gebhart/patrepeval huggingface dataset:
Electrophysiological Properties of Pluripotent Human and Mouse Embryonic Stem Cells (2005)

Pluripotent embryonic stem cells (ESCs) possess promising potential for cell-based therapies, but their electrophysiological properties have not been characterized. Here we describe the presence of ionic currents in mouse (m) and human (h) ESCs and their physiological function. In mESCs, tetraethylammonium (TEA)-sensitive depolarization-activated delayed rectifier K+ currents (IK(DR)) (8.6 +/- 0.9 pA/pF at +40 mV; IC50 = 1.2 +/- 0.3 mM), which contained components sensitive to 4-aminopyridine (4-AP) (IC50 = 0.5 +/- 0.1 mM) and 100 nM Ca2+-activated K+ current (IK(Ca)) blocker iberiotoxin (IBTX),were detected in 52.3% of undifferentiated cells.IK(DR) was similarly present in hESCs (approximately 100%) but with an approximately sixfold higher current density (47.5 +/- 7.9 pA/pF at +40 mV). When assayed by bromodeoxyurindine incorporation, application of TEA, 4-AP, or IBTX significantly reduced the proliferation of mESCs and hESCs in a dose-dependent manner (p < .05). A hyperpolarization-activated inward current (I(h)) (-2.2 +/- 0.4 pA/pF at -120 mV) was detected in 23% of mESCs but not hESCs. Neither Na(v) nor Ca(v) currents were detected in mESCs and hESCs. Microarray and reverse transcription-polymerase chain reaction analyses identified several candidate genes for the ionic currents discovered. Collectively, our results indicate that pluripotent ESCs functionally express several specialized ion channels and further highlight similarities and differences between the two species. Practical considerations for the therapeutic use of ESCs are discussed.
Structure−Activity Relationships in a Series of 2(1H)-Quinolones Bearing Different Acidic Function in the 3-Position:  6,7-Dichloro-2(1H)-oxoquinoline-3-phosphonic Acid, a New Potent and Selective AMPA/Kainate Antagonist with Neuroprotective Properties (1996)

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.
A maize cytokinin gene encoding an O -glucosyltransferase specific to cis -zeatin (2001)

Zeatin is a naturally occurring cytokinin. Biosynthesis and metabolism studies of zeatin have been directed mostly at the trans isomer, although cis-zeatin and its riboside occur as major components in some plant species. It is not known whether parallel regulatory pathways exist for the two isomers. Based on the sequence of the gene ZOG1 encoding a trans-zeatin O-glucosyltransferase from Phaseolus (EC ), a cis-zeatin-specific O-glucosyltransferase was isolated from maize. This gene, cisZOG1, contains an ORF of 1,401 nucleotides encoding a protein of 51.1 kDa with 41% identity to the Phaseolus ZOG1 protein. Unexpectedly, the maize enzyme recognizes as substrates cis-zeatin and UDP-glucose but not cis-ribosylzeatin, trans-zeatin, or trans-ribosylzeatin. This finding indicates the existence of cis-specific regulatory elements in plants and suggests that cis-zeatin and derivatives may be more important in cytokinin homeostasis than currently recognized.
Gene Transfer to Synoviocytes: Prospects for Gene Treatment of Arthritis (1992)

Joints are difficult organs to target therapeutically. Intravenous, intramuscular, and oral routes of drug delivery provide poor access to the joint, and expose the body systemically to the therapeutic agent. Although intraarticular injection provides direct access to the joint, most injected materials have a short intraarticular half-life. We propose to circumvent these problems by introducing into the synovium gene(s) coding for proteins with antiarthritic properties. Two methods of gene delivery to synovium are under development. In the direct approach, in situ transduction of synoviocytes follows the injection of suitable vectors into the joint. In the indirect approach, synovium is removed from the joint, its synoviocytes are isolated, and the cells transduced in vitro. Genetically modified cells are subsequently transplanted back into the synovium. Using retroviral vectors, we have been able to express the lacZ and neo genes in lapine synovial fibroblasts in vitro. Following neoselection, all cells became LacZ+. Neo-selected cells carrying the lacZ marker gene were transplanted back into the knees of recipient rabbits to examine the persistence and expression of these genes in vivo. Islands of LacZ+, transplanted cells persisted in the recipient joints for at least 3 months. Furthermore, Neo+ cells could be grown from synovia recovered from these joints. Initial attempts to use retroviruses for the direct, in situ transduction of synovium have failed, probably because synoviocytes in the normal synovium are mitotically inactive. Present efforts are directed towards further development of our techniques for transferring genes to joints, and using these techniques to antagonize the intraarticular actions of interleukin-1.(ABSTRACT TRUNCATED AT 250 WORDS)
The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive (1996)

The functional architecture of prefrontal cortex is central to our understanding of human mentation and cognitive prowess. This region of the brain is often treated as an undifferentiated structure, on the one hand, or as a mosaic of psychological faculties, on the other. This paper focuses on the working memory processor as a specialization of prefrontal cortex and argues that the different areas within prefrontal cortex represent iterations of this function for different information domains, including spatial cognition, object cognition and additionally, in humans, semantic processing. According to this parallel processing architecture, the 'central executive' could be considered an emergent property of multiple domain-specific processors operating interactively. These processors are specializations of different prefrontal cortical areas, each interconnected both with the domain-relevant long-term storage sites in posterior regions of the cortex and with appropriate output pathways.
Structural and functional characteristics of S1P receptors (2004)

The sphingosine-1-phosphate (S1P) family of G protein-coupled receptors (GPCR) regulates essential cellular processes such as proliferation, migration, cytoskeletal organization, adherens junction assembly, and morphogenesis. S1P, a product from the breakdown of sphingomyelin, binds to the five members of this receptor family, S1P(1), S1P(2), S1P(3), S1P(4), and S1P(5), previously referred to as endothelial differentiation gene (EDG)-1, -5, -3, -6, and -8. S1P receptors are widely expressed in different tissues, so it is not surprising that the S1P receptor family regulates many physiological processes, such as vascular maturation, cardiac development, lymphocyte trafficking, and vascular permeability. FTY720, a new S1P receptor agonist, is undergoing clinical trials as an immunosuppressor. Understanding the physiological role of these receptors and the basics of the ligand-receptor interaction will potentially provide new therapies to control a variety of diseases.
Invited Review: Focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle (2001)

Smooth muscle cells are able to adapt rapidly to chemical and mechanical signals impinging on the cell surface. It has been suggested that dynamic changes in the actin cytoskeleton contribute to the processes of contractile activation and mechanical adaptation in smooth muscle. In this review, evidence for functionally important changes in actin polymerization during smooth muscle contraction is summarized. The functions and regulation of proteins associated with "focal adhesion complexes" (membrane-associated dense plaques) in differentiated smooth muscle, including integrins, focal adhesion kinase (FAK), c-Src, paxillin, and the 27-kDa small heat shock protein (HSP27) are described. Integrins in smooth muscles are key elements of mechanotransduction pathways that communicate with and are regulated by focal adhesion proteins that include FAK, c-Src, and paxillin as well as proteins known to mediate cytoskeletal remodeling. Evidence that functions of FAK and c-Src protein kinases are closely intertwined is discussed as well as evidence that focal adhesion proteins mediate key signal transduction events that regulate actin remodeling and contraction. HSP27 is reviewed as a potentially significant effector protein that may regulate actin dynamics and cross-bridge function in response to activation of p21-activated kinase and the p38 mitogen-activated protein kinase signaling pathway by signaling pathways linked to integrin proteins. These signaling pathways are only part of a large number of yet to be defined pathways that mediate acute adaptive responses of the cytoskeleton in smooth muscle to environmental stimuli.
Reactive Oxygen Intermediates Mediate Angiotensin II-induced c-Jun•c-Fos Heterodimer DNA Binding Activity and Proliferative Hypertrophic Responses in Myogenic Cells (1995)

Angiotensin II (Ang-II) receptor engagement activates many immediate early response genes in both vascular smooth muscle cells and cardiomyocytes whether a hyperplastic or hypertrophic response is taking place. Although the signaling pathways stimulated by Ang-II in different cell lines have been widely characterized, the correlation between the generation of different second messengers and specific physiological responses remains relatively unexplored. In this study, we report how in both C2C12 quiescent myoblasts and differentiated myotubes Ang-II significantly stimulates AP1-driven transcription and c-Jun.c-Fos heterodimer DNA binding activity. Using a set of different protein kinase inhibitors, we could demonstrate that Ang-II-induced increase in AP1 binding is not mediated by the cAMP-dependent pathway and that both protein kinase C and tyrosine kinases are involved. The observation that in quiescent myoblasts Ang-II increase of AP1 binding and induction of DNA synthesis and, in differentiated myotubes, Ang-II stimulation of protein synthesis are abolished by the cysteine-derivative and glutathione precursor N-acetyl-L-cysteine strongly suggests a role for reactive oxygen intermediates in the intracellular transduction of Ang-II signals for immediate early gene induction, cell proliferation, and hypertrophic responses.
Novel Access Technique Facilitating Carotid Artery Stenting (2006)

Carotid artery stenting (CAS) may be impossible, or associated with a high risk, in patients with severe vessel tortuosity. A novel method of catheterization of the carotid artery intended to facilitate CAS is described. It involves the placement of a microcatheter and a coronary wire through a dissected superficial temporal artery (STA), and then advanced to the ascending aorta. The wire is then snared and brought out through a sheath already placed from the common femoral artery (CFA). Thus through-and-through access from the STA to the CFA is established. The sheath is then brought over the coronary artery into the common carotid artery. Using the coronary artery as "buddy wire" the carotid artery stenting is carried out in a standard fashion. The potential benefit of this new technique is the decrease of risk of the procedures in patients with prohibiting vessel tortuosity.
Factor VII mutant V154G models a zymogen-like form of Factor VIIa (2003)

Proteolytic cleavage of the peptide bond between Arg(152) and Ile(153) converts the procoagulant protein Factor VII (FVII) to an activated two-chain form (FVIIa). The formation of a salt bridge between Ile(153) and Asp(343) drives the conversion of FVIIa from being zymogen-like to the active form. In the present paper, we describe the novel FVII mutant V154G (Val(154)-->Gly mutation; residue 17 in the chymotrypsin numbering system), found in three FVII-deficient patients, which models a zymogen-like form of FVIIa. Recombinant V154G FVIIa, although normally cleaved, shows markedly reduced activity towards peptidyl substrate and undetectable activity towards macromolecular substrates. Susceptibility of Ile(153) to chemical modification, in either the presence or the absence of tissue factor (TF), suggests that the reduced V154G FVIIa activity is caused by impaired salt-bridge formation, thus resulting in a zymogen-like FVIIa form. The TF-mediated protection from chemical modification of V154A indicated that Gly(154) is responsible for this peculiar feature, and suggests that this region, proximal to the heavy chain N-terminus, is directly involved in the conversion of FVII into FVIIa. V154G FVII was exploited to study the FVII-TF interaction, together with three additional FVII variants that were expressed to serve as models for different FVII forms. The comparison of binding affinities of full-length TF after relipidation in L-alpha-phosphatidylcholine for the zymogen FVII (Arg(152)-->Gln, K (d)=1.04+/-0.27 nM), inactive FVIIa (Ser(344)-->Ala, K (d)=0.27+/-0.06 nM) and a zymogen-like FVIIa (V154G, K (d)=1.15+/-0.16 nM) supports the hypothesis that preferential binding of TF to active FVIIa is insufficient to drive the 10(5)-fold enhancement of FVIIa activity. In addition, the inability of V154G FVIIa to accommodate an inhibitor in the active site, indicating an improperly shaped specificity pocket, would explain the low activity of the zymogen-like form of FVIIa, which is predominant in the absence of TF.
A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion (1999)

We have identified an agent (SP-303) that shows efficacy against in vivo cholera toxin-induced fluid secretion and in vitro cAMP-mediated Cl- secretion. Administration of cholera toxin to adult mice results in an increase in fluid accumulation (FA) in the small intestine (FA ratio = 0.63 vs. 1.86 in control vs. cholera toxin-treated animals, respectively). This elevation in FA induced by cholera toxin was significantly reduced (FA ratio = 0.70) in animals treated with a 100 mg/kg dose of SP-303 at the same time as the cholera treatment. Moreover, when SP-303 was administered 3 h after cholera toxin, a dose-dependent inhibition of FA levels was observed with a half-maximal inhibitory dose of 10 mg/kg. In Ussing chamber studies of Caco-2 or T84 monolayer preparations, SP-303 had a significant effect on both basal current and forskolin-stimulated Cl- current. SP-303 also induced an increase in resistance that paralleled the observed decrease in current. These data suggest that SP-303 has an inhibitory effect on cAMP-mediated Cl- and fluid secretion. Thus SP-303 may prove to be a useful broad-spectrum antidiarrheal agent.
Production methods for generating human monoclonal antibodies (1993)

The technology explosion that mushroomed from the uses and applications of monoclonal antibodies (MAbs; Re~. 1) .shows. no signs of slowing down. Virtually the entIre bIOmedIcal arena has been transformed with the introduction of the MAb as a routine reagent in both the laboratory and clinic. The promise of MAbs has been their pote~tial selectivity and exquisite specificity. One of the ObVIOUS goals of MAb technology is to develop clinically useful human MAbs (HMAbs). Historically, the first immortalized human cell secreting specific antibody was generated by infection with a ~-tropic Epstein-Barr virus (EBV) in 19772 and the first true human-human hybridoma secreting specific antibody was described in 1980.3 Although the HMAb field was slow to take off (see below), the progress made wit~ murine MAbs has been astonishing. Clearly, the antIbody of the 1980s was of mouse origin. Whatever c.ould h~v~ been done to a MAb was attempted at this tIme: chmcal protocols, simple and elaborate chemical modifications, and some very interesting molecular biology approaches. Unfortunately, the clinical usefulness of murine MAbs has been very disappointing, due for the most part to th~ innate foreigness and immunogenicity of the mouse Immunoglobulin protein, resulting in allergic respon~es,. hepati~ dysfunctions, and immune complex formatIon m the kIdney. With the ultimate aim of trying to control and eventually eradicate human diseases thro~gh immunomodulation and to improve our ability to diagnose abnormalities, it is believed that HMAbs will prove far superior than those of murine origin. H~Abs should be more effective because of their ability to mteract more appropriately with human complement or human effector cells. In addition, HMAbs would not only be less immunogenic, but they may also recognize a se~ of allogenic antigens that are not recognized by munne MAbs. As such, the antibody of the 1990s will
Brownfields and the California Department of Toxic Substances Control: Key Programs and Challenges (2001)

In order to meet the challenges posed by significant increases in population, the recycling of brownfields is essential. Recycling brownfields can also promote infill development which will, in turn, optimize population densities and can serve to reduce negative aspects of sprawl. Infill development can revitalize existing communities as idle or underutilized properties in urban centers will be used for residential, commercial and public purposes (schools, parks, hospitals). However, there exists a delicate balance in California, where urban density has increased, there is increased competition for buildable sites, particularly for public facilities, i.e., schools. The California Department of Toxic Substances Control (DTSC) developed a number of early initiatives to address brownfields problems, and, where available, complemented them with other related State mechanisms. Both legislative and administrative reforms were the cornerstones of these early tools. Additionally, DTSC views all types of cleanup projects as a potential reuse opportunity and seeks to work cooperatively with parties to meet this objective while ensuring that cleanups are conducted in an environmentally sound manner. This article will examine the origins of DTSC's brownfields programs, highlight key new programs enacted or proposed under the Administration of California's Governor Gray Davis (Davis Administration) and examine emerging brownfields issues for the State. This article presents an analysis which is in large part based on the authors' direct observations, interactions and interpretations.
Dual phosphorylation and autophosphorylation in mitogen-activated protein (MAP) kinase activation (1993)

p42mapk [mitogen activated protein (MAP) kinase; extracellular signal-regulated protein kinase (ERK)] is a serine/threonine-specific protein kinase that is activated by dual tyrosine and threonine phosphorylation in response to diverse agonists. Both the tyrosine and threonine phosphorylations are necessary for full enzymic activity. A MAP kinase activator recently purified and cloned has been shown to be a protein kinase (MAP kinase kinase) that is able to induce the dual phosphorylation of MAP kinase on both the regulatory tyrosine and threonine sites in vitro. In the present paper we have utilized MAP kinase mutants altered in the sites of regulatory phosphorylation to show, both in vivo and in vitro, that phosphorylation of the tyrosine and the threonine can occur independently of one another, with no required order of phosphorylation. We also utilized kinase-defective variants of MAP kinase with mutations in either the ATP-binding loop or the catalytic loop, and obtained data suggesting that the activity or structure of the catalytic loop of MAP kinase plays an important role in its own dual phosphorylation.
Evaluation of the Durability of 100 Percent Fly Ash Concrete (2008)

Building upon previous research conducted at Montana State University on concretes in which 100 percent of the binder is Class C fly ash from the Corette power plant in Billings, MT, the specific objectives of this project were threefold: 1) to identify additional fly ashes that could be used in 100 percent fly ash concretes, 2) to develop fly ash concrete mixtures with entrained air (which is a proven mechanism to improve freeze-thaw resistance in traditional concretes), and 3) to determine the durability of these concretes under various environments. Three fly ashes similar in composition and production to the Corette fly ash were screened as potential binders in 100 percent fly ash concrete, namely, fly ashes from the Port Neal (Sioux City, IA), Dave Johnston (Glenrock, WY), and Council Bluffs (Council Bluffs, IA) power plants. Based on laboratory trial mixtures, concretes made with the Port Neal and Dave Johnston fly ashes had properties similar to those obtained using the Corette ash (e.g., 28-day compressive strength approaching 4,000 psi), and the Dave Johnston ash was selected for further consideration in addition to the Corette ash. Entrained air appeared to be readily induced in the Corette concrete using a commercial admixture. This entrained air had little effect on the workability of the fresh concrete, while it noticeably decreased the strength of the hardened concrete. From a durability perspective, the freeze-thaw resistance of the Corette fly ash concrete (determined following ASTM C666) is promising, while there may be concerns about the performance of the Dave Johnston concrete (these tests are ongoing). Relative to alkali silica reaction (ASR), both the Corette and the Dave Johnston concretes exhibited very little reactivity when tested following the test method described in ASTM C 1260. The sulfate resistance test (ASTM C1012) is of relatively long duration, and no meaningful results were obtained by the time this report was prepared (these tests are ongoing). Relative to hydrogen sulfide/microbial related deterioration of fly ash concrete, no significant corrosion was seen in samples exposed for approximately 2 ½ months to a sulfur enriched, wastewater-based microbial environment..