gebhart/patrepeval huggingface dataset:
Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2activation ofEP3andEP4receptors (2015)

The blood-brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14-cis-eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n-6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell(®) inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2 ), an eicosanoid known to facilitate opening of the blood-brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein-labeled dextran from apical to basolateral medium. ARA-mediated permeability was attenuated by specific cyclooxygenase-2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA-mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA. The blood-brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell(®) plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part, through increased prostaglandin E2 production from ARA which acted upon EP3 and EP4 receptors to increase HBMEC monolayer permeability.
Novel pathophysiological aspects of macrophage migration inhibitory factor (review). (1998)

Macrophage migration inhibitory factor (MIF) was the first T-cell-derived soluble lymphokine to be identified. It was originally found to inhibit the migration of macrophages and activate them at inflammatory loci. During the past few years, however, previously unrecognized properties of MIF have been discovered. It also functions, for example, as a pituitary hormone, glucocorticoid-induced immunomodulator and isomerase. We cloned rat MIF cDNA and reported that the nucleotide sequence of the cDNA predicts a protein consisting of 114 amino acids. Northern blot analysis indicated that the MIF mRNA was expressed in a wide variety of organs, including the brain, kidney, and liver. Following this, we demonstrated definitively that MIF was expressed in a variety of cells, suggesting its involvement in various biological events such as wound healing, atopic dermatitis, and, possibly, diabetes/obesity. Furthermore, we elucidated its physicochemical properties, including the tertiary structures of both human and rat MIF. These tertiary structures showed that this protein forms a homotrimer with each monomer consisting of two beta/alpha/beta motifs, thus resembling 5-carboxymethyl-2-hydroxymuconate isomerase and d-dopachrome tautomerase. From the available data on MIF, including ours, it is considered that the protein is associated not only with immune responses but also with cell growth and differentiation during wound repair and carcinogenesis. Thus, MIF could become a major target protein in a variety of pathophysiological states and anti-MIF antibodies and antagonists could be applied therapeutically in the clinical situation for treatment of various diseases. Bearing this in mind, this review discusses the role of MIF, considering its gene and protein structures as well as its pathophysiological functions in various organs and disease states, finally considering perspectives for the future.
Lentiviral-Mediated Interleukin-4 and Interleukin-13 RNA Interference Decrease Airway Inflammation and Hyperresponsiveness (2011)

Interleukin (IL)-4 and IL-13 are two key cytokines released from activated T helper type 2 (Th2) cells and strongly associated with asthma and allergic disease. We applied silencing of the IL-4 and IL-13 gene expression by RNA interference delivered by a lentiviral vector to evaluate the therapeutic role of IL-4 and IL13 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with ovalbumin (OVA), and one treatment of IL-4 and IL-13 shRNA lentiviral vector (Lenti-si-IL-4 and Lenti-si-IL-13) was instilled intratracheally 48 hr before challenge. After three challenges of OVA antigen, mice were assessed for airway inflammation and hyperresponsiveness. With infection of Lenti-si-IL-4 and Lenti-si-IL-13 in EL-4 cells, both RNA and protein expressions of IL-4 and IL-13 were obviously abrogated. Furthermore, intratracheal instillation of Lenti-si-IL-4 and Lenti-si-IL-13 in OVA-immunized mice resulted in a strong inhibition of local IL-4 and IL-13 cytokine release. Treatment with Lenti-si-IL-4 and Lenti-si-IL-13 successfully alleviated OVA-induced airway eosinophilia and Th2 cell cytokine release. Finally, to determine airway hyperresponsiveness by enhanced pause and pulmonary resistance in noninvasive and invasive body plethysmography, we found that administration of Lenti-si-IL-4 and Lenti-si-IL-13 markedly decreased airway hyperresponsiveness in OVA-immunized mice. These results suggest that inhibition of IL-4 and IL-13 gene expression by shRNA lentiviral vector markedly inhibits antigen-induced airway inflammation and hyperresponsiveness in mice.
Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial (2006)

We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m(2) intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m(2) intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.
Cytochrome P450s in the Regulation of Cellular Retinoic Acid Metabolism (2011)

The active metabolite of vitamin A, retinoic acid (RA), is a powerful regulator of gene transcription. RA is also a therapeutic drug. The oxidative metabolism of RA by certain members of the cytochrome P450 (CYP) superfamily helps to maintain tissue RA concentrations within appropriate bounds. The CYP26 family--CYP26A1, CYP26B1, and CYP26C1--is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns. The CYP26A1 gene is regulated by multiple RA response elements. CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development. Enzyme kinetic studies have demonstrated that several CYP proteins are capable of metabolizing at-RA; however, it is likely that CYP26A1 plays a major role in RA clearance. Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future.
Upscaling of polymer solar cell fabrication using full roll-to-roll processing (2010)

Upscaling of the manufacture of polymer solar cells is detailed with emphasis on cost analysis and practical approach. The device modules were prepared using both slot-die coating and screen printing the active layers in the form of stripes that were serially connected. The stripe width was varied and the resultant performance analysed. Wider stripes give access to higher geometric fill factors and lower aperture loss while they also present larger sheet resistive losses. An optimum was found through preparation of serially connected stripes having widths of 9, 13 and 18 mm with nominal geometric fill factors (excluding bus bars) of 50, 67 and 75% respectively. In addition modules with lengths of 6, 10, 20, 22.5 and 25 cm were explored. The devices were prepared by full roll-to-roll solution processing in a web width of 305 mm and roll lengths of up to 200 m. The devices were encapsulated with a barrier material in a full roll-to-roll process using standard adhesives giving the devices excellent stability during storage and operation. The total area of processed polymer solar cell was around 60 m2 per run. The solar cells were characterised using a roll-to-roll system comprising a solar simulator and an IV-curve tracer. After characterisation the solar cell modules were cut into sheets using a sheeting machine and contacted using button contacts applied by crimping. Based on this a detailed cost analysis was made showing that it is possible to prepare complete and contacted polymer solar cell modules on this scale at an area cost of 89 euro m(-2) and an electricity cost of 8.1 euro Wp(-1). The cost analysis was separated into the manufacturing cost, materials cost and also the capital investment required for setting up a complete production plant on this scale. Even though the cost in euro Wp(-1) is comparable to the cost for electricity using existing technologies the levelized cost of electricity (LCOE) is expected to be significantly higher than the existing technologies due to the inferior operational lifetime. The presented devices are thus competitive for consumer electronics but ill-suited for on-grid electricity production in their current form.
Sialic acid contents in chicken eggs and tissues (1994)

Sialic acid contents were determined as potential commercial sources in egg fractions (yolk, white, chalaza, yolk membrane and shell membrane), oviduct, and rooster comb and wattle tissues by the periodate–thiobarbituric acid method with a partial modification. In egg fractions, the concentration of sialic acid was highest (P &lt; 0.05) in yolk membrane (13.7 ± 0.5 μg mg −1 ), higher (P &lt; 0.05) in chalaza (5.1 ± 0.2 μg mg −1 ) and yolk (5.2 ± 0.4 μg mg −1 ) than in white (2.2 ± 0.3 μg mg −1 ), and lowest (P &lt; 0.05) in shell membrane (0.6 ± 0.1 μg mg −1 ). In oviduct, the concentration of sialic acid was lower (P &lt; 0.05) in magnum (3.7 ± 0.6 μg mg −1 ) than in the remaining regions, among which the concentration was similar (5.6 ± 0.3 μg mg −1 ). The sialic acid concentration was similar in comb and wattle tissues (2.6 ± 0.4 μg mg −1 ). Sialic acid containing glycopeptide fractions were isolated from yolk, white, and comb and wattle tissues by papain proteolysis and gel chromatography. Key words: Sialic acid, egg, oviduct, comb, wattle
Is epinephrine administration by sublingual tablet feasible for the first‐aid treatment of anaphylaxis? A proof‐of‐concept study (2002)

HPLC-high performance liquid chromatography; EC - electrochemical detection; C(max) - maximum plasma epinephrine concentration after dosing; t(max) - time of maximum plasma epinephrine concentration.
Lipids and ultrastructure of Thraustochytrium sp. ATCC 26185 (1997)

As a representative of a genus with species considered to be potential commercial producers of the nutritionally important polyunsaturated fatty acid docosahexaenoic acid (DHA), Thraustochytrium sp. ATCC 26185 was investigated to determine its potential for DHA production and lipid composition. Cells from liquid shake cultures contained 32% (w/w) lipid, 18% of which was nonsaponifiable lipid. The major saturated fatty acids (14:0 and 16:0) comprised up to 59% of the total fatty acids, and DHA was up to 25% after 6 d incubation. Squalene represented 63% of the nonsaponifiable lipid, and cholesterol composed 41% of the total sterols. The phospholipids expected for eucaryotic microbes were detected with phosphatidylcholine as the major phospholipid at 76% of the total. The ultrastructure of this species was similar to other Thraustochytrium species except that the cells did not have surface scales and they contained unusual membrane-like structures that appeared to be associated with oil formation.
Ribosome display efficiently selects and evolves high-affinity antibodiesin vitrofrom immune libraries (1998)

Ribosome display was applied for affinity selection of antibody single-chain fragments (scFv) from a diverse library generated from mice immunized with a variant peptide of the transcription factor GCN4 dimerization domain. After three rounds of ribosome display, positive scFvs were isolated and characterized. Several different scFvs were selected, but those in the largest group were closely related to each other and differed in 0 to 5 amino acid residues with respect to their consensus sequence, the likely common progenitor. The best scFv had a dissociation constant of (4 +/- 1) x 10(-11) M, measured in solution. One amino acid residue in complementarity determining region L1 was found to be responsible for a 65-fold higher affinity than the likely progenitor. It appears that this high-affinity scFv was selected from the mutations occurring during ribosome display in vitro, and that this constitutes an affinity maturation inherent in this method. The in vitro-selected scFvs could be functionally expressed in the Escherichia coli periplasm with good yields or prepared by in vitro refolding. Thus, ribosome display can be a powerful methodology for in vitro library screening and simultaneous sequence evolution.
Interaction of the glucocorticoid receptor DNA-binding domain with DNA as a dimer is mediated by a short segment of five amino acids. (1991)

We have previously shown that protein-protein interactions mediate cooperative binding of the glucocorticoid receptor DNA-binding domain to a glucocorticoid response element (Dahlman-Wright, K., Siltala-Roos, H., Carlstedt-Duke, J., and Gustafsson, J.-A. (1990) J. Biol. Chem. 265, 14030-14035). The cooperativity of DNA binding is lost when the distance between the two half-sites constituting a glucocorticoid responsive element is altered or when their relative orientation is changed. We show here that mutations in the responsive element which interfere with cooperative DNA binding by the glucocorticoid receptor DNA-binding domain in vitro also abolish transactivation by the full length glucocorticoid receptor in vivo. We also identify a short segment in the proximity of one of the bound zinc ions that is required for cooperative binding of the glucocorticoid receptor DNA-binding domain to a glucocorticoid response element. We suggest that this segment is involved in dimer formation of the native glucocorticoid receptor and that it is important for correct positioning of the dimeric molecule on the double helix of DNA.
Turismo rural, ¿esperanza o ilusión?: Una aportación vista desde la perspectiva de Suiza (1991)

El turismo en Suiza ha contribuido a elevar de forma decisiva el nivel de vida de las zonas rurales alpinas. Existen destinos turisticos cuya renta per capita es francamente mas elevada que la de las aglomeraciones urbanas de la region central, esos IPC son mas altos en St. Moritz que en la capital federal, Berna. En Suiza, el mantenimiento de paisajes rurales intactos se ha convertido en un tema politico importante. El Gobierno no solo ha declarado zonas de proteccion oficial al 13 % de las zonas rurales, sino que tambien se ocupa de asegurar economicamente tales zonas.
Layered Metal Phosphonate Reinforced Poly(l-lactide) Composites with a Highly Enhanced Crystallization Rate (2009)

Layered metal phosphonate, zinc phenylphosphonate (PPZn), reinforced poly(L-lactide) (PLLA) composites were fabricated by a melt-mixing technique. The nonisothermal and isothermal crystallization, melting behavior, spherulite morphology, crystalline structure, and static and dynamic mechanical properties of the PLLA/PPZn composites were investigated. PPZn shows excellent nucleating effects on PLLA crystallization. With incorporation of 0.02% PPZn, PLLA can finish crystallization under cooling at 10 degrees C/min. The crystallization rate of PLLA further increases with increasing PPZn concentration. Upon the addition of 15% PPZn, the crystallization half-times of a PLLA/PPZn composite decrease from 28.0 to 0.33 min at 130 degrees C, and from 60.2 to 1.4 min at 140 degrees C, compared to the neat PLLA. With the presence of PPZn, the nuclei number of PLLA increases and the spherulite size reduces significantly. Through analysis of the crystal structures of PLLA and PPZn, it was proposed that the nucleation mechanism of the PLLA/PPZn system is epitaxial nucleation. The incorporation of PPZn has no discernible effect on the crystalline structure of PLLA. Moreover, PPZn has good reinforcement effects on the PLLA matrix. The tensile strength of the composite is enhanced with the addition of a relatively small amount of PPZn (<5%). The tensile and storage moduli of composites increase with increasing PPZn loadings, and they respectively improve by 28% and 34% with the incorporation of a 15% PPZn filler, as compared to the neat PLLA.
Potential of the Antibody Against cis–Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury (2016)

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic trans conformation, thereby restoring ptau function. The recent development of antibodies able to distinguish and eliminate both conformations specifically has led to the discovery of cis-ptau as a precursor of tau-induced pathologic change and an early driver of neurodegeneration that directly links TBI to CTE and possibly to AD. Within hours of TBI in mice or neuronal stress in vitro, neurons prominently produce cis-ptau, which causes and spreads cis-ptau pathologic changes, termed cistauosis. Cistauosis eventually leads to widespread tau-mediated neurodegeneration and brain atrophy. Cistauosis is effectively blocked by the cis-ptau antibody, which targets intracellular cis-ptau for proteasome-mediated degradation and prevents extracellular cis-ptau from spreading to other neurons. Treating TBI mice with cis-ptau antibody not only blocks early cistauosis but also prevents development and spreading of tau-mediated neurodegeneration and brain atrophy and restores brain histopathologic features and functional outcomes. Thus, cistauosis is a common early disease mechanism for AD, TBI, and CTE, and cis-ptau and its antibody may be useful for early diagnosis, treatment, and prevention of these devastating diseases.
The Human Factor H-related Protein 4 (FHR-4) (1997)

A novel apoprotein of an apparent molecular mass of 86 kDa in its unreduced form was identified in human triglyceride-rich lipoproteins. This protein was purified and the amino acid sequence of six proteolytic fragments was found to overlap with that of the factor H-related proteins. In parallel we identified the cDNA encoding a new complement factor H-related protein, termed FHR-4. The sequences of the new apoprotein overlapped with that of the FHR-4 protein. Similar to the previously described factor H-related proteins, FHR-4 contains a hydrophobic signal sequence followed by a stretch of five repetitive elements termed short consensus repeats. Recombinant FHR-4 protein was expressed in the baculovirus system and has an apparent molecular mass of 42 kDa. In addition a 84-kDa dimeric form of the recombinant FHR-4 was detected. Using an immunoaffinity column with antibodies raised against the recombinant FHR-4, we isolated a 86-kDa protein from human plasma. The different molecular mass of the recombinant FHR-4 and the dimeric FHR-4 in plasma is due to different carbohydrate moieties. The 86-kDa plasma protein and the novel apolipoprotein had identical mobility on SDS-polyacrylamide gel electrophoresis analysis and reacted with antisera raised against the reFHR-4 and the purified apoprotein. In conclusion, we have identified a novel factor H-related protein, FHR-4, in human plasma and demonstrate that this protein is present in triglyceride-rich lipoproteins in a dimeric form. This observation provides an intriguing new aspect on possible function(s) of this novel protein and the other factor H-related proteins.
The Yeast Iron Regulatory Proteins Grx3/4 and Fra2 Form Heterodimeric Complexes Containing a [2Fe-2S] Cluster with Cysteinyl and Histidyl Ligation (2009)

The transcription of iron uptake and storage genes in Saccharomyces cerevisiae is primarily regulated by the transcription factor Aft1. Nucleocytoplasmic shuttling of Aft1 is dependent upon mitochondrial Fe-S cluster biosynthesis via a signaling pathway that includes the cytosolic monothiol glutaredoxins (Grx3 and Grx4) and the BolA homologue Fra2. However, the interactions between these proteins and the iron-dependent mechanism by which they control Aft1 localization are unclear. To reconstitute and characterize components of this signaling pathway in vitro, we have overexpressed yeast Fra2 and Grx3/4 in Escherichia coli. We have shown that coexpression of recombinant Fra2 with Grx3 or Grx4 allows purification of a stable [2Fe-2S](2+) cluster-containing Fra2-Grx3 or Fra2-Grx4 heterodimeric complex. Reconstitution of a [2Fe-2S] cluster on Grx3 or Grx4 without Fra2 produces a [2Fe-2S]-bridged homodimer. UV-visible absorption and CD, resonance Raman, EPR, ENDOR, Mossbauer, and EXAFS studies of [2Fe-2S] Grx3/4 homodimers and the [2Fe-2S] Fra2-Grx3/4 heterodimers indicate that inclusion of Fra2 in the Grx3/4 Fe-S complex causes a change in the cluster stability and coordination environment. Taken together, our analytical, spectroscopic, and mutagenesis data indicate that Grx3/4 and Fra2 form a Fe-S-bridged heterodimeric complex with Fe ligands provided by the active site cysteine of Grx3/4, glutathione, and a histidine residue. Overall, these results suggest that the ability of the Fra2-Grx3/4 complex to assemble a [2Fe-2S] cluster may act as a signal to control the iron regulon in response to cellular iron status in yeast.