gebhart/patrepeval huggingface dataset:
Severe Sensory Deficits but Normal CNS Development in Newborn Mice Lacking TrkB and TrkC Tyrosine Protein Kinase Receptors (1997)

Analysis of mice carrying targeted mutations in genes encoding neurotrophins and their signalling Trk receptors has provided critical information regarding the role that these molecules play in the mammalian nervous system. In this study we generated mice defective in both TrkB and TrkC tyrosine kinase receptors to determine the biological effects of these receptors in the absence of compensatory mechanisms. trkB(-/-);trkC(-/-) double-mutant mice were born at the expected frequency, indicating that TrkB and TrkC signalling are not required for embryonic survival. However, these double-mutant mice had a significantly shorter lifespan and displayed more severe sensory defects than their single-mutant trkB(-/-) and trkC(-/-) littermates. The most dramatic sensory deficit observed in trkB(-/-);trkC(-/-) mutant mice was the absence of vestibular and cochlear ganglia. Interestingly, these mice developed inner ear sensory epithelia in spite of the complete absence of sensory innervation. Analysis of the CNS in trkB(-/-);trkC(-/-) mutant mice revealed a well formed hippocampus, cortex and thalamus. Moreover, the pattern of expression of several neuronal markers appeared normal in these animals. These observations suggest that neurotrophin signalling through TrkB and TrkC receptors is essential for the development of sensory ganglia; however, it does not play a major role in the differentiation and survival of CNS neurons during embryonic development.
The Effect of Cytokines and Pharmacologic Agents on Chronic HIV Infection (1992)

The ability of the human immunodeficiency virus (HIV) to replicate in CD+ T lymphocytes and mononuclear phagocytes(MP) is strongly influenced by immunoregulatory cytokines. In the T cell system, interleukin-2 (IL-2) provides a mitogenic signal leading to both cell proliferation and virus replication. Among other HIV-inductive cytokines, only tumor necrosis factor-alpha or -beta (TNF-alpha/-beta) have been shown thus far to trigger virus expression both in T cells and MP. The mechanism of action of TNF involves the activation of the cellular transcription factor NF-kB which binds to specific consensus sequences present in the enhancer region of the HIV proviral LTR. In addition, several other cytokines (including colony stimulating factors, IL-1, IL-3, and IL-6) have demonstrated upregulatory effects on HIV production in MP, whereas nonimmune interferons (INF-alpha/-beta) have been shown to suppress HIV replication in T cells and MP by acting at different phases in the virus life cycle. Finally, cytokines such as TGF-beta, IFN-gamma, and IL-4 have demonstrated either upregulatory or suppressive effects on virus expression depending on the experimental conditions. This scenario indicates that HIV expression is under the control of a complex network of immunoregulatory cytokines, in addition to its own endogenous regulatory proteins, suggesting that new pharmacologic strategies may be aimed at either mimicking or interrupting cytokine-dependent virus expression. In this regard, a number of different physiologic and pharmacologic agents capable of interfering with cytokine-mediated events, including glucocorticoids, anti-oxidants, such as N-Acetyl-L-Cysteine (NAC), and retinoic acid (RA) have already been shown to profoundly affect HIV replication in vitro.
Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats (2013)

Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation.
The Anthracycline Antineoplastic Drugs (1981)

PERHAPS no family of chemotherapeutic agents has been so rapidly accepted as a major therapeutic tool in treating patients with cancer as have the anthracyclines. Since the first clinical trials of doxorubicin and daunorubicin little more than a decade ago, these drugs have been extensively studied alone and in combination, and they now have a major role in the effective treatment of acute leukemia, non-Hodgkin lymphomas, breast cancer, Hodgkin's disease, and sarcomas.The successful use of these drugs has been hampered by conventional toxicities (hematopoietic suppression, nausea and vomiting, and alopecia) as well as unique toxicities (cardiomyopathy); these problems have . . .
Interleukin-8 receptor modulates IgE production and B-cell expansion and trafficking in allergen-induced pulmonary inflammation (1999)

We examined the role of the interleukin-8 (IL-8) receptor in a murine model of allergen-induced pulmonary inflammation using mice with a targeted deletion of the murine IL-8 receptor homologue (IL-8r-/-). Wild-type (Wt) and IL-8r-/- mice were systemically immunized to ovalbumin (OVA) and were exposed with either single or multiple challenge of aerosolized phosphate-buffered saline (OVA/PBS) or OVA (OVA/OVA). Analysis of cells recovered from bronchoalveolar lavage (BAL) revealed a diminished recruitment of neutrophils to the airway lumen after single challenge in IL-8r-/- mice compared with Wt mice, whereas multiply challenged IL-8r-/- mice had increased B cells and fewer neutrophils compared with Wt mice. Both Wt and IL-8r-/- OVA/OVA mice recruited similar numbers of eosinophils to the BAL fluid and exhibited comparable degrees of pulmonary inflammation histologically. Both total and OVA-specific IgE levels were greater in multiply challenged IL-8r-/- OVA/OVA mice than in Wt mice. Both the IL-8r-/- OVA/OVA and OVA/PBS mice were significantly less responsive to methacholine than their respective Wt groups, but both Wt and IL-8r mice showed similar degrees of enhancement after multiple allergen challenge. The data demonstrate that the IL-8r modulates IgE production, airway responsiveness, and the composition of the cells (B cells and neutrophils) recruited to the airway lumen in response to antigen.
AlGaN/GaN Recessed MIS-Gate HFET With High-Threshold-Voltage Normally-Off Operation for Power Electronics Applications (2008)

This letter reports normally-off operation of an AlGaN/GaN recessed MIS-gate heterostructure field-effect transistor with a high threshold voltage. The GaN-based recessed MIS-gate structure in conjunction with negative polarization charges under the gate allows us to achieve the high threshold voltage, whereas the low on-state resistance is maintained by the 2-D electron gas remaining in the channel except for the recessed MIS-gate region. The fabricated device exhibits a threshold voltage as high as 5.2 V with a maximum field-effect mobility of 120 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> /Vmiddots, a maximum drain current of over 200 mA/mm, and a breakdown voltage of 400 V.
Silicon nanopillars for mechanical single-electron transport (2004)

Nanomechanical systems have been shown to accurately regulate the flow of electric current. We present the concept and demonstrate experimental operation of a vertical electromechanical single-electron transistor. The device is fabricated from silicon forming a nanopillar situated between source and drain contacts. The advantage of this concept is its straightforward manufacturing, which only includes two processing steps: Electron-beam lithography and reactive ion etching. The device operates at room temperature and at frequencies in the range of 350–400 MHz. A theoretical model of the operation of this device is given, explaining qualitatively the obtained experimental data.
Comparison of a New Anti-Glutamic Acid Decarboxylase (GAD) Enzyme-Linked Immunosorbent Assa (ELISA) with Radioimmunoassay Methods: A Multicenter Study (1997)

Several methods are available for the measurement of antibodies to glutamic acid decarboxylase (anti GAD). These antibodies are valuable tools for the immunodiagnosis of insulin-dependent (type 1) diabetes mellitus (IDDM) and for the assessment of risk for the future development of IDDM. We here describe a new enzyme-linked immunosorbent assay (ELISA) for the detection of anti-GAD which was tested in a multicenter study. The results of the new anti-GAD ELISA correlate well with those obtained by radioimmunoassays (RIA) and they have a higher sensitivity (69%) and specificity (98%) compared to other anti-GAD enzyme immunoassays as determined in the IDW Proficiency Test Program for the detection of GAD antibodies. The new ELISA is simple and easy to perform, with convenient handling of the reagents. Quantitative and reproducible test results are available within approximately four hours. The new anti-GAD ELISA can be used for large scale population screening to indicate a prediabetic state as well as to diagnose autoimmune diabetes in adults (LADA) and the risk for IDDM in pregnant women with gestational diabetes.
Cellular, molecular and biochemical differences in the pathophysiology of healing between acute wounds, chronic wounds and wounds in the aged (2004)

Acute wound healing is a dynamic process involving the coordinated actions of both resident and migratory cell populations within the extracellular matrix environment leading to the repair of injured tissues. In contrast to this some wounds fail to heal in a timely and orderly manner, resulting in chronic non-healing wounds. In addition, chronic wounds are more prevalent in older people due to the altered molecular and cellular characteristics of the aged skin and various associated co-morbidities. This article discusses in detail the cellular, molecular and biochemical differences in healing between acute and chronic wounds, and outlines the effects of ageing on the healing process.
Green Fluorescent Protein-like Proteins in Reef Anthozoa Animals. (2002)

Green fluorescent protein (GFP) from the bioluminescent jellyfish Aequorea victoria has become an important tool in molecular and cellular biology as a transcriptional reporter, fusion tag, and biosensor. Most significantly, it encodes a chromophore intrinsically within its protein sequence, obviating the need for external substrates or cofactors and enabling the genetic encoding of strong fluorescence. Mutagenesis studies have generated GFP variants with new colors, improved fluorescence and other biochemical properties. In parallel, GFPs and GFP-like molecules have been cloned from other organisms, including the bioluminescent sea pansy Renilla reniformis and other non-bioluminescent Anthozoa animals. In the jellyfish and sea pansy, the GFPs are coupled to their chemoluminescence. Instead of emitting the blue light generated by aequorin and luciferase, the GFPs absorb their energy of primary emission and emit green light, which travels farther in the sea. In contrast, GFP-like proteins in reef Anthozoa are thought to play a role in photoprotection of their symbiotic zooxanthellae in shallow water; they transform absorbed UV radiation contained in sunlight into longer fluorescence wavelengths (Salih, A., Larkum, A., Cox, G., Kuhl, M., and Hoegh-Guldberg, O. 2000. Nature, 408: 850-853). In this review, I will describe both the biological and practical aspects of Anthozoan GFP-like proteins, many of which will be greatly improved in utility and commercially available before long. The ubiquity of these molecular tools makes it important to appreciate the interplay between sunlight and GFP-like proteins of Anthozoan animals, and to consider the optimal use of these unique proteins in biological studies.
Two types of transglutaminase in the PC12 pheochromocytoma cell line. Stimulation by sodium butyrate. (1987)

Transglutaminases are a class of enzymes capable of covalently cross-linking both intracellular and extracellular proteins. The activity of tissue transglutaminase is known to decrease precipitously following neoplastic transformation, and it has been hypothesized that transglutaminase may be involved in growth regulation. We have found that the differentiation promoter sodium butyrate is able to cause a marked increase in transglutaminase activity in PC12 pheochromocytoma cells in a time- and dose-dependent manner. This increased transglutaminase activity is associated with growth arrest, as well as with striking morphological changes including increased cell adhesion. The transglutaminase induced by sodium butyrate appears to be tissue transglutaminase, based on its cytosolic localization, thermal lability at basic pH, and elution profile on anion-exchange chromatography. Untreated PC12 cells contain only small amounts of transglutaminase which resembles epidermal transglutaminase, an enzyme previously described only in skin. In contrast to sodium butyrate, nerve growth factor did not stimulate tissue transglutaminase in PC12 cells, although it, too, caused growth arrest. It is hypothesized that transglutaminase may be involved in certain morphological changes accompanying cellular differentiation and neoplastic transformation, rather than in growth regulation per se.
Oral Dextran Sulfate (UAOO1) in the Treatment of the Acquired Immunodeficiency Syndrome (AIDS) and AIDS-Related Complex (1989)

Oral dextran sulfate appears to be well tolerated. No evidence of systemic absorption of the parent compound is available. However, in view of the promising in vitro effects and acceptable toxicity, oral dextran sulfate as a potential antiretroviral agent continues to be studied.
Multi-site optical excitation using ChR2 and micro-LED array (2010)

Studying neuronal processes such as synaptic summation, dendritic physiology and neural network dynamics requires complex spatiotemporal control over neuronal activities. The recent development of neural photosensitization tools, such as channelrhodopsin-2 (ChR2), offers new opportunities for non-invasive, flexible and cell-specific neuronal stimulation. Previously, complex spatiotemporal control of photosensitized neurons has been limited by the lack of appropriate optical devices which can provide 2D stimulation with sufficient irradiance. Here we present a simple and powerful solution that is based on an array of high-power micro light-emitting diodes (micro-LEDs) that can generate arbitrary optical excitation patterns on a neuronal sample with micrometre and millisecond resolution. We first describe the design and fabrication of the system and characterize its capabilities. We then demonstrate its capacity to elicit precise electrophysiological responses in cultured and slice neurons expressing ChR2.
Discovering high-affinity ligands from the computationally predicted structures and affinities of small molecules bound to a target: A virtual screening approach (2005)

We describe a ‘virtual NMR screening’ method to assist in the design of inhibitors that occupy different sites within a target. We dock small molecules into the active site of an enzyme and score them. Keeping the tightest-binding lead fixed in space, we dock and score other small molecules in its presence. Using this approach, linker groups are used to join the compounds together to form a high-affinity inhibitor. We present validation of our computational approach by reproducing experimental results for FKBP and stromelysin. Docking simulations are not subject to experimental problems such as proteolysis, protein or compound insolubility, or enzyme size. Because docking is fast and our scoring method can distinguish between high- and low-affinity inhibitors, this docking procedure shows promise as integral part of a drug-design strategy.
Regulation of Cholesterologenesis by the Oxysterol Receptor, LXRα (2008)

Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regulate the expression of cholesterologenic enzymes. Sterol regulatory element-binding protein-2 is responsive to both sterols and oxysterols and has been shown to mediate the transcriptional response of the cholesterologenic enzymes to these lipids. Here, we show that the nuclear hormone receptor for oxysterols, the liver X receptor alpha (LXRalpha), regulates cholesterol biosynthesis by directly silencing the expression of two key cholesterologenic enzymes (lanosterol 14alpha-demethylase (CYP51A1), and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via novel negative LXR DNA response elements (nLXREs) located in each of these genes. Examination of the CYP51A1 gene revealed that both the SRE and nLXRE are required for normal oxysterol-dependent repression of this gene. Thus, these data suggest that LXRalpha plays an important role in the regulation of cholesterol biosynthesis.
Animal Models of Multiple Myeloma and Their Utility in Drug Discovery (2008)

Abstract To evaluate potential new therapies and targets for treating multiple myeloma (MM), reproducible, biologically relevant in vivo models are required. Preclinical in vivo models of human MM allow investigators to evaluate novel therapies alone and in combination and quickly translate these results to the clinic where patients directly benefit, whether in the form of a new clinical trial, new doses and schedules, or new drug combinations. Presented in this unit are protocols for generating and maintaining a human extramedullary MM tumor in mice. Additionally, the extramedullary tumor can be excised and digested into a single‐cell suspension and the human MM cells injected into mice subcutaneously, intravenously, or intratibially. Once these tumors are generated, they can be used to evaluate novel anti‐MM agents and other therapies. Curr. Protoc. Pharmacol . 40:14.9.1‐14.9.22. © 2008 by John Wiley &amp; Sons, Inc.
Glycosylphosphatidylinositol (GPI)-Anchored Proteins. (2002)

From the numerous studies developed at the last quarter of the 20th century, glycosylphosphatidylinositol (GPI) anchor has been established as a unique mode of protein binding to the plasma membrane. The core structure of this anchor consists of ethanolamine phosphate, trimannoside, glucosamine and inositol phospholipid in this order. The anchor is combined with the carboxyl-terminal of protein by the ethanolamine head. GPI-anchored proteins are ubiquitously distributed among Eucarya from vertebrates to protozoa, and also shown to be present in some of Archaeobacteria such as Sulfolobus. There is no evidence for the presence of GPI-anchored protein in Eubacteria. In the eucaryotic cells, both biosynthesis of GPI precursors and posttranslational protein modification with GPI proceed in the endoplasmic reticulum. On GPI modification, the carboxyl-terminal signal peptide is split off from the protein and the resulting new carboxyl-terminal is then combined with the amino group of ethanolamine residue in the GPI precursors. The whole process of cleavage and GPI attachment is catalyzed by GPI-transamidase complex. Many genes concerning GPI biosynthesis and protein modification have been cloned and sequenced. The carboxyl-terminal signal peptide containing hydrophobic tail is characterized by genetic analysis and shown to be essential for GPI modification of protein. Recent computational analysis further clarified the detailed requirement of the carboxyl-terminal regions for GPI-anchoring. GPI-anchored proteins are assumed to be transported from Golgi to the plasma membrane in the form of "lipid rafts", and expressed as the clusters in the cell surface.
Immortalization of human lymphocytes from a tumor-involved lymph node. (1987)

Lymphocytes isolated from a regional draining lymph node of a patient with a carcinoma of the vulva were fused with human UC 729-6 cells. The generated human-human hybridomas were tetraploid with the 21p+ chromosomal marker of UC 729-6, expressed HLA derived from the patient's cells, and have been stable in culture for 2 yr. Supernatants from six immunoglobulin G (IgG)-secreting hybridomas were found to have broad reactivity profiles with human carcinoma cells and no reactivity with hematopoietic cell lines (B- and T-cells, myelomas, leukemias, lymphomas), red blood cells, peripheral blood lymphocytes, and normal fibroblasts. All six human IgG monoclonal antibodies reacted with the A431 cell line, an epidermoid carcinoma of the vulva, similar to the patient's cancer. The supernatant of one hybridoma, which phenotyped as having T-cell parentage, enhanced the cloning efficiency of human hybrids, suggesting the presence of a growth factor(s). In serum-supplemented cultures these hybrids secreted 200 ng to 3 micrograms of IgG/ml/10(6) cells/24 h and in serum-free medium, an enhanced production of 1 to 9 micrograms of IgG/ml/10(6) cells/24 h. One IgG monoclonal antibody, VLN3G2, precipitated a single chain protein with an apparent molecular weight of 48,000 from Nonidet P-40 extracts of A431 cells. Altogether, the data suggest that regional draining lymph nodes of cancer patients are highly immunoreactive and contain B-cells whose immunoglobulin recognizes putative tumor-associated antigens.
Viral Evolution in Response to the Broad-Based Retroviral Protease Inhibitor TL-3 (2001)

TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M46I/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to wild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity.