gebhart/patrepeval huggingface dataset:
Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors (2008)

Human embryonic stem cells (hESCs) could potentially represent an alternative source for blood transfusion therapies and a promising tool for studying the ontogeny of hematopoiesis. When we cultured hESCs on either C3H10T1/2 or OP-9 cells to facilitate hematopoiesis, we found that exogenous administration of vascular endothelial growth factor promoted the emergence of sac-like structures, which we named embryonic stem cell-derived sacs (ES-sacs). These ES-sacs consisted of multiple cysts demarcated by cellular monolayers that retained some of the properties of endothelial cells. The spherical cells inside ES-sacs expressed primarily CD34, along with VE-cadherin, CD31, CD41a, and CD45, and were able to form hematopoietic colonies in semisolid culture and to differentiate into mature megakaryocytes by day 24 in the presence of thrombopoietin. Apparently, ES-sacs provide a suitable environment for hematopoietic progenitors. Relatively large numbers of mature megakaryocytes could be induced from the hematopoietic progenitors within ES-sacs, which were then able to release platelets that displayed integrin alpha IIb beta 3 activation and spreading in response to ADP or thrombin. This novel protocol thus provides a means of generating platelets from hESCs, which could serve as the basis for efficient production of platelets for clinical transfusion and studies of thrombopoiesis.
Classification Analysis of P-Glycoprotein Substrate Specificity (2003)

Prediction of P-glycoprotein substrate specificity (S(PGP)) can be viewed as a constituent part of a compound's "pharmaceutical profiling" in drug design. This task is difficult to achieve due to several factors that raised many contradictory opinions: (i) the disparity between the S(PGP) values obtained in different assays, (ii) the confusion between Pgp substrates and inhibitors, (iii) the confusion between lipophilicity and amphiphilicity of Pgp substrates, and (iv) the dilemma of describing class-specific relationships when Pgp has no binding sites of high ligand specificity. In this work, we compiled S(PGP) data for 1000 compounds. All data were represented in a binary format, assigning S(PGP) = 1 for substrates and S(PGP) = 0 for non-substrates. Each value was ranked according to the reliability of experimental assay. Two data sets were considered. Set 1 included 220 compounds with S(PGP) from polarized transport across MDR1 transfected cell monolayers. Set 2 included the entire list of 1000 compounds, with S(PGP) values of generally lower reliability. Both sets were analysed using a stepwise classification structure-activity relationship (C-SAR) method, leading to derivation of simple rules for crude estimation of S(PGP) values. The obtained rules are based on the following factors: (i) compound's size expressed through molar weight or volume, (ii) H-accepting given by the Abraham's beta (that can be crudely approximated by the sum of O and N atoms), and (iii) ionization given by the acid and base pKa values. Very roughly, S(PGP) can be estimated by the "rule of fours". Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex "mini-pharmacokinetic" system with fuzzy specificity. This system can be described by a probabilistic version of Abraham's solvation equation, suggesting a certain similarity between Pgp transport and chromatographic retention. The chromatographic model does not work in the case of "marginal" compounds with properties close to the "global" physicochemical cut-offs. In the latter case various class-specific rules must be considered. These can be associated with the "amphiphilicity" and "biological similarity" of compounds. The definition of class-specific effects entails construction of the knowledge base that can be very useful in ADME profiling of new drugs.
Structure of the DNA damage-inducible gene DDR48 and evidence for its role in mutagenesis in Saccharomyces cerevisiae. (1990)

The DDR48 gene of Saccharomyces cerevisiae is a member of a set of genes that displays increased transcription in response to treatments that produce DNA lesions or to heat-shock stress. Other members of this group include the DDRA2 and UBI4 genes. DNA sequence analysis of the DDR48 gene demonstrates the presence of two overlapping open reading frames, each of which has the capacity to encode a protein with a molecular mass of approximately 45 kilodaltons. Fusions of the DDR48 coding sequences to lacZ demonstrates that only one of these frames is expressed in yeast cells. The protein predicted from this sequence is extremely hydrophilic and contains multiple repeats of the peptide sequence Ser-Asn-Asn-X-Asp-Ser-Tyr-Gly where X is either Asn or Asp. Additionally, closely related sequences are found throughout the primary sequence. Primer extension data indicate that, after 4-nitroquinoline-1-oxide and heat-shock treatments, there are three major and two minor transcriptional start sites which are utilized. The function of the DDR48 gene was investigated by disrupting this gene in diploid cells. Viable haploid cells containing the DDR48 gene disruption were isolated after tetrad analysis. Although the ddr48 mutant showed a slightly altered sensitivity to killing by 4-nitroquinoline-1-oxide and to heat shock compared with the DDR48 haploid, the spontaneous mutation rate of reversion of a his4 mutation was reduced 6- to 14-fold in the ddr48 strain. These results implicate the DDR48 gene in the production or recovery of mutations in S. cerevisiae.
Ultrasonic distance detection for a closed-loop spinal cord stimulation system (2002)

When stimulating the spinal cord at a constant strength, the current density in the spinal cord and thus the effects on chronic, intractable pain and vascular insufficiency will change with body position, due to the varying separation of the spinal cord and the stimulating electrode. The current density in the spinal cord has to remain between the perception and discomfort threshold (stimulation window) for a good therapeutic effect, i.e. that the patient does not suffer from pain. The stimulation window is very small. In current SCS systems the stimulus applied to the electrode is set at a constant value. A major improvement could be achieved when the distance between stimulation electrode and spinal cord could be measured and used to control the stimulus amplitude in a closed-loop system. An ultrasonic piezoelectric transducer was chosen to measure the distance between the electrode and the spinal cord.
Inhibitors of Cyclin-dependent Kinases Promote Survival of Post-mitotic Neuronally Differentiated PC12 Cells and Sympathetic Neurons (1996)

Previous studies have demonstrated that multiple agents that promote survival of PC12 cells and sympathetic neurons deprived of trophic support also block cell cycle progression. Presently, we address whether inhibition of cell cycle-related cyclin-dependent kinases (CDKs) prevents neuronal cell death. We show that two distinct CDK inhibitors, flavopiridol and olomoucine, suppress the death of neuronal PC12 cells and sympathetic neurons. In addition, we demonstrate that inhibitor concentrations required to promote survival correlate with their ability to inhibit proliferation. Promotion of survival, however, does not correlate with inhibition of extracellular signal-regulated kinase or c-Jun kinase activities or with interference with the activation of c-Jun kinase that accompanies serum/nerve growth factor deprivation. In contrast to their actions on nerve growth factor-differentiated PC12 cells, the CDK inhibitors do not prevent the death of proliferation-competent PC12 cells and, in fact, promote their cell death. These findings support the hypothesis that post-mitotic neuronal cells die after removal of trophic support due to an attempt to re-enter the cell cycle in an uncoordinated and inappropriate manner. We speculate that cycling PC12 cells are not saved by these agents due to a signaling conflict between an inherent oncogenic signal and the inhibition of CDK activity.
On adaptive acquisition of language (2002)

A system that automatically acquires a language model for a particular task from semantic-level information is described. This is in contrast to systems with predefined vocabulary and syntax. The purpose of the system is to map spoken or typed input into a machine action. To accomplish this task a medium-grain neural network is used. An adaptive training procedure is introduced for estimating the connection weights. It has the advantages of rapid, single-pass and order-invariant learning. The resulting weights have information-theoretic significance and do not require gradient search techniques for their estimation. The system was experimentally evaluated on three text-based tasks; a three-class inward-call manager with an acquired vocabulary of over 1600 words, a 15-action subset of the DARPA Resource Manager with an acquired vocabulary of over 700 words, and discrimination between idiomatic phrases meaning yes or no.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Properties of Membranes Used for Hemodialysis Therapy (2002)

Recent trends show a progressive increase in the use of modified cellulosic and synthetic dialyzers and a corresponding decrease in the utilization rate of unmodified cellulosic dialyzers. The purpose of this article is to describe current membrane and dialyzer technology, with the focus almost entirely on modified cellulosic and synthetic membranes. A general overview of membrane‐related determinants of dialyzer performance is first presented, followed by a discussion of specific characteristics of some of the more commonly used membranes and dialyzers.
Synergistic Induction of Mouse Serum Amyloid A3 Promoter by the Inflammatory Mediators IL-1 and IL-6 (1999)

Serum amyloid A (SAA), one of the major acute-phase proteins, increases several hundredfold in concentration in plasma following acute inflammation, primarily as a result of a 200-fold increase in its transcription rate. We have previously demonstrated that a 350-bp promoter fragment from the mouse SAA3 gene could confer conditioned medium-induced expression in cultured cells. The induction is mediated through a 42-bp distal response element (DRE) consisting of three functional regulatory elements. In this study, we show that interleukin-1 (IL-1) is the major cytokine in the conditioned medium responsible for SAA3 induction, and the induction by IL-1 can be effectively blocked by H-7, a protein kinase C inhibitor. Although IL-6 alone had no effect on SAA3 promoter activity, the addition of IL-6 and IL-1 resulted in dramatic synergistic activation of the reporter gene. We further show that the DRE is both necessary and sufficient to confer synergistic induction by IL-1 and IL-6. Moreover, individual mutation of the three regulatory elements within DRE either abolished or drastically reduced the synergistic induction. Our results indicate that synergistic activation of SAA3 promoter by IL-1 and IL-6 is achieved through integration of signals triggered by these two cytokines onto the DRE and that all three functionally distinct regulatory elements in the DRE are required to effectively and fully activate SAA3 gene transcription.
18F Stilbenes and Styrylpyridines for PET Imaging of Aβ Plaques in Alzheimer’s Disease: A Miniperspective (2009)

Alzheimer’s disease (AD) is a neurodegenerative disease of the brain, characterized by a slowly progressive dementia. This insidious disease is growing in importance because it affects millions of older patients. Clinical symptoms of AD include cognitive decline, irreversible memory loss, disorientation and language impairment. Major neuropathology observations of
Vaccinia virus evasion of regulated cell death (2017)

Regulated cell death is a powerful anti-viral mechanism capable of aborting the virus replicative cycle and alerting neighbouring cells to the threat of infection. The biological importance of regulated cell death is illustrated by the rich repertoire of host signalling cascades causing cell death and by the multiple strategies exhibited by viruses to block death signal transduction and preserve cell viability. Vaccinia virus (VACV), a poxvirus and the vaccine used to eradicate smallpox, encodes multiple proteins that interfere with apoptotic, necroptotic and pyroptotic signalling. Here the current knowledge on cell death pathways and how VACV proteins interact with them is reviewed. Studying the mechanisms evolved by VACV to counteract host programmed cell death has implications for its successful use as a vector for vaccination and as an oncolytic agent against cancer.
Acetate biosynthesis by acetogenic bacteria. Evidence that carbon monoxide dehydrogenase is the condensing enzyme that catalyzes the final steps of the synthesis. (1985)

The purified carbon monoxide dehydrogenase from Clostridium thermoaceticum is the only protein required to catalyze an exchange reaction between carbon monoxide and the carbonyl group of acetyl-CoA. This exchange requires that the CO dehydrogenase bind the methyl, the carbonyl, and the CoA groups of acetyl-CoA, then equilibrate the carbonyl with CO in the solution and re-form acetyl-CoA. CoA is not necessary for the exchange and, in fact, inhibits the reaction. These studies support the view that CO dehydrogenase is the condensing enzyme that forms acetyl-CoA from its component parts. Carbon dioxide also exchanges with the C-1 of acetyl-CoA, but at a much lower rate than does CO. At 50 degrees C and pH 5.3, the optimal pH, the turnover number is 70 mol of CO exchanged per min/mol of enzyme. Low potential electron carriers are stimulatory. The Km app for stimulation by ferredoxin is 50-fold less than the value for flavodoxin. Neither ATP or Pi stimulate the exchange. The EPR spectrum of the CO-reacted enzyme is markedly changed by binding of CoA or acetyl-CoA. Arginine residues of the CO dehydrogenase appear to be involved in the active site, possibly by binding acetyl-CoA. Mersalyl acid, methyl iodide, 5,5-dithiobis-(2-nitrobenzoate), and sodium dithionite inhibit the exchange reaction. A scheme is presented to account for the role of CO dehydrogenase in the exchange reaction and in the synthesis of acetate.
Impact of Intrinsic Affinity on Functional Binding and Biological Activity of EGFR Antibodies (2012)

Aberrant expression and activation of EGF receptor (EGFR) has been implicated in the development and progression of many human cancers. As such, targeted therapeutic inhibition of EGFR, for example by antibodies, is a promising anticancer strategy. The overall efficacy of antibody therapies results from the complex interplay between affinity, valence, tumor penetration and retention, and signaling inhibition. To gain better insight into this relationship, we studied a panel of EGFR single-chain Fv (scFv) antibodies that recognize an identical epitope on EGFR but bind with intrinsic monovalent affinities varying by 280-fold. The scFv were converted to Fab and IgG formats, and investigated for their ability to bind EGFR, compete with EGF binding, and inhibit EGF-mediated downstream signaling and proliferation. We observed that the apparent EGFR-binding affinity for bivalent IgG plateaus at intermediate values of intrinsic affinity of the cognate Fab, leading to a biphasic curve describing the ratio of IgG to Fab affinity. Mathematical modeling of antibody-receptor binding indicated that the biphasic effect results from nonequilibrium assay limitations. This was confirmed by further observation that the potency of EGF competition for antibody binding to EGFR improved with both intrinsic affinity and antibody valence. Similarly, both higher intrinsic affinity and bivalent binding improved the potency of antibodies in blocking cellular signaling and proliferation. Overall, our work indicates that higher intrinsic affinity combined with bivalent binding can achieve avidity that leads to greater in vitro potency of antibodies, which may translate into greater therapeutic efficacy.
Idursulfase in Hunter syndrome treatment (2007)

Hunter syndrome (mucopolysaccharidosis II, MPS II) is a rare X-linked lysosomal storage disorder caused by the deficiency of enzyme iduronate-2-sulfatase (I2S), which results in accumulation of undegraded dermatan and heparan sulfate in various tissues and organs. Enzyme replacement therapy with Elaprase (idursulfase, a recently approved orphan product) is the first treatment for Hunter syndrome. Results of the randomized, double-blind, placebo-controlled phase II/III clinical trial of idursulfase demonstrated that weekly infusions of idursulfase increase walking distance and improve pulmonary function as well as reduce organ size and urinary glycosaminoglycans (GAGs) excretion in MPS II patients. Idursulfase is generally well tolerated, although infusion reactions do occur. Clinical studies demonstrate that idursulfase may be the first successful symptomatic therapy that can benefit patients with MPS II by addressing the enzymatic defect.
Testing the Role of Technical Information in Public Risk Perception (1992)

It is widely believed that more detail about health effects and likely exposure routes is apt to reduce citizens' concerns about low-probability Risks. The authors' study suggests that providing such detail may not be as useful as, e.g., addressing public concerns and keeping citizens current on officials' actions.
Near-isotropic 3D optical nanoscopy with photon-limited chromophores (2010)

Imaging approaches based on single molecule localization break the diffraction barrier of conventional fluorescence microscopy, allowing for bioimaging with nanometer resolution. It remains a challenge, however, to precisely localize photon-limited single molecules in 3D. We have developed a new localization-based imaging technique achieving almost isotropic subdiffraction resolution in 3D. A tilted mirror is used to generate a side view in addition to the front view of activated single emitters, allowing their 3D localization to be precisely determined for superresolution imaging. Because both front and side views are in focus, this method is able to efficiently collect emitted photons. The technique is simple to implement on a commercial fluorescence microscope, and especially suitable for biological samples with photon-limited chromophores such as endogenously expressed photoactivatable fluorescent proteins. Moreover, this method is relatively resistant to optical aberration, as it requires only centroid determination for localization analysis. Here we demonstrate the application of this method to 3D imaging of bacterial protein distribution and neuron dendritic morphology with subdiffraction resolution.
Anaerobic Treatment of Leachates in a Pilot-Scale UASB: Strategy of Start-up (1996)

The anaerobic digestion of leachates from a solid urban wastes landfill was studied using an upflow anaerobic sludge blanket reactor in pilot scale. The strategy of start-up and acclimation was based on gradual substitution of easily biodegradable feed with landfill leachate. All modifications were based on the attainment of 70% COD removal. Having completed the start-up, the kinetics of leachate biodegradation were studied and the values of kinetic parameters were obtained by fitting experimental data to the equation of Chen and Hashimoto. The biodegradability assays indicated that 40–50% of COD in leachate was biodegradable. The highest COD removal was 90–100% if only the biodegradable matter was considered.
Immunoregulatory and Cytokine Imbalances in the Pathogenesis of IDDM: Therapeutic Intervention by Immunostimulation? (1994)

The autoimmune response that leads to destruction of pancreatic islet β-cells and insulin-dependent diabetes mellitus (IDDM) has a genetic basis; however, environmental factors can exert profound modulating effects on the genetic predisposition to this autoimmune response. Recent studies in animal models for human IDDM, the genetically diabetes-prone NOD mouse and BB rat, have revealed that microbial agents—including certain viruses and extracts of bacteria, fungi, and mycobacteria—often have a protective action against diabetes development. Many of these microbial preparations are immune adjuvants, which are agents that stimulate the immune system. The protective effects of these agents against diabetes appear to involve perturbations in the production of cytokines, which are polypeptides produced by and acting on cells of the immune system. Thus, recent studies in NOD mice suggest that the islet β-cell-directed autoimmune response may be mediated by a T-helper 1 (Th1) subset of T-cells producing the cytokines interleukin-2 (IL-2) and interferon-γ. These studies also suggest that the diabetes-protective effects of administering microbial agents, adjuvants, and a β-cell autoantigen (GAD65 [glutamic acid decarboxylase]) may result from activation of a Th2 subset of T-cells that produce the cytokines IL-4 and IL-10 and consequently downregulate the Th1-cell-mediated autoimmune response. The clinical implication of these findings is that the autoimmune response leading to islet β-cell destruction and IDDM may be amenable to prevention or suppression by therapeutic interventions aimed at stimulating the host's own immunoregulatory mechanisms.
Formation of chimeric duplexes between zwitterionic and natural DNA (1993)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFormation of chimeric duplexes between zwitterionic and natural DNAHiromasa Hashimoto, Marek G. Nelson, and Christopher SwitzerCite this: J. Org. Chem. 1993, 58, 16, 4194–4195Publication Date (Print):July 1, 1993Publication History Published online1 May 2002Published inissue 1 July 1993https://pubs.acs.org/doi/10.1021/jo00068a007https://doi.org/10.1021/jo00068a007research-articleACS PublicationsRequest reuse permissionsArticle Views86Altmetric-Citations22LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
THE PHEROMONE RESPONSE PATHWAY IN SACCHAROMYCES CEREVISIAE (1993)

THE PHEROMONE RESPONSE PATHWAY IN SACCHAROMYCES CEREVISIAE, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/genet/27/1/annurev.ge.27.120193.001051-1.gif