gebhart/patrepeval huggingface dataset:
Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis (2003)

The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.
In Situ Estrogen Production via the Estrone Sulfatase Pathway in Breast Tumors: Relative Importance versus the Aromatase Pathway* (1984)

Estrone and estradiol concentrations in breast tumor tissue are an order of magnitude higher than circulating plasma levels in postmenopausal women with breast cancer. Local production of estrogen in the neoplastic tissue is one of several possible explanations for this plasma/tissue gradient. This study evaluated breast tumor estrogen production via the estrone sulfate to estrone (sulfatase) pathway and compared this with the androstenedione to estrone (aromatase) system in human and rodent mammary tumors. Estrogen production from estrone sulfate was related linearly with time and tissue concentrations, exhibited an apparent Km of 20 microM, and produced a linear Eadie-Hofstee kinetic plot consistent with a single class of enzymatic sites. Measurement of sulfatase in 35 human breast tumors using enzyme saturating conditions revealed estrone production ranging from 0.8-125 mumol/g protein . h. The corresponding range in host mammary tumors was 3.5-7.1 mumol/g protein . h. In human breast tumors, sulfatase activity did not correlate with the levels of estrogen receptor or progesterone receptor. Comparison of sulfatase with aromatase activity in human tumors at physiological levels of substrate revealed estrone formation via sulfatase of 2.8 pmol estrone produced/g protein . h, while aromatase produced only 0.27 pmol/g protein . h. In rat mammary tumors, sulfatase activity was similar to that in human tumors, whereas aromatase activity could not be detected, even with a highly sensitive assay. Thus, estrone sulfatase appears to be the enzyme primarily responsible for intratissue estrone production in hormone-dependent breast carcinomas.
Export of O-specific lipopolysaccharide (2003)

The O antigen is the most surface-exposed component of the lipopolysaccharide (LPS) molecule and its biogenesis involves several complex mechanisms not completely well understood. All of these mechanisms involve biochemical reactions that occur on the cytoplasmic side of the plasma membrane as well as several different translocation pathways that deliver the nascent O antigens in a glycolipid form to the periplasmic side of the plasma membrane. This article discusses our current understanding of the mechanisms operating in the biogenesis of the O-specific LPS.
Ideal Mixing in Polyelectrolyte Complexes and Multilayers:  Entropy Driven Assembly (2006)

Calorimetry and variable temperature equilibrium doping methods independently show complexation of common polyelectrolytes to be essentially entropy-driven. The complimentary techniques provide enthalpy and free energies of formation or mixing. These findings highlight the importance of polyelectrolyte complexes as ideally mixed polymer blends.
Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? (2004)

Increasing evidence suggests that selective neuronal loss in neurodegenerative diseases involves activation of cysteine aspartyl proteases (caspases), which initiate and execute apoptosis. In Alzheimer disease both extracellular amyloid deposits and intracellular amyloid beta protein may activate caspases, leading to cleavage of nuclear and cytoskeletal proteins, including tau protein. Proteolysis of tau may be critical to neurofibrillary degeneration, which correlates with dementia.
Structure of the human DNA repair geneHAP1and its localisation to chromosome 14q 11.2–12 (1992)

Apurinic/apyrimidinic (AP) sites are pre-mutagenic DNA lesions which occur spontaneously and following exposure of cells to ionising radiation or chemical mutagens. HAP1 (Human AP endonuclease 1), the major enzyme in human cells initiating repair of AP sites, shows strong sequence homology to DNA repair enzymes from bacteria, Drosophila and other mammalian species. We have cloned the HAP1 gene and determined its complete nucleotide sequence. The site of transcription initiation has been mapped to 452 bp upstream of the ATG initiation codon in the genomic DNA. The HAP1 gene consists of five exons and is unusually small (less than 2.6 kb from transcription initiation site to polyadenylation sequence) with 54% of the protein coding region and the entire 3' untranslated region contained within a single exon. The first exon is non-coding. Regions of three exons show sequence homology to the E.coli xth (exonuclease III) gene. Using in situ hybridisation, the HAP1 gene has been localised to human chromosome 14q 11.2-12.
Measurement of interleukin‐1α and ‐1β in gingival crevicular fluid: Implications for the pathogenesis of periodontal disease (1990)

Samples of gingival crevicular fluid (GCF) were harvested from sites manifesting features characteristic of active disease including inflammation, periodontal attachment loss, and radiographic signs of alveolar bone destruction in untreated patients with advanced periodontitis. The presence and concentrations of interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) were measured using ELISAs specific for these cytokine molecules. IL-1 alpha and/or IL-1 beta were identified in the GCF of 15 of 15 patients having untreated periodontitis. Ninety percent (71 of 79) of the sites tested contained measureable amounts of IL-1, with IL-1 beta as the more frequently occurring form. IL-1 alpha levels ranged from 0.23 nM to 13.9 nM in the GCFs. IL-1 beta levels were between 0.04 nM and 5.28 nM. Marked reductions of total IL-1 levels were observed following effective treatment. Both forms of IL-1 messenger RNA (mRNA) were detected in 17 of 17 gingival tissue samples from 6 patients. These results demonstrate that IL-1 is produced and released locally in periodontal disease at concentrations sufficient to mediate tissue inflammation and bone resorption. IL-1 may serve as a marker of periodontal tissue destruction.
Implantation and development of the gut flora in the newborn animal. (1983)

The newborn mammal, germfree in the mother's uterus, steps in complex microbial environment as soon as born. Bacterial development in the digestive cavities of the newborn animal, from the environmental bacteria, occurs very quickly. Within three hours after birth a small microbial population is present in the piglet, baby mouse or human baby. Within twelve hours after birth, dominant microbial population of the newborn animal can be as important as that of the adult animal. In any case, this highest level is reached within 24 h after birth. Studying several animal species, one observes a certain diversity in the steps of establishment of the principal bacterial groups. For instance, facultative anaerobic bacteria appear before strictly anaerobic bacteria in the young mouse, whereas the opposite situation happens in the young hare. In the calf and the piglet, strictly and facultative bacteria establish approximatively at the same time. On day one after birth E. coli and Streptococci establish in the human infant, and also species belonging to genus Bacteroides and Bifidobacterium. This last genus becomes dominant from 4 to 5 days after birth. The newborn successively meets three different bacterial ecosystems: maternal vagina, maternal feces and finally environment where it is reared. Each of these three ecosystems probably takes a role in the elaboration of the newborn animals flora, but in proportion difficult to estimate. Any way, one can state that the newborn possess powerful systems to sort out certain specific bacterial species among those constituting the environmental population to which he is exposed.(ABSTRACT TRUNCATED AT 250 WORDS)
Crystallographically Mapped Ligand Binding Differs in High and Low IgE Binding Isoforms of Birch Pollen Allergen Bet v 1 (2012)

The ability of pathogenesis-related proteins of family 10 to bind a broad spectrum of ligands is considered to play a key role for their physiological and pathological functions. In particular, Bet v 1, an archetypical allergen from birch pollen, is described as a highly promiscuous ligand acceptor. However, the detailed recognition mechanisms, including specificity factors discriminating binding properties of naturally occurring Bet v 1 variants, are poorly understood. Here, we report crystal structures of Bet v 1 variants in complex with an array of ligands at a resolution of up to 1.2 Å. Residue 30 within the hydrophobic pocket not only discriminates in high and low IgE binding Bet v 1 isoforms but also induces a drastic change in the binding mode of the model ligand deoxycholate. Ternary crystal structure complexes of Bet v 1 with several ligands together with the fluorogenic reporter 1-anilino-8-naphthalene sulfonate explain anomalous fluorescence binding curves obtained from 1-anilino-8-naphthalene sulfonate displacement assays. The structures reveal key interaction residues such as Tyr83 and rationalize both the binding specificity and promiscuity of the so-called hydrophobic pocket in Bet v 1. The intermolecular interactions of Bet v 1 reveal an unexpected complexity that will be indispensable to fully understand its roles within the physiological and allergenic context.
Reduced expression of peptide‐loaded HLA class I molecules on multiple sclerosis lymphocytes (1995)

Lymphocytes from patients with HLA class II-linked autoimmune diseases such as type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Graves' have recently been shown to have a decrease in the expression of self-peptide-filled HLA class I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multiple sclerosis in some cases are also associated with the presence of certain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fresh peripheral blood mononuclear cells (PBMCs) and newly produced Epstein-Barr virus (EBV)-transformed cell lines from multiple sclerosis patients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a decrease in the amount of conformationally correct peptide-filled HLA class I molecules on the cell surface compared with matched controls detectable by flow cytometry. To demonstrate the independence of this defect from exogenous serum factors, newly produced EBV-transformed cell lines from B cells of patients with multiple sclerosis maintained the defect. In addition, DR2 +/+, +/-, and -/- EBV-transformed B cells from these patients similarly demonstrated the self-antigen presentation defect. Analysis of a set of discordant multiple sclerosis twins revealed the class I defect was exclusively found on the affected twin lymphocytes, suggesting a role of this class I complex in disease expression. These data indicate that multiple sclerosis patients have abnormal presentation of self-antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
Ozonolysis Is the Primary Cause of UV Photooxidation of Alkanethiolate Monolayers at Low Irradiance (1998)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTOzonolysis Is the Primary Cause of UV Photooxidation of Alkanethiolate Monolayers at Low IrradianceYumo Zhang, Roger H. Terrill, Troy A. Tanzer, and Paul W. BohnView Author Information Department of Chemistry, Beckman Institute, and Materials Research Laboratory University of Illinois at Urbana-Champaign 600 South Mathews Avenue, Urbana, Illinois 61801 Cite this: J. Am. Chem. Soc. 1998, 120, 11, 2654–2655Publication Date (Web):March 7, 1998Publication History Received7 May 1997Published online7 March 1998Published inissue 1 March 1998https://pubs.acs.org/doi/10.1021/ja9714853https://doi.org/10.1021/ja9714853rapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views510Altmetric-Citations75LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Atmospheric chemistry,Gold,Irradiation,Organic reactions,Redox reactions Get e-Alerts
Blockade of S100A8 and S100A9 Suppresses Neutrophil Migration in Response to Lipopolysaccharide (2003)

Recently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils. Passive immunization against S100A8 and S100A9 led to a 52% inhibition of neutrophil migration in response to LPS at 3 h postinjection. Injection of LPS was also associated with an increase in peripheral blood neutrophils and the presence in serum of S100A9 and S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9 augmented the number of circulating neutrophils and diminished the number of neutrophils in the bone marrow, demonstrating that S100A8 and S100A9 induced the mobilization of neutrophils from the bone marrow to the blood. Finally, passive immunization with anti-S100A9 inhibited the neutrophilia associated with LPS injection in the air pouch. These results suggest that S100A8 and S100A9 play a role in the inflammatory response to LPS by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site.
Adapting the Core Language Engine to French and Spanish (1996)

We describe how substantial domain-independent language-processing systems for French and Spanish were quickly developed by manually adapting an existing English-language system, the SRI Core Language Engine. We explain the adaptation process in detail, and argue that it provides a fairly general recipe for converting a grammar-based system for English into a corresponding one for a Romance language.
Neutrophilic Inflammation in Severe Persistent Asthma (1999)

Airway inflammation in severe asthma is not well characterized but may involve neutrophils. We have compared induced sputum profiles in patients with asthma of varying severity and normal control subjects. We have also measured exhaled nitric oxide (NO) as a noninvasive marker of inflammation. Asthma severity was based on clinical features before treatment and the minimum medication required to maintain asthma control at the time of sputum induction, and classified as (1) mild: treated with inhaled beta(2)-agonist occasionally (n = 23; FEV(1), 91%; peak expiratory flow (PEF) variability, 10.5%), (2) moderate: requiring medium dose inhaled steroids to maintain control (n = 16; FEV(1), 88%; PEF variability, 9.1%), and (3) severe: despite using inhaled and oral steroids (n = 16; FEV(1), 61%; PEF variability, 36.2%). The asthmatic patients were nonsmokers with evidence of airway hyperresponsiveness or reversible airway obstruction, and free of respiratory tract infection for at least 6 wk. Sputum revealed significantly increased neutrophil numbers in severe asthma (53.0 [38.4- 73.5]%, p < 0.05) compared with mild asthma (35.4 [29.8-46.1]%) and normal control subjects (27.7 [20.6-42.2]%). Interleukin-8 (IL-8) and neutrophil myeloperoxidase (MPO) levels were increased in asthmatic patients, with the highest levels in severe asthma. Eosinophil numbers were increased in both mild and severe asthma, but interleukin-5 (IL-5) levels were highest in mild asthma, whereas eosinophil cationic protein (ECP) levels were highest in severe asthma. Exhaled NO levels were highest in asthmatic untreated with corticosteroids, but there was no significant difference between asthmatics using corticosteroids (Groups 2 and 3), regardless of clinical asthma severity. This confirms the role of eosinophils in asthma but suggests a potential role of neutrophils in more severe asthma.
Optimal Corner Detector (2005)

A corner is defined as the junction point of two or more straight line edges. Corners are special features in a image. They are of great use in computing the optical flow and structure from motion. In this paper, we report an optimal corner detector which uses a mathematical model for a corner. An optimal gray tone corner detector is derived for a restricted case of corners, i.e. corners made by lines which are symmetric about a horizontal axis. The resultant corner detector is described by product of sine in x and exponential in y direction in a portion of the mask and by the product of two sines in x and y directions in the remaining portion of it. It is then generalized to include any corner of an arbitrary angle and orientation. This results in an approximation of all corners by a total of twelve major types. It is observed that all the twelve masks can actually be configured with four smaller sub-masks, and this results in a significant reduction in the computetions. The computations are further reduced by using the the separability of masks. Results for synthetic and real scenes are reported.
Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. (1994)

First-generation recombinant adenoviruses that lack E1 sequences have shown tremendous promise in animal and human models of gene therapy. Important limitations of these vectors are that recombinant gene expression is transient and inflammation occurs at the site of gene transfer. Our hypothesis for generating vectors with increased persistence is that present recombinant adenoviruses express viral proteins that stimulate cellular immune responses leading to destruction of the infected cells and repopulation of the organ with non-transgene-containing cells. This model predicts that further crippling of the virus will improve persistence and diminish pathology. We describe in this report second-generation recombinant adenoviruses harboring a beta-galactosidase-expressing transgene in which a temperature-sensitive mutation has been introduced into the E2A gene of an E1-deleted recombinant. At nonpermissive temperature, this virus fails to express late gene products, even when E1 is expressed in trans. The biology of this recombinant was studied in vivo in the context of mouse liver, a setting that is permissive for adenovirus type 5 replication. Animals that received the second-generation virus expressed the transgene for at least 70 days, whereas expression of the first-generation virus was no longer than 14 days. In addition, the inflammatory response, as measured by infiltration of CD8+ T cells, was blunted and delayed in livers infected with second-generation virus. These studies illustrate that modifications that disrupt structural protein expression in recombinant adenoviruses may be useful in enhancing their utility for gene therapy.
The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons (2014)

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by extracellular plaques containing amyloid β (Aβ)-protein and intracellular tangles containing hyperphosphorylated Tau protein. Here, we describe the generation of inducible pluripotent stem cell lines from patients harboring the London familial AD (fAD) amyloid precursor protein (APP) mutation (V717I). We examine AD-relevant phenotypes following directed differentiation to forebrain neuronal fates vulnerable in AD. We observe that over differentiation time to mature neuronal fates, APP expression and levels of Aβ increase dramatically. In both immature and mature neuronal fates, the APPV717I mutation affects both β- and γ-secretase cleavage of APP. Although the mutation lies near the γ-secretase cleavage site in the transmembrane domain of APP, we find that β-secretase cleavage of APP is elevated leading to generation of increased levels of both APPsβ and Aβ. Furthermore, we find that this mutation alters the initial cleavage site of γ-secretase, resulting in an increased generation of both Aβ42 and Aβ38. In addition to altered APP processing, an increase in levels of total and phosphorylated Tau is observed in neurons with the APPV717I mutation. We show that treatment with Aβ-specific antibodies early in culture reverses the phenotype of increased total Tau levels, implicating altered Aβ production in fAD neurons in this phenotype. These studies use human neurons to reveal previously unrecognized effects of the most common fAD APP mutation and provide a model system for testing therapeutic strategies in the cell types most relevant to disease processes.
Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B (2002)

High-throughput screening (HTS) of compound libraries is used to discover novel leads for drug development. When a structure is available for the target, computer-based screening using molecular docking may also be considered. The two techniques have rarely been used together on the same target. The opportunity to do so presented itself in a project to discover novel inhibitors for the enzyme protein tyrosine phosphatase-1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for type II diabetes. A corporate library of approximately 400 000 compounds was screened using high-throughput experimental techniques for compounds that inhibited PTP1B. Concurrently, molecular docking was used to screen approximately 235 000 commercially available compounds against the X-ray crystallographic structure of PTP1B, and 365 high-scoring molecules were tested as inhibitors of the enzyme. Of approximately 400 000 molecules tested in the high-throughput experimental assay, 85 (0.021%) inhibited the enzyme with IC50 values less than 100 microM; the most active had an IC50 value of 4.2 microM. Of the 365 molecules suggested by molecular docking, 127 (34.8%) inhibited PTP1B with IC50 values less than 100 microM; the most active of these had an IC50 of 1.7 microM. Structure-based docking therefore enriched the hit rate by 1700-fold over random screening. The hits from both the high-throughput and docking screens were dissimilar from phosphotyrosine, the canonical substrate group for PTP1B; the two hit lists were also very different from each other. Surprisingly, the docking hits were judged to be more druglike than the HTS hits. The diversity of both hit lists and their dissimilarity from each other suggest that docking and HTS may be complementary techniques for lead discovery.