gebhart/patrepeval huggingface dataset:
Epigenetic Reprogramming ofOCT4andNANOGRegulatory Regions by Embryonal Carcinoma Cell Extract (2007)

Analyses of molecular events associated with reprogramming somatic nuclei to pluripotency are scarce. We previously reported the reprogramming of epithelial cells by extract of undifferentiated embryonal carcinoma (EC) cells. We now demonstrate reprogramming of DNA methylation and histone modifications on regulatory regions of the developmentally regulated OCT4 and NANOG genes by exposure of 293T cells to EC cell extract. OCT4 and NANOG are transcriptionally up-regulated and undergo mosaic cytosine-phosphate-guanosine demethylation. OCT4 demethylation occurs as early as week 1, is enhanced by week 2, and is most prominent in the proximal promoter and distal enhancer. Targeted OCT4 and NANOG demethylation does not occur in 293T extract-treated cells. Retinoic acid-mediated differentiation of reprogrammed cells elicits OCT4 promoter remethylation and transcriptional repression. Chromatin immunoprecipitation analyses of lysines K4, K9, and K27 of histone H3 on OCT4 and NANOG indicate that primary chromatin remodeling determinants are acetylation of H3K9 and demethylation of dimethylated H3K9. H3K4 remains di- and trimethylated. Demethylation of trimethylated H3K9 and H3K27 also occurs; however, trimethylation seems more stable than dimethylation. We conclude that a central epigenetic reprogramming event is relaxation of chromatin at loci associated with pluripotency to create a conformation compatible with transcriptional activation.
Grafting Genetically Modified Cells to the Damaged Brain: Restorative Effects of NGF Expression (1988)

Fibroblasts were genetically modified to secrete nerve growth factor (NGF) by infection with a retroviral vector and then implanted into the brains of rats that had surgical lesions of the fimbria-fornix. The grafted cells survived and produced sufficient NGF to prevent the degeneration of cholinergic neurons that would die without treatment. In addition, the protected cholinergic cells sprouted axons that projected in the direction of the cellular source of NGF. These results indicate that a combination of gene transfer and intracerebral grafting may provide an effective treatment for some disorders of the central nervous system.
Graft Versus Host Disease (2005)

The pathophysiology of acute graft versus host disease (GVHD) can be considered as a three-step process where the innate and adaptive immune systems interact (Fig. 1). The three steps are: 1) tissue damage to the recipient by the radiation/chemotherapy pre-transplant conditioning regimen, 2) donor T cell activation and clonal expansion, and 3) cellular and inflammatory factors. This schema underscores the importance of mononuclear phagocytes and other accessory cells to the development of GVHD after complex interactions with cytokines secreted by activated donor T cells. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage and activation of host tissues throughout the body and the secretion of inflammatory cytokines Tumor Necrosis Factor (TNFα) and Interleukin (IL-1). These cytokines may enhance donor T cell recognition of host alloantigens by increasing expression of major histocompatibility complex (MHC) antigens and other molecules on host antigen presenting cells (APCs). Inflammatory cytokines may also stimulate chemokine release, recruiting donor T cells into host target organs. In step 2, host APCs present alloantigen (an HLApeptide complex) to the donor T cells. Co-stimulatory signals are required for T cell activation and these signals further activate APCs which in turn enhance T cell stimulation, characterized by cellular proliferation and the secretion of cytokines. IL-2 expands the T cell clones and induces cytotoxic T cell (CTL) responses; whereas, IFNγ has multiple effects, including the priming of mononuclear phagocytes to produce TNFα and IL-1. In step 3, effector functions of mononuclear phagocytes and neutrophils are triggered through a secondary signal provided by mediators such as lipopolysaccharides (LPS) that leak through the intestinal mucosa damaged during step 1. This inflammation, along with direct lysis of target cells by CTL, causes pathologic changes in target organs. Risk factors, as well as strategies to prevent GVHD, can be conceptualized according to this three-step model and will be reviewed in this article.
Development of a green LAB process: alkylation of benzene with 1-dodecene over mordenite (2003)

This work examines the linear alkylbenzene (LAB) production reaction by alkylation of benzene with 1-dodecene over a commercial mordenite, containing 30% Al2O3 as a binder, in a fixed bed reactor. The effects of various steam pretreatments on the properties of mordenite were studied in the LAB reaction and characterized by means of temperature programming desorption of ammonia. It was found that with steam pretreatment at 10.7 kPa partial pressure, the mordenite catalyst has a maximum acidity and activity, selectivity of 98% LAB product with 67% 2-phenyl isomer and stability beyond 600 hours operation. In the proposed reaction pathway, the isomer selectivity and catalytic stability were attributed to the result of product shape selectivity from zeolite pore structures and the comparative reaction rate of isomerization and alkylation of 1-dodecene, in which alkylation was catalyzed by strong acid sites. The extent to which external (liquid–solid) and internal (pore diffusion) mass transfer affects the main reaction was also carefully examined. Furthermore, in benzene enriched feeds, the LAB reaction was found to be first order with respective to 1-dodecene, with an apparent activation energy of 17 kcal mol−1.
Skeletal Unloading Induces Resistance to Insulin-Like Growth Factor-I (IGF-I) by Inhibiting Activation of the IGF-I Signaling Pathways (2004)

These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.
Mechanisms of lymphocyte activation and immune regulation IV : cellular communications (1992)

In 23 papers from an international conference in Newport Beach, California, February 1992, immunologists and molecular biologists focus on the role interactions among the cells play in lymphocyte activation and immune regulation. The general topics are cell receptors and T-cell activation; T-cell de
Endotoxemia, pentose cycle, and the oxidant/antioxidant balance in the hepatic sinusoid (1998)

During the innate immune response, excessive release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver and other tissues. The consequence of oxidative stress is determined by the status and adaptive changes of antioxidant pathways. In this review, we present evidence that the synchronized response of hepatic sinusoidal endothelial cells, the primary sites of phagocyte attachment, plays an important role in defense against phagocyte-derived ROS. An essential component of the metabolic adaptation of hepatic sinusoidal cells to lipopolysaccharide (LPS)-induced oxidative stress is the stimulated expression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the pentose cycle (hexose monophosphate shunt, HMS). All major ROS-metabolic enzymes, i.e., glutathione peroxidase, glutathione reductase, catalase, superoxide dismutases, NADPH oxidase, and nitric oxide synthase, directly or indirectly depend on NADPH, which is produced in the HMS in these cells. The functional significance of up-regulated HMS within a particular cell type depends on the accompanying adaptive changes in ROS-metabolizing enzymes. In LPS-activated Kupffer cells, the elevated expression of glucose transporter GLUT1 and G6PD mainly serves primed production of superoxide anion, hydrogen peroxide, and nitric oxide. In sinusoidal endothelial cells, the LPS-induced response pattern of glucose- and ROS-metabolizing enzymes results in elevated ROS detoxifying capacity. The described studies also suggest the existence of an intercellular oxidant balance between pro-oxidant Kupffer cells and antioxidant endothelial cells in the hepatic micro-environment. Maintenance of the intercellular oxidant/antioxidant balance between phagocytes and endothelial cells may represent an important mechanism protecting the hepatic parenchyma against exogenous oxidative stress during the inflammatory response.
<title>Microchannel heat exchangers for advanced climate control</title> (1995)

This paper presents details of fabrication and performance testing of prototype microchannel heat exchangers. The microchannel heat exchangers are being developed for advanced cooling and climate control applications, and are designed for heat loads of 100 W/cm<SUP>2</SUP>. Bulk and surface micromachining techniques are used to fabricate the test devices. Each heat exchanger section consists of over 150 microchannels etched in silicon substrates by either chemical etching or ion milling processes. The channels are 100-micrometers deep, 100-micrometers wide, and spaced 50- to 100-micrometers apart and connected with headers. Other heat exchangers have also been fabricated in copper and aluminum using machining and ion milling processes. Process steps involved photolithographic patterning, deposition of etch masks, ion or chemical etching, electrostatic bonding of the silicon to glass, insulator deposition, lamination of silicon to metals, application of thin heater coatings with busbars, and installation of the inlet/outlet hardware and valves. Recent hear exchangers have the silicon laminated to copper substrates. Performance testing focuses on determining the performance characteristics of the microchannel heat exchangers over a wide range of flow and heat transfer conditions. The working fluid for heat transfer is restricted to water or SUVA refrigerant HCFC-124 (R-124). Testing with water is run under single-phase conditions. The tests with R-124 are run under single-and two-phase flow conditions.
Two Adjacent N-terminal Glutamines of BM-40 (Osteonectin, SPARC) Act as Amine Acceptor Sites in TransglutaminaseC-catalyzed Modification (1995)

The extracellular matrix protein BM-40 (osteonectin, SPARC) has recently been shown to be a major target for transglutaminase-catalyzed cross-linking in differentiating cartilage. In the present study we demonstrate that recombinant human BM-40 can be modified with [3H]putrescine in a 1:1 molar ratio by transglutaminaseC (tissue transglutaminase). Residues Gln3 and Gln4 were identified as major amine acceptor sites. This was confirmed with several mutant proteins, including deletions in the N-terminal domain I of BM-40, site-directed mutagenesis of the reactive glutamines, and fusion of the seven-amino acid-long N-terminal sequence (APQQEAL) to an unrelated protein. The results showed that the N-terminal target site is sufficient for modification by transglutaminase but at a low level. For high efficiency amine incorporation an intact domain I is required. The conservation of at least one of the transglutaminase target glutamines in the known vertebrate BM-40 sequences and their absence in an invertebrate homologue point to an important, but yet unknown, role of this modification in vertebrates.
Activation of ErbB4 by the Bifunctional Epidermal Growth Factor Family Hormone Epiregulin Is Regulated by ErbB2 (1998)

Epiregulin (EPR) is a recently described member of the epidermal growth factor (EGF) family of peptide growth factors. The ever expanding size of the EGF family has made distinguishing the activities of these hormones paramount. We show here that EPR activates two members of the ErbB family of receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and ErbB4. Therefore by these criteria, EPR is qualitatively similar to another EGF family hormone, betacellulin (BTC). Yet, here we also demonstrate quantitative differences between EPR and BTC. EPR stimulates higher levels of EGFR phosphorylation than does BTC, whereas BTC stimulates higher levels of ErbB4 phosphorylation than does EPR. Moreover, the EPR and BTC dose response curves show that although EGFR is more sensitive to EPR than is ErbB4, ErbB4 is more sensitive to BTC than is EGFR. Finally, ErbB2, which is not activated by EPR when expressed on its own, increases the sensitivity of ErbB4 for activation by EPR. Therefore, these results establish that EPR exhibits novel activities and modes of regulation, which may have significant implications for EPR function in vivo.
Hyaluronan as a drug delivery system for diclofenac: a hypothesis for mode of action. (1995)

Hyaluronan (HA) in combination with diclofenac is currently undergoing clinical trials as a topical preparation in the management of osteoarthritic pain, basal-cell carcinoma and actinic keratosis. These are clearly diverse pathologies, but in all cases substance P plays a central role either directly or through secondary mediators such as prostaglandin E2 and nitric oxide. A common mechanism for HA in combination with diclofenac in these conditions may be through ameliorating the direct and indirect effects of substance P. Additionally, HA appears to depot and hold diclofenac in the epidermis, thereby prolonging its pharmacokinetic half-life. In rabbits, stenosis following balloon angioplasty is prevented by a subcutaneous dose of HA, probably through blockade of cell-surface HA receptors (ICAM-1, CD44 & RHAMM). The physicochemical properties of HA, and the binding of HA to HA receptors, suggests that HA will have value as a novel drug delivery system.
Beneficial Effects of Intravenously Administered N-3 Fatty Acids for the Prevention of Atrial Fibrillation after Coronary Artery Bypass Surgery: A Prospective Randomized Study (2009)

Perioperative intravenous infusion of PUFA reduces the incidence of AF after CABG and leads to a shorter stay in the ICU and in hospital. Our data suggest that perioperative intravenous infusion of PUFA should be recommended for patients undergoing CABG.
CD27/CD70 interaction directly drives B cell IgG and IgM synthesis (1995)

CD27 is a T cell activation antigen expressed on a majority of peripheral blood T cells. CD27 is also expressed on a subpopulation of human B cells, and it is reported that CD27+ B cells secrete both IgG and IgM. CD70, a ligand for CD27, is expressed on activated T and B cells, suggesting an interaction between T and B cells via CD27/CD70 ligation. Here, we analyze B cell immunoglobulin synthesis using a CD70 transfectant and present functional data showing that B cells secrete large amounts of IgG and IgM as a result of the CD27/CD70 interaction. A flow cytometric analysis showed that CD27 expression was increased and CD70 was expressed on tonsillar and peripheral blood B cells after activation with Staphylococcus aureus Cowan strain (SAC) plus interleukin (IL-2). In addition, the proliferation of B cells was enhanced mildly by the addition of CD70 transfectant, and its proliferation was blocked by anti-CD70 mAb. More importantly, the CD70 transfectant enhanced IgG and IgM production by purified B cells greatly in the presence of SAC plus IL-2. The enhancement was completely blocked by the addition of either anti-CD70 mAb or anti-CD27 mAb. Strongly suggesting that the interaction of CD27 with its ligand, CD70, on B cells plays an important role in B cell growth and differentiation to produce IgG and IgM.
Differential regulation of expression of three transforming growth factor beta species in human breast cancer cell lines by estradiol. (1990)

Transforming growth factor (TGF)-beta is a potent regulator of many cell functions and a growth inhibitor for mammary epithelial cells. We now know of three highly homologous members of the human TGF-beta gene family. We have studied the expression of TGF-beta 1, -beta 2, and -beta 3 mRNA in four human breast cancer cell lines. Using the RNase protection assay, we have detected mRNA expression of TGF-beta 1, -beta 2, and -beta 3 by T-47D cells, TGF-beta 1 and -beta 3 by ZR-75-1 cells, and TGF-beta 1 by MCF-7 cells. Treatment of these estrogen receptor-positive cells with 10 nM estradiol for 48 h resulted in decreased mRNA levels of TGF-beta 2 and -beta 3 but did not affect mRNA levels of TGF-beta 1. Expression of TGF-beta 1 and -beta 2 mRNA by an estrogen receptor-negative cell line, MDA-MB-231, was not changed by estradiol treatment. Treatment of cells with the antiestrogen tamoxifen (1 microM) did not significantly alter mRNA levels for any of the three TGF-beta species. We have further determined that estradiol treatment of T-47D was associated with diminished secretion of TGF-beta into the medium. Both TGF-beta 1 and -beta 2 inhibited the proliferation of MCF-7 cells, and neither protein affected the growth of T-47D cells. TGF-beta 1 was at least 10-fold more potent than TGF-beta 2 at inhibiting the growth of MCF-7 cells.
Protein Phosphatase 2A Negatively Regulates Insulin's Metabolic Signaling Pathway by Inhibiting Akt (Protein Kinase B) Activity in 3T3-L1 Adipocytes (2004)

Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase which has multiple functions, including inhibition of the mitogen-activated protein (MAP) kinase pathway. Simian virus 40 small t antigen specifically inhibits PP2A function by binding to the PP2A regulatory subunit, interfering with the ability of PP2A to associate with its cellular substrates. We have reported that the expression of small t antigen inhibits PP2A association with Shc, leading to augmentation of insulin and epidermal growth factor-induced Shc phosphorylation with enhanced activation of the Ras/MAP kinase pathway. However, the potential involvement of PP2A in insulin's metabolic signaling pathway is presently unknown. To assess this, we overexpressed small t antigen in 3T3-L1 adipocytes by adenovirus-mediated gene transfer and found that the phosphorylation of Akt and its downstream target, glycogen synthase kinase 3beta, were enhanced both in the absence and in the presence of insulin. Furthermore, protein kinase C lambda (PKC lambda) activity was also augmented in small-t-antigen-expressing 3T3-L1 adipocytes. Consistent with this result, both basal and insulin-stimulated glucose uptake were enhanced in these cells. In support of this result, when inhibitory anti-PP2A antibody was microinjected into 3T3-L1 adipocytes, we found a twofold increase in GLUT4 translocation in the absence of insulin. The small-t-antigen-induced increase in Akt and PKC lambda activities was not inhibited by wortmannin, while the ability of small t antigen to enhance glucose transport was inhibited by dominant negative Akt (DN-Akt) expression and Akt small interfering RNA (siRNA) but not by DN-PKC lambda expression or PKC lambda siRNA. We conclude that PP2A is a negative regulator of insulin's metabolic signaling pathway by promoting dephosphorylation and inactivation of Akt and PKC lambda and that most of the effects of PP2A to inhibit glucose transport are mediated through Akt.
Dendritic Cell Expression of OX40 Ligand Acts as a Costimulatory, Not Polarizing, Signal for Optimal Th2 Priming and Memory Induction In Vivo (2007)

Costimulatory cross-talk can occur at multiple cellular levels to potentiate expansion and polarization of Th responses. Although OX40L ligand (OX40L) is thought to play a key role in Th2 development, the critical cellular source of this molecule has yet to be identified. In this study, we demonstrate that OX40L expression by the initiating dendritic cell (DC) is a fundamental requirement for optimal induction of primary and memory Th2 responses in vivo. Analysis of the kinetics of the residual Th2 response primed by OX40L-deficient DC suggested a failure to stimulate appropriate expansion and/or survival of T cells, rather than an inability to polarize per se. The dependence upon OX40L was predominantly due to the provision of signaling through OX40 rather than retrograde signaling to the DC. Mechanistically, impaired Th2 priming in the absence of OX40L was not due to exaggerated regulation because there was no evidence of increased expansion or function of regulatory cell populations, suppression through IL-10 production, or hyporesponsiveness to secondary challenge. These data define a critical role for DC-derived OX40L in the induction and development of Th2 responses in vivo.
Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma (2018)

Our findings suggested that some TIL subsets could serve as prognostic biomarkers in HCC. High-quality randomized controlled trials are needed to determine if these TILs could serve as targets for immunotherapy in HCC.
Unmet Clinical Needs in Bipolar Disorder (2003)

Bipolar disorder is a complex, chronic condition associated with considerable morbidity and mortality, including a high rate of suicide. Currently available treatment options for bipolar disorder fail to adequately address many of the important needs of bipolar patients. Long-term maintenance therapy with lithium has been shown to prevent further episodes of mania and depression and to decrease the likelihood of suicide. However, many patients stop lithium treatment after only a few weeks, because of either untoward side effects or other factors, such as the belief that they no longer require medication. Even when lithium is taken regularly and at adequate doses, many patients continue to exhibit severe functional disability and also fail to achieve remission. Bipolar depression is also poorly understood and difficult to treat. A number of adjunctive medications are used in combination with lithium, but residual symptoms and recurring episodes of mania and depression remain common. Recently, atypical antipsychotics, such as olanzapine, risperidone, and quetiapine, have been evaluated for the treatment of bipolar disorder. Although considerable research is still needed, preliminary findings suggest that some of these agents may act as mood stabilizers, improving the acute symptoms of mania without inducing depression or rapid cycling. The role of atypical antipsychotics in maintenance therapy for bipolar disorder is currently being evaluated in a number of large clinical trials.
Allostery at opioid receptors: modulation with small molecule ligands (2017)

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.