gebhart/patrepeval huggingface dataset:
Thermosensitive poloxamer-based injectables as controlled drug release platforms for veterinary use: Development and in-vitro evaluation (2011)

The aim of this work was to explore the potential of combining two different poloxamers (P407 and P188) with κ-carrageenan and sodium chloride for their utilization in the design of thermosensitive injectable depot systems for drug release. These delivery platforms were designed by combination of two different poloxamers (P407 and P188) with κ-carrageenan and sodium chloride. The addition of 10-15% w/w P188 in the poloxamer solution containing 28% w/w P407 allowed optimal gelation temperatures (24-28 °C) and a quick gelation process (30 s). The addition of 0.1% w/w of κ- carrageenan increased 3-fold the gel strength and did not change gelation temperature, compared with P407/P188 (28/15% w/w) alone. On the other hand, sodium chloride increased the gel strength and decreased the gelation temperature as a function of its concentration. In in-vitro release experiments, κ-carrageenan decreased the release rate of progesterone and reduced significantly the gel erosion in 48 h. This study demonstrates that addition of κ-carrageenan and sodium chloride into poloxamers blends can be considered a useful tool to design thermosensitive platforms, if added in suitable amounts. In conclusion, this system offers a promising alternative to development of injectable depot controlled drug release platforms for veterinary use.
Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression (2012)

The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.
Production of hydrogen peroxide by rabbit articular chondrocytes. Enhancement by cytokines. (1990)

Recent evidence suggests that reactive oxygen intermediates may play a role in the etiology of cartilage matrix degradation in arthritis. We have previously established that normal articular chondrocytes can functionally act as macrophages. These functions include expression of class II MHC Ag, presentation of Ag and induction of mixed and autologous lymphocyte stimulation. Inasmuch as the production of reactive oxygen intermediates is a hallmark of macrophage activity during inflammatory response, we were interested in examining the ability of normal articular chondrocytes to produce reactive oxygen intermediates. Using the trapped indicator 2',7'-dichlorofluorescin diacetate (DCFH-DA), we measured the levels of intracellular hydrogen peroxide within normal rabbit articular chondrocytes. We found that Concanavalin A induces chondrocytes to rapidly oxidize 2',7'-dichlorofluorescin diacetate to a highly fluorescent dichlorofluorescin in a dose- and time-dependent manner. Fluorescent dichlorofluorescin oxidation by chondrocytes was inhibited by the addition of catalase, an enzyme that detoxifies hydrogen peroxide. Exposure of rabbit chondrocytes to either IFN-gamma or TNF primed the chondrocytes to produce significantly greater amounts of hydrogen peroxide with or without further stimulation. Using scopoletin oxidation as a measure of the release of hydrogen peroxide, we confirmed that chondrocytes released this reactive oxygen intermediate after adherence to serum coated culture plates. Rabbit articular chondrocytes produced and released greater amounts of hydrogen peroxide than pulmonary alveolar macrophages, a well characterized macrophage cell type. These observations suggest that chondrocytes are an important source of reactive oxygen intermediates. Furthermore, the production of reactive oxygen intermediates by chondrocytes may be an important mechanism by which chondrocytes induce structural and functional alterations in cartilage matrix observed during arthritis.
Mutations at sites involved in Suc1 binding inactivate Cdc2. (1991)

suc1+ encodes an essential cell cycle regulator of the fission yeast Schizosaccharomyces pombe. Its product, a 13-kDa protein, interacts with the Cdc2 protein kinase. Both positive and negative effects on cell cycle progression have been attributed to Suc1. To date, the exact mechanisms and the physiological role of the interaction between Suc1 and Cdc2 remain unclear. Here we have studied the molecular basis of this association. We show that Cdc2 can bind Suc1 or its mammalian homolog directly in the absence of any additional protein component. Using an alanine scanning mutagenesis method, we analyzed the interaction between Cdc2 and Suc1. We show that the integrity of several domains on the Cdc2 protein, including sites directly involved in catalytic activity, is required for binding to Suc1. Furthermore, Cdc2 mutant proteins unable to bind Suc1 (but able to bind cyclins) are nonfunctional when overexpressed in S. pombe, indicating that a specific interaction with Suc1 is required for Cdc2 function.
The Second Activating Glucokinase Mutation (A456V) (2002)

In this study, a second case of hyperinsulinemic hypoglycemia due to activation of glucokinase is reported. The 14-year-old proband had a history of neonatal hypoglycemia, treated with diazoxide. He was admitted with coma and convulsions due to nonketotic hypoglycemia. His BMI was 34 kg/m(2), and his fasting blood glucose ranged from 2.1 to 2.7 mmol/l, associated with inappropriately high serum levels of insulin, C-peptide, and proinsulin. An oral glucose tolerance test (OGTT) showed exaggerated responses of these peptides followed by profound hypoglycemia. Treatment with diazoxide and chlorothiazide was effective. His mother never had clinical hypoglycemic symptoms, even though her fasting blood glucose ranged from 2.9 to 3.5 mmol/l. Increases in serum insulin, C-peptide, and proinsulin in response to an OGTT suggested a lower threshold for glucose-stimulated insulin release (GSIR). Screening for mutations in candidate genes revealed a heterozygous glucokinase mutation in exon 10, substituting valine for alanine at codon 456 (A456V) in the proband and his mother. The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S(0.5) (the concentration of glucose needed to achieve the half-maximal rate of phosphorylation) from 8.04 (wild-type) to 2.53 mmol/l. The mutant's Hill coefficient was decreased, and its maximal specific activity k(cat) was increased. Mathematical modeling predicted a markedly lowered GSIR threshold of 1.5 mmol/l. The theoretical and practical implications are manifold and significant.
The proposed accelerator facility for light ion cancer therapy in Heidelberg (1999)

The main characteristics of this facility are the application of the rasterscan method with active intensity, energy and beam size variation in combination with the usage of isocentric light ion gantries. The accelerator is designed to accelerate both low LET ions (p,He) and high LET ions (C,O) to cover the specific medical requirements. Major aspects of the design are influenced from the experiences of the GSI cancer treatment program; the requirements of this facility, however, exceed in many fields those of this GSI therapy program.
Inert benzothiazole functionalised ruthenium(ii) complexes; potential DNA hairpin binding agents (2006)

The two enantiomers of [Ru(bpy)2(bbtb)]2+{bpy = 2,2'-bipyridine; bbtb = 4,4'-bis(benzothiazol-2-yl)-2,2'-bipyridine} have been isolated and fully characterised. Both enantiomers have been shown to have a strong association with calf thymus DNA by UV/visible absorption, emission and CD spectroscopy, with the Lambda enantiomer having the greater affinity. The binding of both enantiomeric forms of [Ru(bpy)2(Me2bpy)]2+ and [Ru(bpy)2(bbtb)]2+{Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine} to a range of oligonucleotides, including an octadecanucleotide and an icosanucleotide which contain hairpin-sequences, have been studied using a fluorescent intercalator displacement (FID) assay. The complex [Ru(bpy)2(bbtb)]2+ exhibited an interesting association with hairpin oligonucleotides, again with the Lambda enantiomer binding more strongly. A (1)H NMR spectroscopic study of the binding of both enantiomers of [Ru(bpy)2(bbtb)]2+ to the icosanucleotide d(CACTGGTCTCTCTACCAGTG) was conducted. This sequence contains a seven-base-pair duplex stem and a six-base hairpin-loop. The investigation gave an indication of the relative binding of the complexes between the two different regions (duplex and secondary structure) of the oligonucleotide. The results suggest that both enantiomers bind at the hairpin, with the ruthenium centre located at the stem-loop interface. NOE studies indicate that one of the two benzothiazole substituents of the bbtb ligand projects into the loop-region. A simple model of the metal complex/oligonucleotide adduct was obtained by means of molecular modelling simulations. The results from this study suggest that benzothiazole complexes derived from inert polypyridine ruthenium(II) complexes could lead to the development of new fluorescent DNA hairpin binding agents.
Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models. (2001)

This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.
IEEE 802.11 wireless LAN: capacity analysis and protocol enhancement (2002)

In WLAN the medium access control (MAC) protocol is the main element for determining the efficiency in sharing the limited communication bandwidth of the wireless channel. This paper focuses on the efficiency of the IEEE 802.11 standard for wireless LANs. Specifically, we derive an analytical formula for the protocol capacity. From this analysis we found (i) the theoretical upper bound of the IEEE 802.11 protocol capacity; (ii) that the standard can operate very far from the theoretical limits depending on the network configuration; (iii) that an appropriate tuning of the backoff algorithm can drive the IEEE 802.11 protocol close to its theoretical limits. Hence we propose a distributed algorithm which enables each station to tune its backoff algorithm at run-time. The performances of the IEEE 802.11 protocol, enhanced with our algorithm, are investigated via simulation. The results indicate that the enhanced protocol is very close to the maximum theoretical efficiency.
Atmospheric Pressure Chemical Vapour Deposition of NbSe2 Thin Films on Glass (2006)

Abstract Atmospheric pressure chemical vapour deposition (APCVD) of niobium selenide films on glass substrates was achieved by reaction of di‐ tert ‐butyl selenide with NbCl 5 at 250–600 °C. X‐ray diffraction showed that the NbSe 2 films were crystalline and of the 2H a poly‐type with cell constants close to those expected ( a = 3.44 Å; c = 12.58 Å). Marked preferred orientation along either (101) or (200) was noted at higher deposition temperature and this unexpectedly varied depending on distance from the reactor inlet. The films produced at 600 °C showed exactly the Nb/Se ratio expected for NbSe 2 by energy dispersive analysis by X‐rays. The films deposited at the substrate temperatures of 500 °C or less were selenium rich with a niobium to selenium ratio of 1:2.5. The films produced at 600 °C were dark‐green, powdery and poorly adhesive. The films produced at 500 °C and below were dark‐brown matte in appearance, they passed the Scotch tape test, but could be scratched with a steel scalpel. SEM showed that the films were composed of plate‐like crystals, which become longer and thicker with increasing deposition temperature. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)
Conjugates of a Novel 7-Substituted Camptothecin with RGD-Peptides as αvβ3 Integrin Ligands: An Approach to Tumor-Targeted Therapy (2010)

Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified with the purpose to understand their effect on receptor affinity, systemic stability, cytotoxicity, and solubility of the corresponding conjugates. Among the new conjugates prepared, C6 and C7 showed high receptor affinity and tumor cell adhesion, acceptable stability in murine blood, and high cytotoxic activity (IC₅₀ = 8 nM). The rationale, synthetic strategy, and preliminary biological results will be presented.
A Finite Element Analysis of Local Oscillometric Blood Pressure Measurements (2007)

Traditional circumferential oscillometric blood pressure measurements are based on a complex interplay between the perturbed underlying artery and the surrounding tissue. When there is a balance in pressures acting across the arterial wall, the pulsation amplitude is expected to be a maximum. The purpose of this study was to examine the change in pulsation amplitude for a given pressure resulting from a focally applied compression. A non-linear, two-dimensional finite element analysis of an average fingerbase was used to determine the overall pressure distributions within the finger as well as to compare the feasibility of the focally applied oscillometric approach for blood pressure (BP) measurements. We found that the focally applied pressure appears to lead to only a slight underestimation of the BP (1.5 mmHg). Furthermore, it does not significantly inhibit global bloodflow and should therefore be an acceptable method for long-term blood pressure monitoring.
X-RAY: a non-invasive exclusive caching mechanism for RAIDs (2004)

RAID storage arrays often possess gigabytes of RAM for caching disk blocks. Currently, most RAID systems use LRU or LRU-like policies to manage these caches. Since these array caches do not recognize the presence of file system buffer caches, they redundantly retain many of the same blocks as those cached by the file system, thereby wasting precious cache space. In this paper, we introduce X-RAY, an exclusive RAID array caching mechanism. X-RAY achieves a high degree of (but not perfect) exclusivity through gray-box methods: by observing which files have been accessed through updates to file system meta-data, X-RAY constructs an approximate image of the contents of the file system cache and uses that information to determine the exclusive set of blocks that should be cached by the array. We use microbenchmarks to demonstrate that X-RAY's prediction of the file system buffer cache contents is highly accurate, and trace-based simulation to show that X-RAY considerably outperforms LRU and performs as well as other more invasive approaches. The main strength of the X-RAY approach is that it is easy to deploy - all performance gains are achieved without changes to the SCSI protocol or the file system above.
Complete amino acid sequence of the light chain of human blood coagulation factor X: evidence for identification of residue 63 as .beta.-hydroxyaspartic acid (1983)

The complete amino acid sequence of the light chain of human blood coagulation factor X has been determined by automated Edman degradation of peptides isolated from chemical and enzymatic digests of the carboxymethylated light chain. The protein consists of 139 amino acid residues, which include 11 residues of gamma-carboxyglutamic acid. The first 100 residues of the human factor X light chain exhibit approximately 80% homology when compared to the amino-terminal sequence of bovine factor X light chain. This homology decreases to approximately 50% in the remaining 39 residues of the carboxyl-terminal region of the protein. Proton nuclear magnetic resonance spectroscopy and mass spectrometry analyses of isolated residue 63 identified this residue as L-erythro-beta-hydroxyaspartic acid, a hitherto unrecognized amino acid in proteins. Evidence is also presented for the presence of this residue in the corresponding regions of the light chains of bovine factor X and bovine protein C. The biological function of beta-hydroxyaspartic acid in these proteins is unknown.
A further comparison of splitting rules for decision-tree induction (1992)

One approach to learning classification rules from examples is to build decision trees. A review and comparison paper by Mingers (Mingers, 1989) looked at the first stage of tree building, which uses a “splitting rule” to grow trees with a greedy recursive partitioning algorithm. That paper considered a number of different measures and experimentally examined their behavior on four domains. The main conclusion was that a random splitting rule does not significantly decrease classificational accuracy. This note suggests an alternative experimental method and presents additional results on further domains. Our results indicate that random splitting leads to increased error. These results are at variance with those presented by Mingers.
Electrophoretic Deposition of Star Polymer-Europium Chalcogenide Nanocomposite Films (2009)

The electrophoretic deposition of polystyrene/divinylbenzene (PS/DVB) star polymer-europium sulphide (EuS) nanocomposite films from a colloidal suspension is reported. Liquid suspension, containing both the PS/DVB star polymer and EuS nanocrystals were prepared by separately injecting dichloromethane (DCM) based solutions of EuS nanocrystals and of the star polymers, respectively, into a stratified liquid combination of hexane and DCM. Scanning electron microscopy illustrates images of the dependence of surface morphology on nanocrystal concentration of the PS/DVB-EuS star polymer film. These polymer-encased nanocrystal films may be a more practical option for the fabrication of magneto-optical thin film devices, such as optical switches, optical isolators, and optical memories.
Computer-assisted drug design (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted drug designA. J. HopfingerCite this: J. Med. Chem. 1985, 28, 9, 1133–1139Publication Date (Print):September 1, 1985Publication History Published online1 May 2002Published inissue 1 September 1985https://pubs.acs.org/doi/10.1021/jm00147a001https://doi.org/10.1021/jm00147a001research-articleACS PublicationsRequest reuse permissionsArticle Views843Altmetric-Citations82LEARN 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-Alertsclose Get e-Alerts
Template boundary definition in mammalian telomerase (2003)

Telomerase uses a short template sequence in its intrinsic RNA component to synthesize telomere repeats. Disruption of the helix P1b in human telomerase RNA or alteration of its distance from the template resulted in telomerase copying residues past the normal template boundary both in vivo and in vitro. Therefore, helix P1b is important for template boundary definition in human telomerase. Mouse telomerase RNA lacks helix P1b, and the boundary is established at 2 nt downstream of the 5'-end. The divergent structure of boundary definition elements in mammals, yeast, and ciliates suggests diverse mechanisms for template boundary definition in telomerase.