relaxations in diabetic arteries, indicating that the impaired relaxation noted in diabetic arteries does not result from decreased production of EDNO. EDNO-mediated relaxations in diabetic arteries were impaired by increased production of endothelium-derived free radicals. Superoxide dismutase, a scavenger of superoxide anion, and dimethylthiourea, a scavenger of hydroxyl radicals, normalized EDNO-mediated relaxations in diabetic arteries. The ED50 values for acetylcholine were 13.5, 5.5, and 4 nM for untreated and SOD- and DMTU-treated diabetic arteries, respectively (P < 0.05 for treated vs. untreated arteries). Superoxide anion and hydroxyl radicals appear to block EDNO-mediated relaxation by inactivating EDNO.(ABSTRACT TRUNCATED AT 250 WORDS)
Thermal desorption and infrared studies of ammonia, amines and pyridines chemisorbed on chromic oxide (1982)

The thermal desorption spectra of ammonia, amines and pyridines chemisorbed on Cr2O3 as well as the infrared absorption spectra have been measured in order to elucidate the acidic properties of the surface. The adsorption of ammonia on the bare Cr2O3 surface at room temperature leads to the formation of two kinds of coordination species giving rise to desorption peaks at 443 and 543 K, and the bonding of the latter species to the surface is strengthened to cause a shift in the peak to 593 K when the adsorption temperature is raised to 473 K. Dimethylamine bonded to Lewis-acid sites on Cr2O3 causes the N—H bond-cleavage reaction when the sample is heated at 473 K. Pyridine is strongly held on the surface: half the pyridine molecules absorbed on Cr2O3 at room temperature remain on the surface even after evacuation at 773 K. The infrared study of these molecules suggests the formation of an α-pyridone-like complex.
Physical and Functional Interaction of Filamin (Actin-binding Protein-280) and Tumor Necrosis Factor Receptor-associated Factor 2 (2000)

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an intracellular protein involved in signal transduction from TNF receptor I and II and related receptors. TRAF2 is required for TNF-induced activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and TRAF2 can also mediate activation of NF-kappaB. Here we have identified the actin-binding protein Filamin (actin-binding protein-280) as a TRAF2-interacting protein. Filamin binds to the Ring zinc finger domain of TRAF2. Overexpressed Filamin inhibits TRAF2-induced activation of JNK/SAPK and of NF-kappaB. Furthermore, ectopically expressed Filamin inhibits NF-kappaB activation induced via TNF, interleukin-1, Toll receptors, and TRAF6 but not activation induced via overexpression of NIK, a downstream effector in these pathways. Importantly, TNF fails to activate SAPK or NF-kappaB in a human melanoma cell line deficient in Filamin. Reintroduction of Filamin into these cells restores the TNF response. The data imply a role for Filamin in inflammatory signal transduction pathways.
Post-translational Modifications Differentially Affect IgG1 Conformation and Receptor Binding (2010)

Post-translational modifications (PTMs) can have profound effects on protein structure and protein dynamics and thereby can influence protein function. To understand and connect PTM-induced functional differences with any resulting conformational changes, the conformational changes must be detected and localized to specific parts of the protein. We illustrate these principles here with a study of the functional and conformational changes that accompany modifications to a monoclonal immunoglobulin gamma1 (IgG1) antibody. IgG1s are large and heterogeneous proteins capable of incorporating a multiplicity of PTMs both in vivo and in vitro. For many IgG1s, these PTMs can play a critical role in affecting conformation, biological function, and the ability of the antibody to initiate a potential adverse biological response. We investigated the impact of differential galactosylation, methionine oxidation, and fucosylation on solution conformation using hydrogen/deuterium exchange mass spectrometry and probed the effects of IgG1 binding to the FcgammaRIIIa receptor. The results showed that methionine oxidation and galactosylation both impact IgG1 conformation, whereas fucosylation appears to have little or no impact to the conformation. FcgammaRIIIa binding was strongly influenced by both the glycan structure/composition (namely galactose and fucose) and conformational changes that were induced by some of the modifications.
Fructosyl Amine Sensing Based on Prussian Blue Modified Enzyme Electrode (2001)

Low potential amperometric enzyme sensor for fructosyl-valine, a model compound of glycated hemoglobin (HbA1c), was constructed using a fructosyl-amine oxidase (FAO) and Prussian blue film as the artificial peroxidase. The Prussian blue-based FAO electrode exhibits a good linear correlation between 0.1 to 0.3 mM, similar to what was observed with the low potential enzyme electrode employing FAO, peroxidase, and ferrocene as the electron mediator. These results indicated that the Prussian blue-based FAO electrode may avoid the inherent problems of hydrogen peroxide measurement at the high potential and also have advantage in its simple construct of the system compared with the two enzyme peroxidase - FAO - ferrocene system.
Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function (2005)

The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes beta cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon beta cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated beta cells and in Irs2(-/-) mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased beta cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive beta cell loss in Irs2(-/-) mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon beta cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.
Chimeric interferon-gamma receptors demonstrate that an accessory factor required for activity interacts with the extracellular domain. (1992)

We determined the species specificity and function of structural domains of the interferon-gamma receptor (IFN-gamma R) by construction of human/murine chimeric IFN-gamma R cDNA clones and their expression in various cells. We demonstrate that we can reconstitute a biologically active IFN-gamma R in eukaryotic cells with chimeric receptors as long as the extracellular domain and an accessory factor are from the same species. These results indicate that the extracellular domain of the receptor interacts directly or indirectly with the species-specific accessory factor.
Tissue-specific alternative splicing of the beta-galactoside alpha 2,6-sialyltransferase gene. (1992)

The rat alpha 2,6-sialyltransferase gene produces three different sized mRNAs (4.7, 4.3, and 3.6 kilobases (kb)) which exhibit striking tissue-specific expression. Recently, we characterized the cDNA and genomic organization of the 4.3-kb mRNA which is unique to rat liver. In this report cDNAs of the 4.7-kb mRNA found in most tissues and the 3.6-kb mRNA(s) unique to kidney have been cloned and characterized as well as the corresponding genomic sequences which differed from those of the previously characterized 4.3-kb mRNA. The 4.7-kb mRNA was found to be identical to the 4.3-kb mRNA with the exception of two additional exons at the 5'-untranslated end of the transcript. The constitutively expressed 4.7-kb mRNA therefore codes for the same sialyltransferase as the liver-restricted 4.3-kb mRNA. The additional 5'-exons of the 4.7-kb mRNA are located at least 15-40 kb upstream of the promoter responsible for the production of the 4.3-kb liver message. The 3.6-kb mRNA of rat kidney was found to be comprised of three transcripts of similar size. They were only expressed in kidney and were found to be generated from the alpha 2,6-sialyltransferase gene by alternative splicing and alternative promoter utilization. The results reveal the complexity of the alpha 2,6-sialyltransferase gene which produces at least five transcripts via alternative splicing in a tissue-specific fashion.
Structural and thermodynamic characterization of a cytoplasmic dynein light chain–intermediate chain complex (2007)

Cytoplasmic dynein is a microtubule-based motor protein complex that plays important roles in a wide range of fundamental cellular processes, including vesicular transport, mitosis, and cell migration. A single major form of cytoplasmic dynein associates with membranous organelles, mitotic kinetochores, the mitotic and migratory cell cortex, centrosomes, and mRNA complexes. The ability of cytoplasmic dynein to recognize such diverse forms of cargo is thought to be associated with its several accessory subunits, which reside at the base of the molecule. The dynein light chains (LCs) LC8 and TcTex1 form a subcomplex with dynein intermediate chains, and they also interact with numerous protein and ribonucleoprotein partners. This observation has led to the hypothesis that these subunits serve to tether cargo to the dynein motor. Here, we present the structure and a thermodynamic analysis of a complex of LC8 and TcTex1 associated with their intermediate chain scaffold. The intermediate chains effectively block the major putative cargo binding sites within the light chains. These data suggest that, in the dynein complex, the LCs do not bind cargo, in apparent disagreement with a role for LCs in dynein cargo binding interactions.
Modified viral capsid protein mediates non-viral targeting of unique non-covalent drug conjugates to HER2+ breast cancer cells. (2007)

1505 The purpose of this study is to test whether a unique recombinant cell-penetrating viral protein can transport DNA intercalating drugs by non-covalent interaction via a tiny nucleic acid carrier, and target such drugs to HER2+ breast cancer cells. Targeted conjugates were assembled by mixing the recombinant protein, HerPBK10, with a double-stranded oligonucleotide, and the chemotherapeutic agent, doxorubicin (Dox) at room temperature, then purified by size exclusion chromatography. Stability over time during different storage temperatures was tested by ultrafiltration through molecular weight limiting spin columns. Targeted toxicity was tested on separate and mixed cultures of HER2+ and HER2- human breast cancer cell lines by 4 hour exposure to conjugates (0.5 uM, with respect to Dox concentration) in cell media, then exchanging for fresh media, and measuring cytotoxicity by metabolic assay up to 3 days post-treatment. Receptor specificity was tested by competitive inhibition with excess free ligand. In vivo targeting was tested by IV injection in a mouse xenograft model of HER2+ human breast cancer and monitoring Dox fluorescence in live mice. The conjugate, called HerDox, exhibited undetectable Dox release under high speed centrifugation and high pressure chromatography conditions, as well as under storage at 4°C, 25°C, and 37°C for up to 12 days. In separate wells of HER2+ and HER2- human breast cancer cells, HerDox reduced HER2+ cell survival by over 75% whereas HER2- cells were unaffected. Dox alone reduced both cell types by the same order of magnitude. In mixed cultures of HER2- and HER2+ cells, HerDox nearly completely inhibited HER2+ cell proliferation whereas HER2- cells were little to modestly affected. Free heregulin ligand at 10x molar excess (compared to HerDox) completely inhibited HER2+ cell killing by HerDox. IV injection of HerDox in tumor-bearing nude mice exhibited widespread Dox fluorescence by 10 min, followed by fluorescence accumulation in the tumors by 20 min, which persisted up to 100 min after injection. Tissues harvested at 4h after injection showed that tumors exhibited the highest intensity of Dox fluorescence while residual fluorescence was observed in the liver and kidneys. Fluorescence was undetectable in the heart, lung, spleen and skeletal muscle. Targeting ligand alone showed similar biodistribution. These studies indicate that a stable non-covalent conjugate can assemble and deliver a well-established chemotherapy drug to target cells in serum-containing media. Toxicity can be targeted to HER2+ cells in a mixed cell culture, and is mediated via the heregulin receptor. HerDox exhibits preferential accumulation in HER2+ human breast cancer tumors in vivo, and appears to avoid other tissues including the heart, lung, spleen, and skeletal muscle, while exhibiting relatively low to negligible levels of delivery to the liver and kidney.