gebhart/patrepeval huggingface dataset:
Pyk2 and Syk participate in functional activation of granulocytic HL-60 cells in a different manner (2000)

The roles of the protein tyrosine kinases Pyk2 (also called RAFTK or CAK beta) and Syk in the process of functional activation of human myeloid cells were examined. During granulocytic differentiation of HL-60 cells with dimethyl sulfoxide (DMSO), the amounts of Pyk2 and beta2 integrin increased, whereas the amount of Syk was abundant before differentiation and did not change during differentiation. When the granulocytic cells were stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), tyrosine phosphorylation of Pyk2 occurred promptly and subsequent association of Pyk2 with beta2 integrin was detected. In contrast, Syk was not tyrosine phosphorylated by fMLP stimulation but constitutively associated with beta2 integrin. Stimulation with fMLP also caused the alteration of beta2 integrin to an activated form, a finding that was confirmed by the observation of fMLP-induced cell attachment on fibrinogen-coated dishes and inhibition of this attachment by pretreatment with anti-beta2 integrin antibody. Cell attachment to fibrinogen caused the enhanced tyrosine phosphorylation of Pyk2 and the initial tyrosine phosphorylation of Syk, which was also inhibited by pretreatment with anti-beta2 integrin antibody. In vitro kinase assays revealed that Pyk2 and Syk represented kinase activities to induce tyrosine phosphorylation of several molecules in the anti-beta2 integrin immunoprecipitates of the attached cells. These results showed that Pyk2 is involved in the functional activation of granulocytic cells in 2 signaling pathways: an fMLP receptor-mediated "inside-out" signaling pathway that might cause beta2 integrin activation and a subsequent beta2 integrin-mediated "outside-in" signaling pathway. Syk was activated in relation to cell attachment to fibrinogen as a result of "outside-in" signaling, although it was already associated with beta2 integrin before fMLP stimulation. (Blood. 2000;96:1733-1739)
General and facile method for determination of configuration of steroid-17-yl methyl glycolates at C-20 based on kinetic examination (1998)

Plots of the amount of the isomeric steroid-17-yl methyl glycolate produced by a reaction of the corresponding steroids, prednisolone, dexamethasone and hydrocortisone with cupric acetate in absolute methanol, and kinetic examination of methoxycarbonylation of their products provide a general and facile method for determination of the configuration of the steroid-17-yl methyl glycolates at C-20.
Direct Activation of Genes Involved in Intracellular Iron Use by the Yeast Iron-Responsive Transcription Factor Aft2 without Its Paralog Aft1 (2005)

The yeast Saccharomyces cerevisiae contains a pair of paralogous iron-responsive transcription activators, Aft1 and Aft2. Aft1 activates the cell surface iron uptake systems in iron depletion, while the role of Aft2 remains poorly understood. This study compares the functions of Aft1 and Aft2 in regulating the transcription of genes involved in iron homeostasis, with reference to the presence/absence of the paralog. Cluster analysis of DNA microarray data identified the classes of genes regulated by Aft1 or Aft2, or both. Aft2 activates the transcription of genes involved in intracellular iron use in the absence of Aft1. Northern blot analyses, combined with chromatin immunoprecipitation experiments on selected genes from each class, demonstrated that Aft2 directly activates the genes SMF3 and MRS4 involved in mitochondrial and vacuolar iron homeostasis, while Aft1 does not. Computer analysis found different cis-regulatory elements for Aft1 and Aft2, and transcription analysis using variants of the FET3 promoter indicated that Aft1 is more specific for the canonical iron-responsive element TGCACCC than is Aft2. Finally, the absence of either Aft1 or Aft2 showed an iron-dependent increase in the amount of the remaining paralog. This may provide additional control of cellular iron homeostasis.
EGFR-directed therapies to treat non-small-cell lung cancer (2009)

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development including targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.
Contribution of CFTR to apical-basolateral fluid transport in cultured human alveolar epithelial type II cells (2005)

Previous studies in intact lung suggest that CFTR may play a role in cAMP-regulated fluid transport from the distal air spaces of the lung. However, the potential contribution of different epithelial cells (alveolar epithelial type I, type II, or bronchial epithelial cells) to CFTR-regulated fluid transport is unknown. In this study we determined whether the CFTR gene is expressed in human lung alveolar epithelial type II (AT II) cells and whether the CFTR chloride channel contributes to cAMP-regulated fluid transport in cultured human AT II cells. Human AT II cells were isolated and cultured on collagen I-coated Transwell membranes for 120-144 h with an air-liquid interface. The cultured cells retained typical AT II-like features based on morphologic studies. Net basal fluid transport was 0.9+/-0.1 mul.cm-2.h-1 and increased to 1.35+/-0.11 mul.cm-2.h-1 (mean+/-SE, n=18, P<0.05) by stimulation with cAMP agonists. The CFTR inhibitor, CFTRinh-172, inhibited cAMP stimulated but not basal fluid transport. In short-circuit current (Isc) studies with an apical-to-basolateral transepithelial Cl- gradient, apical application of CFTRinh-172 reversed the forskolin-induced decrease in Isc. Real time RT-PCR demonstrated CFTR transcript expression in human AT II cells at a level similar to that in airway epithelial cells. We conclude that CFTR is expressed in cultured human AT II cells and may contribute to cAMP-regulated apical-basolateral fluid transport.
M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea‐pig intracardiac neurones in culture. (1990)

1. The effects of muscarine upon intracardiac neurones cultured from ganglia within the atria and interatrial septum of the newborn guinea-pig heart were studied using intracellular recording techniques. 2. Muscarine applied to the neuronal soma typically produced a biphasic change in membrane potential which consisted of a small hyperpolarization followed by a depolarization. In addition, muscarine (0.01-10 microM) inhibited the calcium-dependent, after-hyperpolarization (AHP) and greatly increased the number of action potentials that could be evoked by a given depolarizing current. 3. The hyperpolarization was associated with a decrease in input resistance and it reversed to become a depolarization at a potential of -86.5 mV. This response was antagonized by 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP; 100 nM) and AF-DX 116 (500 nM), but was unaffected by pirenzepine (0.1-5 microM). 4. Two types of slow depolarization were observed in the presence of muscarine. The most common was associated with an increase in input resistance in the potential range -70 to -40 mV. Pirenzepine (100 nM) selectively antagonized this response, 4-DAMP (100 nM) similarly antagonized the response, but was non-selective. AF-DX 116 (0.5-5 microM) showed no antagonist effect. The less common depolarization (5% of cells) had a long latency and was associated with a decrease in input resistance. 5. Muscarine reduced the duration of the action potential and inhibited the AHP. Cadmium chloride (100 microM) mimicked these actions of muscarine. Application of muscarine immediately following a train of action potentials did not inhibit the AHP, suggesting that muscarine did not directly inhibit the calcium-activated potassium current (IK(Ca)). Muscarine-induced depression of the slow AHP was antagonized by 4-DAMP (100 nM) but was not antagonized by either pirenzepine (0.1-0.5 microM) or AF-DX 116 (0.5-5 microM). 6. It is concluded that the muscarine-induced depolarization of guinea-pig intracardiac neurones results from reduction of a potassium conductance similar to the M-conductance, through activation of M1 muscarinic receptors. The hyperpolarization results from an increase in potassium conductance, through activation of M2 muscarinic receptors.
1TOPS/W software programmable media processor (2011)

This article consists of a collection of slides from the author's conference presentation on the special features, system design, processing capabilities, and targeted markets for Movidius's 1TOPS/W, a software programmable media processor.
Cancer gene therapy using adeno-associated virus vectors (2007)

Gene therapy has offered highly possible promises for treatment of cancers, as many potential therapeutic genes involved in regulation of molecular processes may be introduced by gene transfer, which can arrest angiogenesis, tumor growth, invasion, metastasis, and/or can stimulate the immune response against tumors. Therefore, viral and non-viral gene delivery systems have been developed to establish an ideal delivery vector for cancer gene therapy over the past several years. Among the currently developed virus vectors, the adeno-associated virus (AAV) vector is considered as one of those that are closest to the ideal vector mainly for genetic diseases due to the following prominent features; the lack of pathogenicity and toxicity, ability to infect dividing and non-dividing cells of various tissue origins, a very low host immune response and long-term expression. Particularly, the most important attribute of AAV vectors is their safety profile in clinical trials ranging from CF to Parkinson's disease. Although adenovirus and several other oncolytic viruses have been more frequently used to develop cancer gene therapy, AAV also has many critical properties to be exploited for a cancer gene delivery vector. In this review, we will briefly summarize the basic biology of AAV and then mainly focus on recent progresses on AAV vector development and AAV-mediated therapeutic vectors for cancer gene therapy.
Regulation of metabolic shifts inClostridium acetobutylicumATCC 824 (1995)

Alcohol formation was initiated in continuous cultures of Clostridium acetobutylicum under distinct steady-state conditions: (i) in glucose-limited cultures established at low operating pH with formation of butanol, ethanol and acetone (induction of the solventogenesis) in which cells contained normal levels of NADH and a high level of ATP and butyric acid; and (ii) by increasing the NADH pressure at neutral pH in glucose-limited cultures after addition of Neutral red, or in glucose-glycerol or glucose-glycerol-pyruvate grown cultures, with a strictly alcohologenic metabolism (no acetone produced) associated with high levels of intracellular NADH and various levels of ATP. These two different metabolic shift systems are correlated with the expression of different genes involved in the solvent-forming pathways and the electron flow distribution. A high NADH level leading to butanol and ethanol formation was accompanied by increased activities of the NADH-dependent alcohol and butyraldehyde dehydrogenases, and ferredoxin:NAD(P)+ reductases, and by decreased activities of the NADH:ferredoxin reductase. This last group of enzymes constitutes the key enzymes regulating electron flow, since no change in hydrogenase activity was observed. On the other hand, classical solventogenesis appears to be characterized by high levels of expression of the NADPH-dependent alcohol and butyraldehyde dehydrogenases, and of the two enzymes involved in the acetone-forming pathway, while the ferredoxin:NAD(P)+ reductases were not synthesized. A decrease of the in vitro hydrogenase activity explains the lower hydrogen generation. In addition, the regulation of the intracellular pH was different between the alcohologenic culture grown at neutral pH and the solventogenic cultures grown at low pH. An inversion of the transmembrane pH gradient was observed during the production of alcohol at neutral pH and was related to a lower in vivo specific rate of hydrogen production while in the cultures grown at low pH the transmembrane pH generation was not linked to the F1F0 ATPase activity.
Stereoselective Photochemical 1,3-Dioxolane Addition to 5-Alkoxymethyl-2(5H)-furanone:  Synthesis of Bis-tetrahydrofuranyl Ligand for HIV Protease Inhibitor UIC-94017 (TMC-114) (2004)

A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity nonpeptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (+/-)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).
Microwave life-detection systems for searching human subjects under earthquake rubble or behind barrier (2000)

A new sensitive microwave life-detection system which can be used to locate human subjects buried under earthquake rubble or hidden behind various barriers has been constructed. This system operating at 1150 MHz or 450 MHz can detect the breathing and heartbeat signals of human subjects through an earthquake rubble or a construction barrier of about 10-ft thickness. The basic physical principle for the operation of a microwave life-detection system is rather simple. When a microwave beam of appropriate frequency (L or S band) is aimed at a pile of earthquake rubble covering a human subject or illuminated through a barrier obstructing a human subject, the microwave beam can penetrate the rubble or the barrier to reach the human subject. When the human subject is illuminated by a microwave beam, the reflected wave from the human subject will be modulated by the subject's body movements, which include the breathing and the heartbeat. If the clutter consisting of the reflected wave from stationary background can be completely eliminated and the reflected wave from the human subject's body is properly modulated, the breathing and heartbeat signals of the subject can be extracted. Thus, a human subject buried under earthquake rubble or hidden behind barriers can be located. This system has been tested extensively in a simulated earthquake rubble in the laboratory and also in a field test using realistic earthquake rubble conducted by a Federal Emergency Management Agency (FEMA) Task Force.
Identification of MET and SRC Activation in Melanoma Cell Lines Showing Primary Resistance to PLX4032 (2011)

PLX4032/vemurafenib is a first-in-class small-molecule BRAF(V600E) inhibitor with clinical activity in patients with BRAF mutant melanoma. Nevertheless, drug resistance develops in treated patients, and strategies to overcome primary and acquired resistance are required. To explore the molecular mechanisms involved in primary resistance to PLX4032, we investigated its effects on cell proliferation and signaling in a panel of 27 genetically characterized patient-derived melanoma cell lines. Cell sensitivity to PLX4032 was dependent on BRAF(V600E) and independent from other gene alterations that commonly occur in melanoma such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines lacking sensitivity to PLX4032 and harboring a different set of genetic alterations were studied as models of primary resistance. Treatment with the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and ERK activation. Resistance to PLX4032 was maintained after CRAF down-regulation by siRNA indicating alternative activation of MEK-ERK signaling. Genetic characterization by multiplex ligation-dependent probe amplification and analysis of phosphotyrosine signaling by MALDI-TOF mass spectrometry analysis revealed the activation of MET and SRC signaling, associated with the amplification of MET and of CTNNB1 and CCND1 genes, respectively. The combination of PLX4032 with drugs or siRNA targeting MET was effective in inhibiting cell growth and reducing cell invasion and migration in melanoma cells with MET amplification; similar effects were observed after targeting SRC in the other cell line, indicating a role for MET and SRC signaling in primary resistance to PLX4032. Our results support the development of classification of melanoma in molecular subtypes for more effective therapies.
A Role for the Wnt Gene Family in Hematopoiesis: Expansion of Multilineage Progenitor Cells (1997)

The microenvironment is a key regulator of hematopoietic stem cells (HSCs) and is a likely source of extracellular factors that control stem cell fate. A better understanding of these microenvironmental factors may come from investigations of developmental cell fate determination in which the critical roles of cell-cell interactions of multipotential cells have been shown. The Wnt gene family is known to regulate the cell fate and cell-cell interactions of multipotential cells in a variety of tissues. Expression of Wnts and of their putative receptors encoded by murine homologs of the Drosophila frizzled gene in hematopoietic tissues was examined by reverse transcriptase-polymerase chain reaction. Wnt-5a and Wnt-10b were expressed in day-11 murine yolk sac, day-14 fetal liver, and fetal liver AA4+ cells. The expression profiles of four murine frizzled homologs, Mfz3-7, were nearly identical to that of Wnt-5a and Wnt-10b. Notably, Wnt-10b was expressed in the fetal liver AA4+ Sca+ c-kit+ flASK) HSC population. A role for Wnts in HSC fate determination was studied by treatment of HSC populations in culture with soluble WNT proteins. The addition of conditioned media from cells transfected with Wnt-1, Wnt-5a, or Wnt-10b cDNAs to cultures of flASK cells stimulated a sevenfold, eightfold, and 11-fold expansion in cell number, respectively, relative to control media. Removal of WNT-5a from this media by immunodepletion depleted the stimulatory activity from the media, whereas addition of a partially purified WNT-5a stimulated a fivefold expansion relative to control cells. Transduction of flASK cells with a retrovirus bearing a Wnt-5a cDNA enhanced proliferation. We conclude that WNTs stimulate the survival/proliferation of hematopoietic progenitors, demonstrating that WNTs comprise a novel class of hematopoietic cell regulators.
The Design and Testing of an Epi-Retinal Vision Prosthesis Neurostimulator Capable of Concurrent Parallel Stimulation (2006)

An application specific integrated circuit (ASIC) neurostimulator capable of stimulating multiple electrodes in unison has been designed and tested. The ASIC utilizes multiple matched current sinks and sources to provide localized stimulation and is designed to drive electrodes organized in a hexagonal mosaic. This organization allows each stimulating electrode to be surrounded by up to six return electrodes, effectively isolating each stimulation site. The ASIC was manufactured using a high-voltage complementary metal-oxide-semiconductor process, which allows up to 20 V to be applied across the circuitry. This provides the greatest versatility for testing with electrodes and tissues of varying impedances in-situ and allows the device to be used in other neurostimulation applications such as functional electrical stimulation. The design has been thoroughly tested and meets all the design specifications.
CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms (2005)

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.
Enantioselective Total Synthesis of (−)‐Acylfulvene and (−)‐Irofulven (2006)

Antitumor agents (−)-acylfulvene and (−)-irofulven are prepared in an approach that employs the powerful enyne ring-closing metathesis reaction to secure the spiro-bicyclic AB rings. Other key features of this synthesis include an efficient aldol-based introduction of the stereocenter at C2, a diazene-mediated reductive allylic transposition, and a ring-closing metathesis/oxidation sequence.
Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein (2004)

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.