gebhart/patrepeval huggingface dataset:
Glycan-Dependent Immunogenicity of Recombinant Soluble Trimeric Hemagglutinin (2012)

Recombinant soluble trimeric influenza A virus (IAV) hemagglutinin (sHA(3)) has proven an effective vaccine antigen against IAV. Here, we investigate to what extent the glycosylation status of the sHA(3) glycoprotein affects its immunogenicity. Different glycosylation forms of subtype H5 trimeric HA protein (sH5(3)) were produced by expression in insect cells and different mammalian cells in the absence and presence of inhibitors of N-glycan-modifying enzymes or by enzymatic removal of the oligosaccharides. The following sH5(3) preparations were evaluated: (i) HA proteins carrying complex glycans produced in HEK293T cells; (ii) HA proteins carrying Man(9)GlcNAc(2) moieties, expressed in HEK293T cells treated with kifunensine; (iii) HA proteins containing Man(5)GlcNAc(2) moieties derived from HEK293S GnTI(-) cells; (iv) insect cell-produced HA proteins carrying paucimannosidic N-glycans; and (v) HEK293S GnTI(-) cell-produced HA proteins treated with endoglycosidase H, thus carrying side chains composed of only a single N-acetylglucosamine each. The different HA glycosylation states were confirmed by comparative electrophoretic analysis and by mass spectrometric analysis of released glycans. The immunogenicity of the HA preparations was studied in chickens and mice. The results demonstrate that HA proteins carrying terminal mannose moieties induce significantly lower hemagglutination inhibition antibody titers than HA proteins carrying complex glycans or single N-acetylglucosamine side chains. However, the glycosylation state of the HA proteins did not affect the breadth of the antibody response as measured by an HA1 antigen microarray. We conclude that the glycosylation state of recombinant antigens is a factor of significant importance when developing glycoprotein-based vaccines, such as recombinant HA proteins.
Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand (2014)

IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (Kd = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets.
Human Endotoxemia as a Model of Systemic Inflammation (2008)

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.
New concepts in pharmacological efficacy at 7TMreceptors:IUPHAR Review 2 (2012)

The present-day concept of drug efficacy has changed completely from its original description as the property of agonists that causes tissue activation. The ability to visualize the multiple behaviours of seven transmembrane receptors has shown that drugs can have many efficacies and also that the transduction of drug stimulus to various cellular stimulus-response cascades can be biased towards some but not all pathways. This latter effect leads to agonist 'functional selectivity', which can be favourable for the improvement of agonist therapeutics. However, in addition, biased agonist potency becomes cell type dependent with the loss of the monotonic behaviour of stimulus-response mechanisms, leading to potential problems in agonist quantification. This has an extremely important effect on the discovery process for new agonists since it now cannot be assumed that a given screening or lead optimization assay will correctly predict therapeutic behaviour. This review discusses these ideas and how new approaches to quantifying agonist effect may be used to circumvent the cell type dependence of agonism. This article, written by a corresponding member of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), reviews our current understanding of the interaction of ligands with seven transmembrane receptors. Further information on these pharmacological concepts is being incorporated into the IUPHAR/BPS database GuideToPharmacology.org.
Real-Time Change Point Detection with Application to Smart Home Time Series Data (2018)

Change Point Detection (CPD) is the problem of discovering time points at which the behavior of a time series changes abruptly. In this paper, we present a novel real-time nonparametric change point detection algorithm called SEP, which uses Separation distance as a divergence measure to detect change points in high-dimensional time series. Through experiments on artificial and real-world datasets, we demonstrate the usefulness of the proposed method in comparison with existing methods.
A Small Arterial substitute (1975)

Eighty-nine grafts of expanded microporous polytetrafluoroethylene (PTFE) with a diameter of 4 mm, were placed in the carotid and femoral arteries of dogs. The animals were sacrificed at varying intervals beginning three days after operation. Four animals remain alive with patent grafts 10 months post-operatively. Twenty-four of 89 grafts were occluded, an overall patency of 73%. Fibril length (pore size) of the graft material was varied from 4 to 110 microns. Average pore size ranged from 9 to 65 microns. Wall thickness varied from 0.3 to 0.75 mm. Density ranged from 0.24 to 0.35 g/ml. Tissue ingrowth, neointimization and patency rate as compared to pore size, wall-thickness and density of expanded PTFE were observed. Pore size is the primary determinant of tissue ingrowth, neointimization and patency. Of 51 grafts with an average pore size of 22 microns or less, there were 6 occlusions, an 88% patency rate. There were 38 grafts with an average pore size of 34 microns or greater. In these 38 grafts, 18 occlusions were observed, a 53% patency rate. Patent grafts demonstrated tissue ingrowth, capillary formation an a thin neointima. Using small pore grafts, patency rates of 90% can be anticipated in the dog. Expanded microporous PTFE with its ease of handling, strength and pliability may be the vascular prosthesis of choice in man.
Unmatched projector/backprojector pairs in an iterative reconstruction algorithm (2000)

Computational burden is a major concern when an iterative algorithm is used to reconstruct a three-dimensional (3-D) image with attenuation, detector response, and scatter corrections. Most of the computation time is spent executing the projector and backprojector of an iterative algorithm. Usually, the projector and the backprojector are transposed operators of each other. The projector should model the imaging geometry and physics as accurately as possible. Some researchers have used backprojectors that are computationally less expensive than the projectors to reduce computation time. This paper points out that valid backprojectors should satisfy a condition that the projector/backprojector matrix must not contain negative eigen-values. This paper also investigates the effects when unmatched projector/backprojector pairs are used.
Surgical Results and the Diagnostic Evaluation of Renovascular Hypertension (1968)

Smith, Gardner W. M.D.; Muller, William H. Jr. M.D.; Beckwith, Julian R. M.D. Author Information
Laser noise compression by filamentation at 400 nm in argon (2007)

Filamentation is an efficient way to produce an intense and spectrally broad, but poorly stable, source for coherent control spectroscopy. We first described both theoretically and experimentally the filamentation and broadening of a 410 nm ultrashort laser pulse in Argon. By observing the theoretical and experimental spectral cross-correlation in the filament, we then show that the stability of the source can be improved. The Signal-to-Noise Ratio of the intensity inside the filament is increased up to 7 dB by its spectral filtering which provide a low noise broad spectrum source.
Regulatable Gutless Adenovirus Vectors Sustain Inducible Transgene Expression in the Brain in the Presence of an Immune Response against Adenoviruses (2005)

In view of recent serious adverse events and advances in gene therapy technologies, the use of regulatable expression systems is becoming recognized as indispensable adjuncts to successful clinical gene therapy. In the present work we optimized high-capacity adenoviral (HC-Ad) vectors encoding the novel tetracycline-dependent (TetOn)-regulatory elements for efficient and regulatable gene expression in the rat brain in vivo. We constructed two HC-Ad vectors encoding beta-galactosidase (beta-gal) driven by a TetOn system containing the rtTAS(s)M2 transactivator and the tTS(Kid) repressor under the control of the murine cytomegalovirus (mCMV) (HC-Ad-mTetON-beta-Gal) or the human CMV (hCMV) promoter (HC-Ad-hTetON-beta-Gal). Expression was tightly regulatable by doxycycline (Dox), reaching maximum expression in vivo at 6 days and returning to basal levels at 10 days following the addition or removal of Dox, respectively. Both vectors achieved higher transgene expression levels compared to the expression from vectors encoding the constitutive mCMV or hCMV promoter. HC-Ad-mTetON-beta-Gal yielded the highest transgene expression levels and expressed in both neurons and astrocytes. Antivector immune responses continue to limit the clinical use of vectors. We thus tested the inducibility and longevity of HC-Ad-mediated transgene expression in the brain of rats immunized against adenovirus by prior intradermal injections of RAds. Regulated transgene expression from HC-Ad-mTetON-beta-Gal remained active even in the presence of a significant systemic immune response. Therefore, these vectors display two coveted characteristics of clinically useful vectors, namely their regulation and effectiveness even in the presence of prior immunization against adenovirus.
LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. (2003)

Within 33 weeks of life, all 10 mammary glands of virgin BALB/c mice transgenic for the transforming rat HER-2/neu oncogene under the mammary tumor virus promoter (BALB-neuT mice) progress from atypical hyperplasia to invasive palpable carcinoma. Repeated DNA vaccination with plasmids coding for the extracellular and transmembrane domain of the protein product of rat HER-2/neu (r-p185(neu)) delayed tumor onset and reduced tumor multiplicity, but this protection eventually declined, and few mice were tumor free at 1 year of age. Association of plasmid vaccination with administration of soluble mouse LAG-3 (lymphocyte activation gene-3/CD223) generated by fusing the extracellular domain of murine LAG-3 to a murine IgG2a Fc portion (mLAG-3Ig) elicited a stronger and sustained protection that kept 70% of 1-year-old mice tumor free. Moreover, this combined vaccination, which was performed when multiple in situ carcinomas were already evident, extended disease-free survival and reduced carcinoma multiplicity. Inhibition of carcinogenesis was associated with markedly reduced epithelial cell proliferation and r-p185(neu) expression, whereas the few remaining hyperplastic foci were heavily infiltrated by reactive leukocytes. A stronger and enduring r-p185(neu)-specific cytotoxicity, a sustained release of IFN-gamma and interleukin 4, and a marked expansion of both CD8(+)/CD11b(+)/CD28(+) effector and CD8(+)/CD11b(+)/CD28(-) memory effector T-cell populations were induced in immunized mice. This combined vaccination also elicited a quicker and higher antibody response to r-p185(neu), as well as an early antibody isotype switch. These data suggest that the appropriate costimulation provided by mLAG-3Ig enables DNA vaccination to establish an effective protection, probably by enhancing cross-presentation of the DNA coded antigen.
Bisquaternary Ligands of the Common Allosteric Site of M2 Acetylcholine Receptors:  Search for the Minimum Essential Distances between the Pharmacophoric Elements (1999)

Structurally diverse molecules, such as alcuronium, gallamine, and tubocurarine as well as W84 and WDUO, are known to interact allosterically with ligand binding to muscarinic M2 acetylcholine receptors. Preliminary molecular modeling studies revealed two positive charges in the middle and two lateral aromatic areas to be essential elements of a high allosteric potency. To find out the optimum distances between these pharmacophoric elements, a systematic variation of the spacer in the series of W84, WDUO, and IWDUO compounds was performed. The allosteric reduction of the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine heart M2 receptors served as a test system. The minimal essential distance between the positive charges was found to be 10 A. The length of the peripheral spacers connecting the positive charge and the lateral aromatic moiety appears to depend on the chemical functionality; the peripheral spacers have to be long and flexible enough to position the aromatic skeletons in the spatial neighborhood of the alkane middle chain: in the case of an oxime ether containing peripheral spacer, six atoms are required, and in the case of an alkane chain, four carbon atoms are necessary to adopt the pharmacophoric S-shape conformation.
Sensory adaptation of Dictyostelium discoideum cells to chemotactic signals. (1983)

Postvegetative Dictyostelium discoideum cells react chemotactically to gradients of cAMP, folic acid, and pterin. In the presence of a constant concentration of 10(-5) M cAMP cells move at random. They still are able to respond to superimposed gradients of cAMP, although the response is less efficient than without the high background level of cAMP. Cells which are accommodated to 10(-5) M cAMP do not react to a gradient of cAMP if the mean cAMP concentration is decreasing with time. This indicates the involvement of adaptation in the detection of chemotactic gradients: cells adapt to the mean concentration of chemoattractant and respond to positive deviations from the mean concentration. Cells adapted to high cAMP concentrations react normally to gradients of folic acid or pterin. Adaptation to one of these compounds does not affect the response to the other attractants. This suggests that cAMP, folic acid, and pterin are detected by different receptors, and that adaptation is localized at a step in the transduction process before the signals from these receptors coincide into one pathway. I discuss the implications of adaptation for chemotaxis and cell aggregation.
Mapping of epitopes, glycosylation sites, and complement regulatory domains in human decay accelerating factor (1992)

Decay accelerating factor (DAF, CD55) is a glycophospholipid-anchored membrane protein that protects cells from complement-mediated damage by inhibiting the formation and accelerating the decay of C3/C5 convertases. DAF deletion mutants lacking each of the four short consensus repeats (SCR) or the serine/threonine-rich region (S/T) were created by site-directed mutagenesis. These deletion mutants were expressed by stable transfection in Chinese hamster ovary cells for the purpose of mapping important structural and functional sites in DAF. The epitopes on DAF for 16 murine mAb were mapped by immunoprecipitation studies as follows: SCR1, 6; SCR2, 3; SCR3, 3; SCR4, 3; S/T, 1. Testing of 13 mAb showed complete blocking of DAF function only by 1C6 and 1H4, both directed at SCR3. The single N-linked glycosylation site was confirmed at a location between SCR1 and SCR2, and the multiple O-linked oligosaccharides were localized to the S/T region. Functional activity of DAF mutants was assessed by the ability of these transfected constructs to protect Chinese hamster ovary cells from cytotoxicity induced by rabbit antibody plus human complement. Removal of SCR1 had no effect on DAF function, but individual deletion of SCR2, SCR3, or SCR4 totally abolished DAF function. Surprisingly, deletion of the S/T region totally abrogated DAF function, but this could be restored by a fusion construct placing the four SCR domains of DAF onto the HLA-B44 molecule, implying that the O-glycosylated S/T region serves as an important but nonspecific spacer projecting the DAF functional domains above the plasma membrane. Overall, the creation of DAF deletion mutants has elucidated important structure-function relations in the DAF molecule.
Spurious modes suppression in Stacked Crystal Filter (2010)

Stacked Crystal Filters (SCFs) are used in Bandpass filters and other applications where frequency control is required. SCFs use the Solidly Mounted Resonator (SMR) structure to enable operations at RF frequencies, typically 1-5 GHz. In the response spectrum of the SCFs, besides the main resonance mode, there are some unwanted additional modes present which affect the filter's performance away from the primary passband frequency. A single passband is typically a required specification of a band pass filter; therefore the other unwanted modes are to be suppressed as a transmission band can manifest at each unwanted mode. It will turn out that with proper choice of layer materials and thicknesses the unwanted modes can be suppressed, but the level of suppression will be sensitive to the exact layer thicknesses fabricated. A research work is needed to focus on evaluating the materials used in the SCF's resonating mirror and seek a novel mirror methodology for the suppression of these unwanted modes even over manufacturing variations. In this paper, we will investigate careful control of the acoustic mirror stack above which the SMR stack is fabricated to create the SCF. By choosing appropriate materials and adjusting their respective thicknesses, the spurious modes can be suppressed without degrading the overall primary mode performance of the SCF. Trade-offs between the acoustic mirror properties relating to the filter's addressable bandwidth, and the desired suppression of lateral modes of one/two stage SCFs will be discussed.
Binding specificity of serum amyloid P component for the pyruvate acetal of galactose. (1984)

Serum amyloid P component (SAP) is a normal plasma protein that is of interest because of its presence in amyloid deposits, its presence in normal human glomerular basement membrane, and its stable evolutionary conservation. It has calcium-dependent ligand-binding specificity for amyloid fibrils, fibronectin (Fn), C4-binding protein (C4bp), and agarose. Although the binding to agarose, a linear galactan hydrocolloid derived from some marine algae, is unlikely per se to be related to the physiological function of SAP, it does provide a model system in which to explore the precise ligand requirements of SAP. We report here that the amount of SAP from human, mouse, and plaice (Pleuronectes platessa L.) serum able to bind to agarose from different sources reflect precisely their pyruvate content. Methylation with diazomethane of the carboxyl groups in the pyruvate moiety of agarose completely abolishes SAP binding to agarose. The pyruvate in agarose exists as the 4,6-pyruvate acetal of beta-D-galactopyranose. We have therefore synthesized this galactoside, using a novel procedure, established its structure by analysis of its nuclear magnetic resonance spectra, and shown that it completely inhibits all known calcium-dependent binding reactions of SAP. The R isomer of the cyclic acetal, methyl 4,6-O-(1-carboxyethylidene)-beta-D-galactopyranoside (MO beta DG) was effective at millimolar concentration and was more potent than its noncyclic analogue, while pyruvate, D-galactose, and methyl beta-D-galactopyranoside were without effect. The autologous protein ligands of SAP presumably, therefore express a structural determinant(s) that stereochemically resembles MO beta DG. Availability of this specific, well-characterized, low molecular weight ligand for SAP should facilitate further investigation of the function of SAP and its role in physiological and pathophysiological processes.
Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. (1988)

Since the antithrombin action of heparin fails to interrupt arterial thrombosis, a mediating role for thrombin (EC 3.4.21.5) in the formation of high-shear platelet-dependent thrombus has been unproven. To determine whether thrombin is important in acute arterial thrombus formation and to assess the therapeutic potential of inhibiting its action, the effects of the synthetic covalent antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2Cl) on arterial-flow vascular graft thrombosis and occlusion have been studied in a nonhuman primate model. Continuous intravenous infusion of FPRCH2Cl (100 nmol/kg per min) into vascular graft-bearing baboons (Papio anubis) abolished (i) vascular graft 111In-platelet deposition, (ii) vascular graft occlusion, (iii) thrombus-associated in vivo release of platelet-specific proteins and fibrinopeptides, (iv) platelet hemostatic plug formation, (v) thrombin-induced platelet aggregation ex vivo, and (vi) thrombin-induced blood clotting. The effects of FPRCH2Cl largely disappeared within 15 min after the infusion had been discontinued. FPRCH2Cl produced no detectable cardiovascular or other acute side effects. In contrast, sustained comparably anticoagulating levels of heparin had no effect upon 111In-platelet graft deposition, graft occlusion, platelet function as measured by the bleeding time, platelet aggregation ex vivo, or release of platelet-specific proteins in vivo. We conclude that thrombin is the principal mediator of platelet-dependent hemostatic plug formation and of the formation of platelet-dependent high-flow acute graft thrombosis and occlusion. Moreover, FPRCH2Cl or other synthetic antithrombins may provide effective antithrombotic therapy for both arterial and venous thrombosis by simultaneously inhibiting platelet activation and fibrin formation.