gebhart/patrepeval huggingface dataset:
Prothrombin activation on dioleoylphosphatidylcholine membranes (1994)

Factor-Xa-catalyzed prothrombin activation is greatly accelerated by negatively charged phospholipids plus calcium ions. In 1990, we reported that neutral phosphatidylcholine membranes also stimulated prothrombin activation [Gerads, I., Govers-Riemslag, J.W.P., Tans, G., Zwaal, R. F. A. & Rosing, J. (1990) Biochemistry 29, 7967-7974]. In the present study, we have performed a detailed analysis of the prothrombin-converting activity of phosphatidylcholine membranes. Stimulation of prothrombin activation by phosphatidylcholine vesicles was particularly observed (a) with phosphatidylcholine molecules that contained unsaturated hydrocarbon side chains, (b) in the presence of factor Va, (c) at low ionic strength and (d) when Ca2+ were present in the reaction medium. It is unlikely that the prothrombinase activity of phosphatidylcholine preparations was due to contaminating anionic phospholipids. This is concluded from the fact that thin-layer chromatographic analysis showed that dioleoylphosphatidylcholine [(Ole)2GroPCho] contained less than 0.1 mol/100 mol anionic phospholipid, and that incorporation of such amounts of anionic lipids in (Ole)2-GroPCho membranes hardly increased their prothrombin-converting activity. At low ionic strength and in the presence of factor Va and Ca2+ (Ole)2GroPCho membranes accelerated prothrombin activation about 100-fold. At ionic strength (I) 0.06, prothrombin activation on 100 microM (Ole)2-GroPCho was characterized by a Km for prothrombin of 2 microM, a Vmax of 3020 IIa min-1.Xa-1 and a Kd for factor XaVa complex formation at the membrane surface of 7.5 nM. Prothrombin activation on (Ole)2GroPCho membranes was drastically reduced when the ionic strength was increased. The inhibition at high ionic strength could be explained by an effect on the Kd for XaVa complex formation which increased from 7.5 nM at I = 0.06 to 100 nM at I = 0.22. Prothrombin activation on (Ole)2GroPCho required Ca2+ and was dependent on the presence of gamma-carboxyglutamic acid domains in prothrombin and factor Xa. This indicates that similar interactions may account for the assembly of prothrombinase complexes on phosphatidylcholine and an anionic lipid-containing membranes.
Multiepitope HER2 Targeting Enhances Photoimmunotherapy of HER2-Overexpressing Cancer Cells with Pyropheophorbide-a Immunoconjugates (2005)

Multi-targeting strategies improve the efficacy of antibody and immunotoxin therapies but have not yet been thoroughly explored for HER2-based cancer treatments. We investigated multi-epitope HER2 targeting to boost photosensitizer immunoconjugate uptake as a way of enhancing photoimmunotherapy. Photoimmunotherapy may allow targeted photodynamic destruction of malignancies and may also potentiate anticancer antibodies. However, one obstacle preventing its clinical use is the delivery of enough photosensitizer immunoconjugates to target cells. Anti-HER2 photosensitizer immunoconjugates were constructed from two monoclonal antibodies (mAb), HER50 and HER66, using a novel method originally developed to label photosensitizer immunoconjugates with the photosensitizer, benzoporphyrin derivative verteporfin. Photosensitizer immunoconjugates were labeled instead with a promising alternative photosensitizer, pyropheophorbide-a (PPa), which required only minor changes to the conjugation procedure. Uptake and phototoxicity experiments using human cancer cells were conducted with the photosensitizer immunoconjugates and, for comparison, with free PPa. SK-BR-3 and SK-OV-3 cells served as HER2-overexpressing target cells. MDA-MB-468 cells served as HER2-nonexpressing control cells. Photosensitizer immunoconjugates with PPa/mAb molar ratios up to approximately 10 specifically targeted and photodynamically killed HER2-overexpressing cells. On a per mole basis, photosensitizer immunoconjugates were less phototoxic than free PPa, but photosensitizer immunoconjugates were selective for target cells whereas free PPa was not. Multiepitope targeted photoimmunotherapy with a HER50 and HER66 photosensitizer immunoconjugate mixture was significantly more effective than single-epitope targeted photoimmunotherapy with a single anti-HER2 photosensitizer immunoconjugate, provided photosensitizer immunoconjugate binding was saturated. This study shows that multiepitope targeting enhances HER2-targeted photoimmunotherapy and maintains a high degree of specificity. Consequently, it seems that multitargeted photoimmunotherapy should also be useful against cancers that overexpress other receptors.
Tau isoform expression and regulation in human cortical neurons (2008)

Differential expression, activity, phosphorylation, and oligomerization of tau play a critical role during neuronal development and in a number of age-related neurodegenerative diseases. An experimental system that accurately models the molecular changes involved in tauopathies, particularly changes in tau isoform activity, requires the expression at physiological levels of the full complement of tau isoforms present in the adult human brain. To this end, we analyzed tau expression in human cortical neurons (HCNs) in culture. Here, we show that the isoform profile of tau in HCNs is similar to that in the adult human brain and that isoform expression is regulated during neuronal development and by cellular substrates. Interestingly, 4R tau exhibited a distinct pattern of expression and subcellular localization, suggesting the presence of specific functional roles for tau isoforms in HCNs. Tau phosphorylation, microtubule binding, and subcellular localization were markedly altered by pharmacological manipulation of tau-directed phosphatase activities, which also induced the appearance of tau oligomeric forms associated with memory loss in animal models of tauopathy. Thus, experimentally induced changes in tau activity and function in HCNs recapitulate critical features of tauopathies that may lead to neuronal dysfunction and degeneration in the human brain.
Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate (2009)

Metachromatic leukodystrophy (MLD) is a lethal neurodegenerative disease caused by a deficiency in the lysosomal arylsulfatase A (ARSA) enzyme leading to the accumulation of sulfatides in glial and neuronal cells. We previously demonstrated in ARSA-deficient mice that intracerebral injection of a serotype 5 adeno-associated vector (AAV) encoding human ARSA corrects the biochemical, neuropathological and behavioral abnormalities. However, before considering a potential clinical application, scaling-up issues should be addressed in large animals. Therefore, we performed intracerebral injection of the same AAV vector (total dose of 3.8 x 10(11) or 1.9 x 10(12) vector genome, three sites of injection in the right hemisphere, two deposits per site of injection) into three selected areas of the centrum semiovale white matter, or in the deep gray matter nuclei (caudate nucleus, putamen, thalamus) of six non-human primates to evaluate vector distribution, as well as expression and activity of human ARSA. The procedure was perfectly tolerated, without any adverse effect or change in neurobehavioral examination. AAV vector was detected in a brain volume of 12-15 cm(3) that corresponded to 37-46% of the injected hemisphere. ARSA enzyme was expressed in multiple interconnected brain areas over a distance of 22-33 mm. ARSA activity was increased by 12-38% in a brain volume that corresponded to 50-65% of injected hemisphere. These data provide substantial evidence for potential benefits of brain gene therapy in patients with MLD.
Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Role of Proinflammatory Cytokines and Therapeutic Approaches (2010)

Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a broad range of clinical manifestations, is associated with accelerated atherosclerosis (AT) and increased risk of cardiovascular complications. Relevant factors directly influencing the development of AT comprise immune complex generation, complement activation, and changes in the production and activity of a complex network of cytokines, including type I and II interferons, B lymphocyte stimulator (BLyS), TNFα, IL-6, IL-17 and migration macrophage inhibitor (MIF). Autoantibodies, also responsible for cytokine expression and activation, play a supplementary key role in the development of AT. Genomic and proteomic studies have contributed to the discovery of genes and proteins involved in AT, including some that may be suitable to be used as biomarkers. All that data has allowed the development of new drugs, most of them evaluated in clinical trials: inhibitors of IFN and TNFα, B cell directed therapies, synthetic oligodeoxynucleotides, intravenous immunoglobulin, or statins. The focus of the present paper is to summarize recent evidence showing the role of cytokines in the development of AT in SLE and the rationale, and safety concerns, in the use of combined therapy to prevent AT and cardiovascular disease.
Agile beam steering using binary optics microlens arrays (1990)

Agile steering of a helium-neon laser beam (X = 632.8 nm) has been demonstrated using a complementary pair of 5-cm-aperture binary optic microlens arrays in the Galilean telescope geometry. Segmentation of a collimated input beam by illuminating approximately 60,000 /5 microlenses of 200-jim diameter and parabolic phase profile results in nearly aberration free beam steering over an 1 1° field of view for 100- pm lateral displacements of one array relative to the other. Wavefront quality and steering efficiency of the deflected beam has been measured as a function of steering angle and is compared to a simple theoretical model.
Immunoglobulin Gene Transcripts Have Distinct VHDJH Recombination Characteristics in Human Epithelial Cancer Cells (2009)

It was well accepted that only B-lymphocytes and plasma cells expressed immunoglobulin (Ig) gene. However, our group and others have confirmed that non-B-cells, such as epithelial cancer cells, can also express Ig. The aim of this work is to elucidate the role of non-B-cell-derived Ig by investigating the characteristics of the Ig heavy chain (IgH) gene repertoire in epithelial cancer cells. We cloned and sequenced 89 V(H)DJ(H) (V-D-J recombination of the IgH variable region) transcripts by microdissecting cells from eight different types of epithelial cancers and two cancer cell lines (HT-29 and HeLa S3). The cancer-derived Ig gene repertoire showed specific restricted patterns of V(H)DJ(H) recombination with seven sets of predominant V(H)DJ(H) sequences. Surprisingly, within a set of V(H)DJ(H) recombination, the variable (V) sequences derived from different cancer types had not only identical heavy chain variable (VH), diversity (D), and joining (JH) segments usage, but also identical junctions and mutation targets in the V(H) region. The V(Hgamma)DJ(Hgamma) (but not V(Hmicro)DJ(Hmicro)) in the cancer-derived sequences had a high mutation rate; however, it was shown that the mechanism of hypermutation was different from antigen selection in B-cell-derived V(Hgamma)DJ(Hgamma)sequences. In contrast to V(Hmicro)DJ(Hmicro), the V(Hgamma)DJ(Hgamma) sequences did not appear to originate from classical class switching. These results suggest that cancer-derived Ig genes have a distinct repertoire that may have implications for their role in carcinogenesis.
Occasional Review: Group-B Streptococcus--Profile of an Organism (1984)

Microbiology Society journals contain high-quality research papers and topical review articles. We are a not-for-profit publisher and we support and invest in the microbiology community, to the benefit of everyone. This supports our principal goal to develop, expand and strengthen the networks available to our members so that they can generate new knowledge about microbes and ensure that it is shared with other communities.
The Oral Vaccination of HBV by Cherry Tomatillo transdformed with HBsAg (2003)

Cotyledons of cherry tomatillo were co-cultured with Agrobacterium tumefaciens strain EHA105(harbouring p1301HBs) for three days. Through hygromycin delay-selection, transformed cherry tomatillo were obtained. The presence an integration of foreign DNA in transgenic cherry tomatillo was confirmed by hygromycin resiostance selection, Gus detection, polymerase chain reaction(PCR) and dot blot analysis. The immunoactivity of recombinant HBsAg(rHBsAg) was identified by ELISA. The expression levels of rHBsAg in different organs of transgenic cherry tomatillo were compared. Immunogenicity of rHBsAg derived from transgenic cherry tomatillo tissues was confirmed by oral feed of transformed tissues to Balb/c mice primed with commercial HBV vaccines. Specific serum antibody was boosted in this case. The feasibility of transgenic cherry tomatillo as oral vaccine is proved, and this study will provide some theoretic and experimental directions for the production of large-scale, low-cost oral HBV vaccines using transgenic cherry tomatillo.
Antithrombin-mediated Anticoagulant Activity of Sulfated Polysaccharides (2004)

We investigated the mechanisms of anticoagulant activity mediated by sulfated galactans. The anticoagulant activity of sulfated polysaccharides is achieved mainly through potentiation of plasma cofactors, which are the natural inhibitors of coagulation proteases. Our results indicated the following. 1) Structural requirements for the interaction of sulfated galactans with coagulation inhibitors and their target proteases are not merely a consequence of their charge density. 2) The structural basis of this interaction is complex because it involves naturally heterogeneous polysaccharides but depends on the distribution of sulfate groups and on monosaccharide composition. 3) Sulfated galactans require significantly longer chains than heparin to achieve anticoagulant activity. 4) Possibly, it is the bulk structure of the sulfated galactan, and not a specific minor component as in heparin, that determines its interaction with antithrombin. 5) Sulfated galactans of approximately 15 to approximately 45 kDa bind to antithrombin but are unable to link the plasma inhibitor and thrombin. This last effect requires a molecular size above 45 kDa. 6) Sulfated galactan and heparin bind to different sites on antithrombin. 7) Sulfated galactans are less effective than heparin at promoting antithrombin conformational activation. Overall, these observations indicate that a different mechanism predominates over the conformational activation of antithrombin in ensuring the antithrombin-mediated anticoagulant activity of the sulfated galactans. Possibly, sulfated galactan connects antithrombin and thrombin, holding the protease in an inactive form. The conformational activation of antithrombin and the consequent formation of a covalent complex with thrombin appear to be less important for the anticoagulant activity of sulfated galactan than for heparin. Our results demonstrate that the paradigm of heparin-antithrombin interaction cannot be extended to other sulfated polysaccharides. Each type of polysaccharide may form a particular complex with the plasma inhibitor and the target protease.
Insulin-Like Growth Factor-I Action on Growth Hormone Secretion and Messenger Ribonucleic Acid Levels: Interaction with Somatostatin* (1989)

Insulin-like growth factor I (IGF-I) suppresses GH gene transcription and GH secretion, while somatostatin (SRIF) only suppresses GH secretion. The interaction of these inhibitors of GH was, therefore, tested in primary rat pituitary cells grown in serum-free medium. Maximal inhibition of GH secretion (to 30% of the control value) was achieved by 13 nM IGF-I, while 5 nM SRIF suppressed GH to 36% of control secretion. The respective ED50 values for IGF-I and SRIF inhibition of GH secretion were similar (approximately 2.5 nM). Treatment of cells with the two agents together resulted in a further inhibition of basal GH secretion to 18% of control untreated cells (P less than 0.005). Increasing doses of SRIF (2.5-10 nM) in the presence of IGF-I caused a dose-dependent suppression of GH secretion. PRL levels were not altered by these treatments, indicating a selective effect on GH. GRH-induced GH secretion was further attenuated by combined IGF-I and SRIF treatment compared to the effect of either of these two agents alone. Northern analysis showed that IGF-I suppressed GH mRNA transcripts, while SRIF did not alter GH mRNA levels. The results indicate that physiological concentrations of both IGF-I and SRIF suppress long term basal GH secretion. Only IGF-I alters GH mRNA levels. These two peptides, therefore, appear to attenuate in vitro GH secretion by different mechanisms.
Chronic administration of the L-type calcium channel blocker nimodipine can facilitate the acquisition of sequence learning in a radial-arm maze (2004)

Nimodipine, a dihydropyridine L-type voltage-gated calcium-channel blocker, was examined for its potential effect on the acquisition of a complex-arm sequence task in an automated radial maze. Young (60-day-old) male Wistar rats were injected with saline or nimodipine (5 mg/kg) 15 min prior to radial maze training, or immediately following the radial maze testing. The results of the learning task (over 7 days of testing) showed that rats injected with nimodipine each training session acquired the task more quickly and more efficiently compared to saline-treated animals. There were no significant differences for rats that were pre-/post-treated with nimodipine during the maze-learning task. The number of incorrect arm entries and number of additional lever presses in the same arm were found to be significantly lower in rats treated with nimodipine compared to saline-injected controls. The beneficial effect of nimodipine treatment occurred only in rats that were acquiring the task, and not in rats that had already learned the arm sequence paradigm. There were no potential non-specific influences on locomotor activity or appetite caused by chronic nimodipine treatments. These results strongly suggest that nimodipine can facilitate the acquisition of a complex learning task.
Improved Endpoints for Cancer Immunotherapy Trials (2010)

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
Lubrication at Physiological Pressures by Polyzwitterionic Brushes (2009)

The very low sliding friction at natural synovial joints, which have friction coefficients of mu < 0.002 at pressures up to 5 megapascals or more, has to date not been attained in any human-made joints or between model surfaces in aqueous environments. We found that surfaces in water bearing polyzwitterionic brushes that were polymerized directly from the surface can have mu values as low as 0.0004 at pressures as high as 7.5 megapascals. This extreme lubrication is attributed primarily to the strong hydration of the phosphorylcholine-like monomers that make up the robustly attached brushes, and may have relevance to a wide range of human-made aqueous lubrication situations.
An improved guided restoration algorithm for ATM crossconnect networks (2002)

This paper proposes the guided restoration algorithm starting at different timing (GRA-DT) which is a scaleable self-healing algorithm that takes into account the buffer size required for the self-healing OAM cells arriving at an ATM crossconnect. In the guided restoration algorithm (GRA) all self-healing processes are started just after VP-AIS cells are detected. Thus if many VPs are affected by failures, a lot of self-healing OAM cells are transmitted during a short period of time. To avoid losing such cells, ATM crossconnects must be equipped with a large size buffer to store the self-healing OAM cells waiting for processing. To reduce the buffer size, we propose the GRA-DT with which self-healing processes are started at different timing for different VPs. This scheme has the effect of dispersing self-healing OAM cell transmission in time. Thus the number of self-healing OAM cells waiting in a buffer decreases and the buffer size can be smaller. This can be achieved by a simple alternation of GRA that adds information on starting timing to one of the VP terminating nodes. The result obtained in evaluating GRA-DT in some lattice networks shows that the number of self-healing OAM cells is about 55-86% of that for GRA in the case of double link failures. In addition, GRA-DT effectively reduces the redundant link resource reservation, and thus the restoration ratio was increased by 20% for the 36 node network in the event of node failures.
Three-Dimensional Engineered Bone from Bone Marrow Stromal Cells and Their Autogenous Extracellular Matrix (2008)

Most bone tissue-engineering research uses porous three-dimensional (3D) scaffolds for cell seeding. In this work, scaffold-less 3D bone-like tissues were engineered from rat bone marrow stromal cells (BMSCs) and their autogenous extracellular matrix (ECM). The BMSCs were cultured on a 2D substrate in medium that induced osteogenic differentiation. After reaching confluence and producing a sufficient amount of their own ECM, the cells contracted their tissue monolayer around two constraint points, forming scaffold-less cylindrical engineered bone-like constructs (EBCs). The EBCs exhibited alizarin red staining for mineralization and alkaline phosphatase activity and contained type I collagen. The EBCs developed a periosteum characterized by fibroblasts and unmineralized collagen on the periphery of the construct. Tensile tests revealed that the EBCs in culture had a tangent modulus of 7.5 +/- 0.5 MPa at 7 days post-3D construct formation and 29 +/- 9 MPa at 6 weeks after construct formation. Implantation of the EBCs into rats 7 days after construct formation resulted in further bone development and vascularization. Tissue explants collected at 4 weeks contained all three cell types found in native bone: osteoblasts, osteocytes, and osteoclasts. The resulting engineered tissues are the first 3D bone tissues developed without the use of exogenous scaffolding.