gebhart/patrepeval huggingface dataset:
NR0B1 Is Required for the Oncogenic Phenotype Mediated by EWS/FLI in Ewing's Sarcoma (2006)

A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma, and myxoid liposarcoma, are associated with recurrent translocation events that encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a prototype for this tumor class. Ewing's sarcomas usually harbor the (11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key target genes that are involved in oncogenesis are largely unknown. Although some target genes have been defined, many of these have been identified in heterologous model systems with uncertain relevance to the human disease. To understand the function of EWS/FLI and its targets in a more clinically relevant system, we used retroviral-mediated RNAi to "knock-down" the fusion protein in patient-derived Ewing's sarcoma cell lines. By combining transcriptional profiling data from three of these lines, we identified a conserved transcriptional response to EWS/FLI. The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan nuclear receptor with no previously defined role in oncogenesis. We validated NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary human tumor samples. Functional studies revealed that ongoing NR0B1 expression is required for the transformed phenotype of Ewing's sarcoma. These studies define a new role for NR0B1 in oncogenic transformation and emphasize the utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells.
Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification (1991)

Introduction.Macrolide, lincosamide, and streptogramin (MLS) antibiotics are chemically distinct but have a similar mode of action.They have a narrow spectrum of activity that includes gram-positive cocci (in particular, staphylo- cocci, streptococci, and enterococci) and bacilli and gram- negative cocci.These drugs, especially clindamycin, are also potent against anaerobic bacteria.Gram-negative bacilli are usually resistant to MLS antibiotics, but certain enteric bacilli and Haemophilus spp.are susceptible to azithromy- cin in vitro.However, the activities of these antibiotics against Campylobacter, Legionella, and Chlamydia spp.are at the origin of the recent renaissance of erythromycin.Macrolides are composed of a minimum of two amino and/or neutral sugars attached to a lactone ring of variable size.Macrolides commercially available or in clinical devel- opment can be divided into 14-, 15-, and 16-membered lactone ring macrolides.These classes differ in their phar- macokinetic properties and in their responses to bacterial resistance mechanisms.Lincosamides (lincomycin and the more active semisynthetic derivative clindamycin) are alkyl derivatives of proline and are devoid of a lactone ring.Streptogramin antibiotics are used in clinical practice in certain countries, including Belgium and France.They are composed of two factors, A and B (II and I in pristinamycin and M and S in virginiamycin, respectively), that act in synergy and are produced by the same microorganism.In 1956, a few years after the introduction of erythromycin in therapy, resistance of staphylococci to this drug emerged and subsequently spread in France, the United Kingdom, and the United States (13,22,37).The MLS cross-resistance phenotype due to modification of the drug target is widely distributed and has, since then, been detected in Staphylo- coccus spp.(41, 72), Streptococcus spp.(18, 23, 30), Entero- coccus spp.(16), Corynebacterium diptheriae (17), Bacteroides spp.(61, 65), Clostridium spp.(64, 79), Bacillus spp.(47, 48), Lactobacillus spp.(5, 57), Mycoplasma pneumoniae (69), Campylobacter spp.(11) and, recently, Propionibacte- rium spp.(20) and members of the family Enterobac- teriaceae (1).This paper reviews the biochemical mechanism and the genetic basis of resistance to MLS antibiotics in human pathogens by target modification.Biochemical mechanism.Clinical isolates resistant to erythromycin synthesize an enzyme that N6 dimethylates an adenine residue in 23S rRNA (40).The precise site of
Nowcasting the Local Economy: Using Yelp Data to Measure Economic Activity (2017)

Can new data sources from online platforms help to measure local economic activity? Government datasets from agencies such as the U.S. Census Bureau provide the standard measures of local economic activity at the local level. However, these statistics typically appear only after multi-year lags, and the public-facing versions are aggregated to the county or ZIP code level. In contrast, crowdsourced data from online platforms such as Yelp are often contemporaneous and geographically finer than official government statistics. In this paper, we present evidence that Yelp data can complement government surveys by measuring economic activity in close to real time, at a granular level, and at almost any geographic scale. Changes in the number of businesses and restaurants reviewed on Yelp can predict changes in the number of overall establishments and restaurants in County Business Patterns. An algorithm using contemporaneous and lagged Yelp data can explain 29.2 percent of the residual variance after accounting for lagged CBP data, in a testing sample not used to generate the algorithm. The algorithm is more accurate for denser, wealthier, and more educated ZIP codes.
Human Neutrophils Secrete Bioactive Paucimannosidic Proteins from Azurophilic Granules into Pathogen-Infected Sputum (2015)

Unlike plants and invertebrates, mammals reportedly lack proteins displaying asparagine (N)-linked paucimannosylation (mannose(1-3)fucose(0-1)N-acetylglucosamine(2)Asn). Enabled by technology advancements in system-wide biomolecular characterization, we document that protein paucimannosylation is a significant host-derived molecular signature of neutrophil-rich sputum from pathogen-infected human lungs and is negligible in pathogen-free sputum. Five types of paucimannosidic N-glycans were carried by compartment-specific and inflammation-associated proteins of the azurophilic granules of human neutrophils including myeloperoxidase (MPO), azurocidin, and neutrophil elastase. The timely expressed human azurophilic granule-resident β-hexosaminidase A displayed the capacity to generate paucimannosidic N-glycans by trimming hybrid/complex type N-glycan intermediates with relative broad substrate specificity. Paucimannosidic N-glycoepitopes showed significant co-localization with β-hexosaminidase A and the azurophilic marker MPO in human neutrophils using immunocytochemistry. Furthermore, promyelocyte stage-specific expression of genes coding for paucimannosidic proteins and biosynthetic enzymes indicated a novel spatio-temporal biosynthetic route in early neutrophil maturation. The absence of bacterial exoglycosidase activities and paucimannosidic N-glycans excluded exogenous origins of paucimannosylation. Paucimannosidic proteins from isolated and sputum neutrophils were preferentially secreted upon inoculation with virulent Pseudomonas aeruginosa. Finally, paucimannosidic proteins displayed affinities to mannose-binding lectin, suggesting immune-related functions of paucimannosylation in activated human neutrophils. In conclusion, we are the first to document that human neutrophils produce, store and, upon activation, selectively secrete bioactive paucimannosidic proteins into sputum of lungs undergoing pathogen-based inflammation.
RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy (2011)

Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression.
Chimeric NK-receptor–bearing T cells mediate antitumor immunotherapy (2005)

NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. The aim of this study was to determine whether chimeric NK-receptor-bearing T cells would directly kill tumor cells and lead to induction of host immunity against tumors. Chimeric NK receptors were produced by linking NKG2D or DNAX activating protein of 10 kDa (Dap10) to the cytoplasmic portion of the CD3zeta chain. Our results showed that chimeric (ch) NKG2D-bearing T cells responded to NKG2D-ligand-bearing tumor cells (RMA/Rae-1beta, EG7) but not to wild-type tumor cells (RMA). This response was dependent upon ligand expression on the target cells but not on expression of major histocompatibility complex (MHC) molecules, and the response could be blocked by anti-NKG2D antibodies. These T cells produced large amounts of T-helper 1 (Th1) cytokines and proinflammatory chemokines and killed ligand-expressing tumor cells. Adoptive transfer of chNKG2D-bearing T cells inhibited RMA/Rae-1beta tumor growth in vivo. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.
TNF-α and IL-1α induce heme oxygenase-1 via protein kinase C, Ca2+, and phospholipase A2in endothelial cells (1999)

Heme oxygenase-1 (HO-1), an enzyme important in protection against oxidant stress, is induced in human vascular endothelial cells by the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha (IL-1alpha). However, the signaling mediators that regulate the induction are not known. This study examined the involvement of protein kinase C (PKC), phospholipase A2 (PLA2), calcium, and oxidants in cytokine induction of HO-1. Acute exposure to the PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated HO-1 mRNA. However, prolonged exposure, which downregulates most PKC isoforms, blocked induction of HO-1 mRNA by IL-1alpha and TNF-alpha. Additionally, the phosphatase inhibitors okadaic acid and calyculin enhanced cytokine induction of HO-1. Mepacrine, a PLA2 inhibitor, prevented HO-1 induction by cytokine, suggesting a role for arachidonate, the product of PLA2 hydrolysis of phospholipids, in HO-1 expression. The intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) blocked cytokine induction of HO-1. Paradoxically, the calcium ionophore A-23187 prevented HO-1 induction by cytokine but not by PMA. Finally, the oxidant scavenger N-acetylcysteine inhibited HO-1 induction by cytokines. These results demonstrate that TNF-alpha and IL-1alpha induction of HO-1 requires PKC-mediated phosphorylation and PLA2 activation as well as oxidant generation.
Stoichiometric Binding of Low Density Lipoprotein (LDL) and Monoclonal Antibodies to Ldl Receptors in a Solid Phase Assay (1989)

The current paper describes a solid phase ligand binding assay for the low density lipoprotein (LDL) receptor that takes advantage of the domain structure of the protein. An antibody directed against one domain, e.g. the cytoplasmic tail, is adsorbed to a microtiter well. A detergent solution containing the LDL receptor is added, and the receptor is allowed to bind to the antibody. The wells are then washed, and one of the following radioiodinated ligands is added: 125I-LDL or an 125I-labeled monoclonal antibody directed against a different domain than the antibody adsorbed to the well. Under these conditions, the human LDL receptor shows high affinity for 125I-LDL and for 125I-IgG-HL1, a monoclonal antipeptide antibody directed against a 10-amino-acid "linker" between repeats 4 and 5 in the ligand binding domain. The binding affinity is the same at 4 degrees C and 37 degrees C. The binding of 125I-LDL and 125I-IgG-HL1 occurs with 1:1 molar stoichiometry, suggesting that the human LDL receptor binds 1 mol of LDL per mol of receptor. The acid-dependent dissociation of 125I-LDL and 125I-labeled monoclonal antibody from LDL receptors that is observed in intact cells was also shown to occur in the solid phase binding assay. We used the solid phase assay to demonstrate the secretion of LDL receptors from monkey cells that have been transfected with a cDNA encoding a truncated form of the human receptor that lacks the membrane-spanning domain. This assay may be useful in measuring the relative amounts of the intact LDL receptor in tissue extracts and the secreted receptor in transfected cells.
Involvement of AMP-Activated Protein Kinase in Glucose Uptake Stimulated by the Globular Domain of Adiponectin in Primary Rat Adipocytes (2003)

Adiponectin is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties that suppresses hepatic glucose production and enhances glucose uptake into skeletal muscle. To characterize the potential effects of adiponectin on glucose uptake into adipose cells, we incubated isolated epididymal rat adipocytes with the globular domain of recombinant adiponectin purified from an E. coli expression system. Globular adiponectin increased glucose uptake in adipocytes without stimulating tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1, and without enhancing phosphorylation of Akt on Ser-473. Globular adiponectin further enhanced insulin-stimulated glucose uptake at submaximal insulin concentrations and reversed the inhibitory effect of tumor necrosis factor-alpha on insulin-stimulated glucose uptake. Cellular treatment with globular adiponectin increased the Thr-172 phosphorylation and catalytic activity of AMP-activated protein kinase and enhanced the Ser-79 phosphorylation of acetyl CoA carboxylase, an enzyme downstream of AMP kinase in adipose cells. Inhibition of AMP kinase activation using two pharmacological inhibitors (adenine 9-beta-D-arabinofuranoside and compound C) completely abrogated the increase in glucose uptake stimulated by globular adiponectin, indicating that AMP kinase is integrally involved in the adiponectin signal transduction pathway. Coupled with recent evidence that the effects of adiponectin are mediated via AMP kinase activation in liver and skeletal muscle, the findings reported here provide an important mechanistic link in the signaling effects of adiponectin in diverse metabolically responsive tissues.
Characterization of a Bispecific FLT3 X CD3 Antibody in an Improved, Recombinant Format for the Treatment of Leukemia (2015)

FLT3 is a receptor-tyrosine-kinase that is expressed on leukemic cells of the myeloid and lymphoid lineage rather specifically. We here report on the construction and selection of bispecific FLT3 X CD3 antibodies in a new recombinant format, termed Fabsc, that resembles the normal antibody structure more closely than the well-established bispecific single chain (bssc)-format. Our preferred antibody, which emerged from an initial selection procedure utilizing different FLT3- and CD3-antibodies, contains the FLT3-antibody 4G8 and the CD3-antibody UCHT1. The 4G8 X UCHT1 Fabsc-antibody was found to be superior to a bssc-antibody with identical specificities with respect to (i) affinity to the target antigen FLT3, (ii) production yield by transfected cells, and (iii) the diminished formation of aggregates. T-cell activation in the presence and absence of cultured leukemic cells and killing of these cells was comparable for both molecules. In addition, the 4G8 X UCHT1 Fabsc-antibody was found to induce T-cell activation and efficient killing of leukemic blasts in primary peripheral blood mononuclear cell (PBMC) cultures of acute myeloid leukemia (AML) patients. In these experiments, the bispecific molecule was clearly superior to an Fc-optimized monospecific FLT3-antibody described previously, indicating that within PBMC of AML patients the recruitment of T cells is more effective than that of natural killer cells.
Sensitivity analysis and applications to nuclear power plant (2003)

Sensitivity analysis is used to ascertain important variables for a nuclear power plant system in order to control the variation of the plant thermal performance. In this project, thermal performance data have been taken weekly from the Tennessee Valley Authority (TVA) Sequoyah nuclear power plant units one and two, which include about 40 measured or calculated variables. Recorded data indicate that the heat rate is changing constantly, and the plant may lose some megawatts of electric power due to the heat rate variation. Hybrid neural networks and neural modeling provide useful information to power plant personnel in determining the cause of the deviation of thermal performance and heat rate, and provide a controlling basis for them in order to operate the plant more efficiently.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Stem cells and regenerative medicine — future perspectives (2012)

Stem cell research has expanded at an exponential rate, but its therapeutic applications have progressed much more slowly. Currently, the research focuses on understanding embryonic, adult, and inducible pluripotent stem cells. Translation of adult stem cell research has established a definitive benefit that is greater than that of the current standard of care in the field of cardiovascular medicine. The future of stem cell research and therapy will continue to provide novel avenues of diagnostics, therapeutics, and tissue regeneration. Here we discuss a brief history of stem cell research as it transitioned from the 20th to the 21st century. We address lessons learned in the first decade of the new millennium that could help guide others to translate research into therapy across disciplines. Finally, we highlight future goals and challenges that must be overcome and offer some perspective on the bright future of stem cell research and therapy.
The mouse SCA2 gene: cDNA sequence, alternative splicing and protein expression (1998)

Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of a CAG trinucleotide repeat located in the coding region of the human SCA2 gene. Sequence analysis revealed that SCA2 is a novel gene of unknown function. In order to provide insights into the molecular mechanisms of pathogenesis of SCA2 and to identify conserved domains, we isolated and characterized the mouse homolog of the SCA2 gene. Sequence and amino acid analysis revealed 89% identity at the nucleotide and 91% identity at the amino acid level. However, there was no extended polyglutamine tract in the mouse SCA2 cDNA, suggesting that the normal function of SCA2 is not dependent on this domain. Northern blot analysis of different mouse tissues indicated that the mouse SCA2 gene was expressed in most tissues, but at varying levels. Alternative splicing seen in human SCA2 was conserved in the mouse. By northern blot analysis, SCA2 was expressed during embryogenesis as early as day 8 of gestation (E8). Immunohistochemical staining using affinity-purified antibodies demonstrated that ataxin 2 was expressed in the cytoplasm of Purkinje cells as well as in other neurons of the CNS.
Generation and Regeneration of Cells of the Liver and Pancreas (2008)

Liver and pancreas progenitors develop from endoderm cells in the embryonic foregut. Shortly after their specification, liver and pancreas progenitors rapidly acquire markedly different cellular functions and regenerative capacities. These changes are elicited by inductive signals and genetic regulatory factors that are highly conserved among vertebrates. Interest in the development and regeneration of the organs has been fueled by the intense need for hepatocytes and pancreatic beta cells in the therapeutic treatment of liver failure and type I diabetes. Studies in diverse model organisms have revealed evolutionarily conserved inductive signals and transcription factor networks that elicit the differentiation of liver and pancreatic cells and provide guidance for how to promote hepatocyte and beta cell differentiation from diverse stem and progenitor cell types.
Abstract 1751: Engineered toxin bodies with specific cell kill activity against mesenchymal cells (2011)

Abstract The epithelial-to-mesenchymal transition is associated with progression and poor outcome in numerous cancers. Discovery of selective agents that target mesenchymal cancer cells has been an area of significant interest. Here we describe the identification of several novel compounds that specifically recognize and kill H358 Non-small cell lung carcinoma (NSCLC) cells that have been transitioned to a mesenchymal phenotype while showing no activity against H358 epithelial cells. These compounds were identified from a screen of a novel biologic library derived from a de-immunogenized Shiga-like toxin 1 A subunit (SLT1A); SLT1A has no intrinsic binding ability of its own but can drive internalization, retrograde transport to the cytosol, and enzymatic inhibition of ribosome activity. This modified library of engineered toxin bodies (ETBs) was created through the insertion of random amino acids near the C-terminus of the SLT1A scaffold to confer selective binding ability of SLT1A while preserving the therapeutic PK and ADME profile of the scaffold. This library of approximately 10⁁15 variants was pre-cleared against epithelial H358 cells and then screened against mesenchymal H358 cells. The screen was performed in an etiology driven manner where the receptor was not known a priori and selection was based on variants ability to induce cell-kill. Sequence convergence was observed as a result of the biopanning and further characterization of a selected group of mesenchymal-specific ETBs is on-going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1751. doi:10.1158/1538-7445.AM2011-1751
The Role of Bacterial ICE Nucleation in Frost Injury to Plants (1983)

Beneficial microbes in the microbiome of plant roots improve plant health. Induced systemic resistance (ISR) emerged as an important mechanism by which selected plant growth–promoting bacteria and fungi in the rhizosphere prime the whole plant body for ...Read More