gebhart/patrepeval huggingface dataset:
Immunological adjuvants in allergy vaccines: Past, present future (2001)

Hundreds of compounds have been tested over the years in a search for adjuvants to incorporate with antigens or allergens to enhance the immune response. Despite this, aluminum salts have been the only adjuvants that have been both registered for clinical application and used on a large scale until recently. Salts of aluminum, such as aluminum hydroxide, have been used as general immunologic adjuvants for several decades. Some allergen vaccines used for the treatment of allergy are still formulated with aluminum-based adjuvants. These formulations have generally proved efficacious and have a good safety profile compared with simple aqueous extracts. However, there is reported sensitivity and toxicity associated with use of aluminum. In addition, aluminum salts are known to be potent stimulators of T helper (h) 2 cell activity. Because Th2 activity directs towards an allergic response, aluminum salts are potentially counterproductive when used as adjuvants in the immunologic treatment of type 1 hypersensitivity. Many soluble and insoluble molecules have been reported to have adjuvant activity in experimental systems. Some of these have been used clinically, but side effects, such as local granuloma formation, have led to their withdrawal from clinical use. Newer depot-type adjuvants, such as insoluble calcium salts, tyrosine (now registered) and coupled alginates, may eliminate some of the potential problems of aluminum salts and are currently used in some allergy vaccines but have not as yet formed a complete replacement. Liposomes, iscoms and biodegradable microspheres are now being considered for clinical use as adjuvants for both oral and parenteral routes. Soluble adjuvants that are capable of directing the immune response in a more selective way are currently in development for use in allergy vaccines. One of these, the Th1-directing adjuvant monophosphoryl lipid A (MPL®; Corixa, Seattle, WA, USA), is now in clinical use in allergy vaccines formulated with the depot adjuvant L-tyrosine. Other ways of stimulating a Th 1 response using immunostimulatory DNA sequences (immunostimulatory DNA sequences (ISS) or CpG motifs) as 'built-in' adjuvants are being studied. Further interesting adjuvants reported in the literature, such as Montanide ISA 720, SAF-m, RC-529 and QS21, may also be applicable to allergy vaccination.
Cell Surface Labeling of Escherichia coli via Copper(I)-Catalyzed [3+2] Cycloaddition (2003)

Labeling of the cell surface of Escherichia coli was accomplished by expression of a recombinant outer membrane protein, OmpC, in the presence of the unnatural amino acid azidohomoalanine, which acts as a methionine surrogate. The surface-exposed azide moieties of whole cells were biotinylated via Cu(1)-catalyzed [3+2] azide-alkyne cycloaddition. The specificity of labeling of both wild-type OmpC and a mutant containing additional methionine sites for azidohomoalanine incorporation was confirmed by Western blotting. Flow cytometry was performed to examine the specificity of the labeling. Cells that express the mutant form of OmpC in the presence of azidohomoalanine, which were biotinylated and stained with fluorescent avidin, exhibit a mean fluorescence 10-fold higher than the background. Incorporation of an unnatural amino acid can thus be determined on a single-cell basis.
Two CACGTG Motifs with Proper Spacing Dictate the Carbohydrate Regulation of Hepatic Gene Transcription (1995)

Regulatory sequences involved in the transcriptional induction of the rat S14 gene in response to increased glucose metabolism in the hepatocyte were investigated and compared with those of the liver-type pyruvate kinase (L-PK) gene. The carbohydrate response element (ChoRE) of the S14 gene was found to consist of two motifs related to the consensus binding site for the c-myc family of transcription factors, CACGTG. These two motifs are separated by five base pairs, a similar arrangement to that found in the L-PK ChoRE. In its natural context, the S14 ChoRE requires a novel accessory factor to support the full response glucose. This factor, as well as the factor hepatic nuclear factor-4, are both capable of binding to the L-PK gene to enhance its carbohydrate regulation. The need for an accessory factor for supporting the glucose response can be overcome in two ways. First, multimers of the ChoREs of either the L-PK or S14 genes can function independently to support the glucose response. Second, mutations in the S14 ChoRE that create a perfect match to the consensus CACGTG motif at each locus no longer require an accessory factor site. The spacing of the two CACGTG motifs, but not the nature of the bases within the spacer, are critical for control. These observations suggest that a carbohydrate responsive factor binds to both motifs in a highly specific spatial orientation to confer the response to increased carbohydrate metabolism.
Efficient excision of phage lambda from the Escherichia coli chromosome requires the Fis protein (1991)

The Escherichia coli protein Fis has been shown to bind a single site in the recombination region of phage lambda and to stimulate excisive recombination in vitro (J. F. Thompson, L. Moitoso de Vargas, C. Koch, R. Kahmann, and A. Landy, Cell 50:901-908, 1987). We demonstrate that mutant strains deficient in fis expression show dramatically reduced rates of lambda excision in vivo. Phage yields after induction of a stable lysogen are reduced more than 200-fold in fis cells. The defect observed in phage yield is not due to inefficient phage replication or lytic growth. Direct examination of excisive recombination products reveals a severe defect in the rate of recombination in the absence of Fis. The excision defect observed in fis cells can be fully reproduced in fis+ cells by using phages that lack the Fis binding site on attR, indicating that the entire stimulatory effect of Fis on excisive recombination is due to binding at that site.
KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer (2017)

Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of <i>KEAP1</i>, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.
Intracellular Ca2+ stores in chicken Purkinje neurons: differential distribution of the low affinity-high capacity Ca2+ binding protein, calsequestrin, of Ca2+ ATPase and of the ER lumenal protein, Bip. (1991)

To identify intracellular Ca2+ stores, we have mapped (by cryosection immunofluorescence and immunogold labeling) the distribution in the chicken cerebellar cortex of an essential component, the main low affinity-high capacity Ca2+ binding protein which in this tissue has been recently shown undistinguishable from muscle calsequestrin (Volpe, P., B. H. Alderson-Lang, L. Madeddu, E. Damiani, J. H. Collins, and A. Margreth. 1990. Neuron. 5:713-721). Appreciable levels of the protein were found exclusively within Purkinje neurons, distributed to the cell body, the axon, and the elaborate dendritic tree, with little labeling, however, of dendritic spines. At the EM level the protein displayed a dual localization: within the ER (rough- and smooth-surfaced cisternae, including the cisternal stacks recently shown [in the rat] to be highly enriched in receptors for inositol 1,4,5-triphosphate) and, over 10-fold more concentrated, within a population of moderately dense, membrane-bound small vacuoles and tubules, identified as calciosomes. These latter structures were widely distributed both in the cell body (approximately 1% of the cross-sectional area, particularly concentrated near the Golgi complex) and in the dendrites, up to the entrance of the spines. The distribution of calsequestrin was compared to those of another putative component of the Ca2+ stores, the membrane pump Ca2+ ATPase, and of the ER resident lumenal protein, Bip. Ca2+ ATPase was expressed by both calciosomes and regular ER cisternae, but excluded from cisternal stacks; Bip was abundant within the ER lumena (cisternae and stacks) and very low within calciosomes (average calsequestrin/Bip immunolabeling ratios were approximately 0.5 and 36.5 in the two types of structure, respectively). These results suggest that ER cisternal stacks do not represent independent Ca2+ stores, but operate coordinately with the adjacent, lumenally continuous ER cisternae. The ER and calciosomes could serve as rapidly exchanging Ca2+ stores, characterized however by different properties, in particular, by the greater Ca2+ accumulation potential of calciosomes. Hypotheses of calciosome biogenesis (directly from the ER or via the Golgi complex) are discussed.
Palmitic and linoleic acids induce ER stress and apoptosis in hepatoma cells (2012)

The results suggest that linoleic acid promotes cell apoptosis through the release of cytochrome C, only if the intracellular calcium flux is unperturbed and intact. These results confirm that ER stress contributes to fatty acid-induced liver cell apoptosis.
The Anti‐Inflammatory Actions of Antithrombin – A Review (2002)

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.
N-Glycosylation as Novel Strategy to Improve Pharmacokinetic Properties of Bispecific Single-chain Diabodies (2008)

The therapeutic efficacy of recombinant antibodies such as single-chain Fv fragments and small bispecific or bifunctional molecules is often limited by rapid elimination from the circulation because of their small size. Here, we have investigated the effects of N-glycosylation on the activity and pharmacokinetics of a small bispecific single-chain diabody (scDb CEACD3) developed for the retargeting of cytotoxic T cells to CEA-expressing tumor cells. We could show that the introduction of N-glycosylation sequons into the flanking linker and a C-terminal extension results in the production of N-glycosylated molecules after expression in transfected HEK293 cells. N-Glycosylated scDb variants possessing 3, 6, or 9 N-glycosylation sites, respectively, retained antigen binding activity and bispecificity for target and effector cells as shown in a target cell-dependent IL-2 release assay, although activity was reduced approximately 3-5-fold compared with the unmodified scDb. All N-glycosylated scDb variants exhibited a prolonged circulation time compared with scDb, leading to a 2-3-fold increase of the area under curve (AUC). In comparison, conjugation of a branched 40-kDa PEG chain increased AUC by a factor of 10.6, while a chimeric anti-CEA IgG1 molecule had the longest circulation time with a 17-fold increase in AUC. Thus, N-glycosylation complements the repertoire of strategies to modulate pharmacokinetics of small recombinant antibody molecules by an approach that moderately prolongs circulation time.
Coupled resonator filters (2003)

Coupled Resonator Filters (CRF) are a new form of bulk acoustic wave device that involves the vertical stacking of resonators. In that regard, the CRF can be thought of as a variation on the better known Stacked Crystal Filter (SCF). This paper will review the SCF and expand on the basic concepts of the CRF. Experimental results will be shown for SCFs operating to 12 GHz and CRFs near 3 GHz. Manufacturing issues associated with both filter types will be reviewed with greater emphasis on the CRF.
Stable Expression and Secretion of Apolipoproteins E3 and E4 in Mouse Neuroblastoma Cells Produces Differential Effects on Neurite Outgrowth (1995)

Previously, we demonstrated in cultured dorsal root ganglion neurons that, in the presence of beta-migrating very low density lipoproteins (beta-VLDL), apolipoprotein (apo) E4, but not apoE3, suppresses neurite outgrowth. In the current studies, murine neuroblastoma cells (Neuro-2a) were stably transfected with human apoE3 or apoE4 cDNA, and the effect on neurite outgrowth was examined. The stably transfected cells secreted nanogram quantities of apoE (44-89 ng/mg of cell protein in 48 h). In the absence of lipoproteins, neurite outgrowth was similar in the apoE3- and apoE4-secreting cells. The apoE4-secreting cells, when incubated with beta-VLDL, VLDL, cerebrospinal fluid lipoproteins (d < 1.21 g/ml), or with triglyceride/phospholipid (2.7:1 (w/w)) emulsions, showed a reduction in the number of neurites/cell, a decrease in neurite branching, and an inhibition of neurite extension, whereas in the apoE3-secreting cells in the presence of a lipid source, neurite extension was increased. Uptake of beta-VLDL occurred to a similar extent in both the apoE3- and apoE4-secreting cells. With low density lipoproteins or with dimyristoylphosphatidylcholine emulsions, either alone or complexed with cholesterol, no differential effect on neurite outgrowth was observed. A slight differential effect was observed with apoE-containing high density lipoproteins. The differential effect of apoE3 and apoE4 in the presence of beta-VLDL was blocked by incubation of the cells with heparinase and chlorate, with lactoferrin, or with receptor-associated protein, all of which prevent the uptake of lipoproteins by the low density lipoprotein receptor-related protein (LRP). The data suggest that the secreted and/or cell surface-bound apoE interact with the lipoproteins and facilitate their internalization via the heparan sulfate proteoglycan-LRP pathway. The mechanism by which apoE3 and apoE4 exert differential effects on neurite outgrowth remains speculative. However, the data suggest that apoE4, which has been shown to be associated with late onset familial and sporadic Alzheimer's disease, may inhibit neuronal remodeling and contribute to the progression of the disease.
A novel AC photovoltaic module system based on the impedance-admittance conversion theory (2002)

A novel photovoltaic (PV) power generation system based on impedance-admittance conversion theory is described in this paper. AC photovoltaic module systems (AC modules) have attracted interest for their application in PV power generation systems. An AC module has an integrated inverter that allows the module to supply AC power to the utility power line. One distinctive feature of system proposed in this paper is that the output current supplied to the utility line has a similar waveform to the utility voltage, and is proportional only to the output voltage of the voltage source inverter on the AC module. This effect is achieved through use of the impedance-admittance conversion theory, by which the voltage source is converted to the current source, and vice versa. Therefore, in the proposed system, the output current supplied to the utility line can be controlled without being affected by the utility line voltage. Hence, it is not necessary to use current feedback control. The effectiveness of the proposed system is confirmed through simulations and experiments.
Greater focus needed on methane leakage from natural gas infrastructure (2012)

Natural gas is seen by many as the future of American energy: a fuel that can provide energy independence and reduce greenhouse gas emissions in the process. However, there has also been confusion about the climate implications of increased use of natural gas for electric power and transportation. We propose and illustrate the use of technology warming potentials as a robust and transparent way to compare the cumulative radiative forcing created by alternative technologies fueled by natural gas and oil or coal by using the best available estimates of greenhouse gas emissions from each fuel cycle (i.e., production, transportation and use). We find that a shift to compressed natural gas vehicles from gasoline or diesel vehicles leads to greater radiative forcing of the climate for 80 or 280 yr, respectively, before beginning to produce benefits. Compressed natural gas vehicles could produce climate benefits on all time frames if the well-to-wheels CH(4) leakage were capped at a level 45-70% below current estimates. By contrast, using natural gas instead of coal for electric power plants can reduce radiative forcing immediately, and reducing CH(4) losses from the production and transportation of natural gas would produce even greater benefits. There is a need for the natural gas industry and science community to help obtain better emissions data and for increased efforts to reduce methane leakage in order to minimize the climate footprint of natural gas.
Evidence in vivo for induction of cardiovascular growth processes by vasoconstrictor systems. (1995)

Greater smooth muscle growth is an important feature of the changes in blood vessel morphology in hypertension. The increase in vessel wall thickness: lumen ratio resulting from vascular hypertrophy impacts directly on total peripheral vascular resistance thereby influencing the severity of hypertension. The roles played by mechanical forces, vasoactive substances, growth factors and endocrine hormones in mediating hypertrophic vascular growth responses in vivo are currently under investigation. Here we review our current research aimed at: (a) defining the roles in vivo, of the renin-angiotensin system (RAS) and sympathetic nervous system (SNS), in the development of cardiovascular hypertrophy; (b) defining the importance of endogenous vasodilator systems, in particular, the ability of nitric oxide to inhibit trophic responses induced by the RAS and SNS and (c) examining whether trophic stimulation via the two neurohumoral systems as well as the antitrophic activity of the vasodilator systems is in part dependent on changes in blood pressure. In these studies the obligatory enzyme ornithine decarboxylase has proved to be a useful marker of ongoing hypertrophic cardiovascular growth.
Production of Monoclonal Antibody SP-21 to Colon-Ovarian Tumor Antigen, COTA (1986)

An IgG monoclonal antibody, SP-21, directed against colon-ovarian tumor antigen, COTA, is reported. The antibody had no reactivity with CEA, normal colonic mucin, CSAp, ABO blood group antigens, or with normal human lung, liver, spleen, kidney, plasma and saliva in studies using the enzyme-linked immunoassay method (ELISA). Immunoperoxidase staining of colon, lung, kidney, and prostate cancer tissues and benign and inflammatory colon disease tissues revealed a specificity identical to that of the polyclonal (goat) anti-COTA antibodies.
The role of link-protein in the structure of cartilage proteoglycan aggregates (1979)

Proteoglycan fractions were prepared from pig laryngeal cartilage. The effect of link-protein on the properties of proteoglycan-hyaluronate aggregates was examined by viscometry and analytical ultracentrifugation. Aggregates containing link-protein were more stable than link-free aggregates at neutral pH, at temperatures up to 50 degrees C and in urea (up to 4.0M). Oligosaccharides of hyaluronate were able to displace proteoglycans from link-free aggregates, but not from the link-stabilized aggregates. Both types of aggregate were observed in the ultracentrifuge, but at the concentration investigated (less than 2 mg/ml) the link-free form was partially dissociated and the proportion aggregated varied with the pH and temperature and required more hyaluronate for saturation than did link-stabilized aggregate. The results showed that link-protein greatly strengthened the binding of proteoglycans to hyaluronate and suggest that under physiological conditions it ‘locks’ proteoglycans on to the hyaluronate chain.
Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties (2002)

MLL (mixed lineage leukemia; also ALL-1 or HRX) is a proto-oncogene that is mutated in a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. Here we demonstrate that MLL (mixed lineage leukemia) is proteolytically processed into 2 fragments (MLL(N) and MLL(C)) that display opposite transcriptional properties and form an intramolecular MLL complex in vivo. Proteolytic cleavage occurs at 2 amino acids (D2666 and D2718) within a consensus processing sequence (QXD/GZDD, where X is a hydrophobic amino acid and Z is an alanine or a valine) that is conserved in TRX, the Drosophila homolog of MLL, and in the MLL-related protein MLL2, suggesting that processing is important for MLL function. Processed MLL(N) and MLL(C) associate with each other via N-terminal (1253-2254 amino acids) and C-terminal (3602-3742 amino acids) intramolecular interaction domains. MLL processing occurs rapidly within a few hours after translation and is followed by the phosphorylation of MLL(C). MLL(N) displays transcriptional repression activity, whereas MLL(C) has strong transcriptional activation properties. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLL(C). These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions.
Physiological changes of Salmonella typhimurium cells under osmotic and starvation conditions by image analysis (1999)

The effects of starvation and salinity on the physiology of Salmonella typhimurium were investigated in a microcosm study. The physiological changes were monitored by using fluorochromes dyes such as DAPI (4′,6-diamidino-2-phenylindole) for evaluation of the genomic content, CTC (5-cyano-2,3-ditolyl tetrazolium chloride) for respiratory activity and syto 9 and propidium iodide for cytoplasmic membrane damages. The metabolic activity of the cellular population was assessed with the method of Kogure (direct viable count), to enumerate the substrate-responsive cells. These different staining procedures were objectively analysed by an image analysis system. This paper describes the progressive alteration of Salmonella typhimurium physiology under salinity and starvation conditions.