gebhart/patrepeval huggingface dataset:
IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration (2008)

Loss-of-function mutations in the IKBKAP gene, which encodes IKAP (ELP1), cause familial dysautonomia (FD), with defective neuronal development and maintenance. Molecular mechanisms leading to FD are poorly understood. We demonstrate that various RNA-interference-based depletions of IKAP lead to defective adhesion and migration in several cell types, including rat primary neurons. The defects could be rescued by reintroduction of wild-type IKAP but not by FD-IKAP, a truncated form of IKAP constructed according to the mutation found in the majority of FD patients. Cytosolic IKAP co-purified with proteins involved in cell migration, including filamin A, which is also involved in neuronal migration. Immunostaining of IKAP and filamin A revealed a distinct co-localization of these two proteins in membrane ruffles. Depletion of IKAP resulted in a significant decrease in filamin A localization in membrane ruffles and defective actin cytoskeleton organization, which both could be rescued by the expression of wild-type IKAP but not by FD-IKAP. No downregulation in the protein levels of paxillin or beclin 1, which were recently described as specific transcriptional targets of IKAP, was detected. These results provide evidence for the role of the cytosolic interactions of IKAP in cell adhesion and migration, and support the notion that cell-motility deficiencies could contribute to FD.
Complementary roles for CD2 and LFA‐1 adhesion pathways during T cell activation (1991)

The influence of T cell receptor (TcR) triggering on T cell adhesion function has been systematically investigated in the present studies; we show that the adhesion function of LFA-1 is minimal in non-activated T cells but is augmented within minutes following TcR-mediated activation. In contrast, CD2 function is essentially optimal in non-activated T cells and undergoes no detectable modification within 12 h of TcR stimulation. Protein kinase C activation augments LFA-1 but not CD2 adhesion function and cyclic AMP reduces LFA-1 adhesion without affecting CD2-LFA-3 interactions. Up-regulation of the LFA-1 pathway occurs in the absence of any detectable surface redistribution of this molecule, suggesting an activation dependent modification leading to a high-affinity ICAM-1 binding state. The TcR independence of CD2 adhesion function implies a critical role of the CD2 pathway in initiating cell-cell interactions prior to TcR engagement and LFA-1-ICAM-1 binding and underscores the complementary nature of the CD2 and LFA-1 adhesion pathways during the immune response.
An interactive visual language for term subsumption languages (1991)

A visual language is defined equivalent in expressive power to term subsumption languages expressed in textual form. To each knowledge representation primitive there corresponds a visual form expressing it concisely and completely. The visual language and textual languages are intertranslatable. Expressions in the language are graphs of labeled nodes and directed or undirected arcs. The nodes are labeled textually or iconically and their types are denoted by six different outlines. Computer-readable expressions in the language may be created through a structure editor that ensures that syntactic constraints are obeyed. The editor exports knowledge structures to a knowledge representation server computing subsumption and recognition, and maintaining a hybrid knowledge base of concept definitions and individual assertions. The server can respond to queries graphically displaying the results in the visual language in editable form. Knowledge structures can be entered directly in the edito...
Structural characterization of cationic liposome/poly(I:C) complexes showing high ability in eliminating prostate cancer cells (2013)

Polyriboinosinic acid–polyribocytidylic acid (poly(I:C)) is a mimic of viral double-strand (ds)RNA that induces apoptosis in many cancer cells. However, toxicity and stability issues so far prevented its application as it undergoes enzymatic degradation and bear the potential to trigger undue immune stimulation as well as autoimmune disorders. Encapsulation of antitumor drugs is frequently used to improve their effectiveness by lowering the necessary dosage. In this study we examined the ability of cationic liposomes to deliver poly(I:C) into PC3 and DU145 cell lines, derived from human bone and brain prostate cancer metastasis, respectively. The first formulation was made of the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic lipid dioleoylphosphocholine (DOPC). The second one was the binary lipid system made of the cationic 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and the zwitterionic helper lipid dioleoylphosphatidylethanolamine (DOPE), while the third formulation was the multicomponent (MC) lipid system encapsulating the four lipid species simultaneously. Synchrotron small angle X-ray scattering revealed that cationic liposome/poly(I:C) complexes exhibit lamellar phases structurally similar to cationic liposome/DNA complexes. We further found that cationic liposomes/poly(I:C) complexes were up to 10 times more efficient in eliminating metastatic prostate cancer cells than the free drug. Finally, the ability of distinct lipid formulations to induce apoptosis could inversely correlate with their endosomal escape ability. This property of cationic liposome/poly(I:C) complexes contrasts to cationic liposome/DNA complexes, where the endosomal escape ability is the rate-limiting step for the transfection efficiency.
Enhanced binding of the hypoxic cell marker [3H]fluoromisonidazole in ischemic myocardium. (1989)

The 2-nitroimidazole fluoromisonidazole is metabolically trapped in viable hypoxic cells in inverse proportion to PO2. This attribute suggests that [18F]fluoromisonidazole may be useful for imaging hypoxic tissue using positron emission tomography. To examine this potential, we studied the pharmacokinetics and biodistribution of [3H]fluoromisonidazole in six open chest dogs. In two normal dogs, plasma and urine samples were collected over a 4-hr period following i.v. injection of the drug. In four animals, regional myocardial ischemia was produced 2 hr prior to drug injection by occlusion of the circumflex coronary artery and maintained during the 4-hr sampling period. In all animals, postmortem samples of myocardium and other organs were obtained and tissue, plasma, and urine tritium activity were determined by liquid scintillation counting. In areas of reduced flow, [3H]fluoromisonidazole accumulated in myocardium in inverse proportion to myocardial blood flow measured by microspheres, indicating enhanced binding in hypoxic tissues. Maximum tissue concentrations in ischemic myocardium were two- to three-fold greater than in normal myocardium and plasma. Plasma clearance data indicate the drug is rapidly distributed into the total-body water, clears from the body with a half-life of 275 +/- 50 min, and undergoes minimal metabolism by 4 hr. We conclude [18F]fluoromisonidazole may be a suitable agent for radionuclide imaging of hypoxic myocardium.
ASIC Clouds: Specializing the Datacenter (2016)

GPU and FPGA-based clouds have already demonstrated the promise of accelerating computing-intensive workloads with greatly improved power and performance. In this paper, we examine the design of ASIC Clouds, which are purpose-built datacenters comprised of large arrays of ASIC accelerators, whose purpose is to optimize the total cost of ownership (TCO) of large, high-volume chronic computations, which are becoming increasingly common as more and more services are built around the Cloud model. On the surface, the creation of ASIC clouds may seem highlyimprobable due to high NREs and the inflexibility of ASICs. Surprisingly, however, large-scale ASIC Clouds have already been deployed by a large number of commercial entities, to implement the distributed Bitcoin cryptocurrency system. We begin with a case study of Bitcoin mining ASIC Clouds, which are perhaps the largest ASIC Clouds to date. From there, we design three more ASIC Clouds, including a YouTube-style video transcoding ASIC Cloud, a Litecoin ASIC Cloud, and a Convolutional Neural Network ASIC Cloud and show 2-3 orders of magnitude better TCO versus CPU and GPU. Among our contributions, we present a methodology that given an accelerator design, derives Pareto-optimal ASIC Cloud Servers, by extracting data from place-and-routed circuits and computational fluid dynamic simulations, and then employing clever but brute-force search to find the best jointly-optimized ASIC, DRAM subsystem, motherboard, power delivery system, cooling system, operating voltage, and case design. Moreover, we show how data center parameters determine which of the many Pareto-optimal points is TCO-optimal. Finally we examine when it makes sense to build an ASIC Cloud, and examine the impact of ASIC NRE.
Directed mutagenesis in Candida albicans: one-step gene disruption to isolate ura3 mutants. (1987)

A method for introducing specific mutations into the diploid Candida albicans by one-step gene disruption and subsequent UV-induced recombination was developed. The cloned C. albicans URA3 gene was disrupted with the C. albicans ADE2 gene, and the linearized DNA was used for transformation of two ade2 mutants, SGY-129 and A81-Pu. Both an insertional inactivation of the URA3 gene and a disruption which results in a 4.0-kilobase deletion were made. Southern hybridization analyses demonstrated that the URA3 gene was disrupted on one of the chromosomal homologs in 15 of the 18 transformants analyzed. These analyses also revealed restriction site dimorphism of EcoRI at the URA3 locus which provides a unique marker to distinguish between chromosomal homologs. This enabled us to show that either homolog could be disrupted and that disrupted transformants of SGY-129 contained more than two copies of the URA3 locus. The A81-Pu transformants heterozygous for the ura3 mutations were rendered homozygous and Ura- by UV-induced recombination. The homozygosity of a deletion mutant and an insertion mutant was confirmed by Southern hybridization. Both mutants were transformed to Ura+ with plasmids containing the URA3 gene and in addition, were resistant to 5-fluoro-orotic acid, a characteristic of Saccharomyces cerevisiae ura3 mutants as well as of orotidine-5'-phosphate decarboxylase mutants of other organisms.
Performance monitoring of java applications (2002)

Over the past few years, Java has evolved into a mature platform for developing enterprise applications. A critical factor for the commercial success of these applications is end-to-end performance, e.g., in terms of response times, throughput and availability. This raises the need for the development, validation and analysis of performance models to predict performance metrics of interest. To develop and validate performance models, insight in the execution behavior of the application is essential, requiring advanced monitoring capabilities.In this paper we introduce our Java Performance Monitoring Toolkit (JPMT). JPMT represents internal execution behavior of Java applications by event traces. An event represents the occurrence of some activity, such as thread creation, method invocation, and locking contention. Events are annotated by high-resolution performance attributes, e.g., duration of locking contention and CPU time usage by method invocations. JPMT is an open toolkit, its event trace API can be used to develop custom performance analysis applications. JPMT comes with an event trace visualizer and a command-line event trace query tool for scripting. JPMT supports event filtering during and after application execution. The instrumentation required for monitoring the application is added transparently to the user during run-time. Overhead is minimized by only instrumenting for events the user is interested in. Furthermore, the instrumentation itself is carefully optimized.This paper discusses the architecture and implementation of the toolkit in detail and reports on our experience in applying the toolkit to model a CORBA implementation.
The acceptor substrate specificity of porcine submaxillary UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase is dependent on the amino acid sequences adjacent to serine and threonine residues. (1993)

The acceptor substrate specificity of a pure polypeptide N-acetylgalactosaminyltransferase has been examined with synthetic polypeptides with sequences identical, or similar to those found in porcine mucin or human erythropoietin. The sequences adjacent to either threonine or serine markedly influence the formation of GalNAc-O-Thr and GalNAc-O-Ser. Examination of the mucin-like peptide VLGXXAV, where X is Thr, Ser, or Ala, shows only Thr-containing peptides to be acceptors. The best substrate is formed when XX is TT. Peptides with XX as either AT or TA are less effective and those with XX as either ST or TS are much less effective acceptors. The amino acids adjacent to serine in the peptide formed by residues 121-131 in human erythropoietin, PPDAASAAPLR, also markedly influence the formation of GalNAc-O-Ser. Thus, PPDASSSAPLR and PPDVVSVVPLR are about 5- and 30-fold, respectively, less active than the erythropoietin peptide. The peptide PPDGGSGGPLR is inactive. The shorter peptide DAASAAPL is also about 5-fold less active than the full-length peptide, but the peptide AASAA is inactive. These studies indicate that one transferase can form both GalNAc-O-Ser and GalNAc-O-Thr residues when the sequences adjacent to the glycosylated residue are of the proper kind. Thus, in contrast to earlier suggestions, there is no evidence that different transferases form GalNAc-O-Ser and GalNAc-O-Thr. Examination of tissue homogenates from various tissues confirms this conclusion.
Improving the treatment of hepatitis C infection in the UK (2007)

The UK lags behind its European neighbours in the identification and treatment of hepatitis C virus infection. Having recognised this problem, national guidelines are evolving based on detailed examination of clinical evidence. This article reviews recommended treatments for hepatitis C virus infection in the UK, recent advances in the understanding of how to use these treatments and new developments.
Why are mobile phones annoying? (2003)

Abstract Sixty four members of the public were exposed to the same staged conversation either while waiting in a bus station or travelling on a train. Half of the conversations were by mobile phone, so that only one end of the conversation was heard, and half were co present face-to-face conversations. The volume of the conversations was controlled at one of two levels: the actors' usual speech level and exaggeratedly loud. Following exposure to the conversation participants were approached and asked to give verbal ratings on six scales. Analysis of variance showed that mobile phone conversations were significantly more noticeable and annoying than face-to-face conversations at the same volume when the content of the conversation is controlled. Indeed this effect of medium was as large as the effect of loudness. Various explanations of this effect are explored, with their practical implications. Acknowledgements Monk and Blythe were supported by the UK EPSRC during the period of this work. We would also like to thank Virgin Trains for their part in making the study possible. Thanks are also due to Gordon Baxter and David Grayson, for their help with previous versions of this paper.
Characterization of a specific erythromegakaryocytic enhancer within the glycoprotein IIb promoter. (1992)

The gene coding for glycoprotein IIb (GPIIb), the alpha subunit of platelet integrin GPIIb/IIIa is an early and specific marker of the megakaryocytic lineage. Thus, studies on the regulation of this gene may provide helpful information on the mechanisms controlling cell specificity and differentiation in this lineage. The promoter region of this gene was isolated and analyzed to understand its tissue-specific transcriptional activity. A region extending from nucleotides -414 to -554 was found to be extremely important for the promoter function. Deletion of this region results in a 70% decrease of the promoter activity, as measured in CAT assays. This region has the properties of an enhancer. It is able to activate a heterologous promoter, in a distance- and orientation-independent manner, in both megakaryocytic and erythroid cells. This enhancer contains binding sites for nuclear factors and mutation of these sites, individually or together, abolish the enhancer activity. These nuclear factors are present in megakaryocytic and erythroid cell lineages, but they are absent in the other tested cells. One of the sites, named domain D, contains a TTATC motif that may interact with the transcription factor GATA1, active in erythroid and megakaryocytic cells. These results indicate that the promoter of a megakaryocytic gene contains a tissue specific enhancer, active in both the erythroid and the megakaryocytic lineages, and may implicate the erythroid factor GATA1.
Versatile Carbon Hybrid Films Composed of Vertical Carbon Nanotubes Grown on Mechanically Compliant Graphene Films (2010)

A hybrid system with vertical carbon nanotubes (CNTs) grown on reduced graphene films composed of overlapping and reduced graphene oxide platelets is reported. Such carbon hybrid films have excellent flexibility and stretchability (see image), can be readily transferred to any substrate including nonplanar surfaces, and were found to have Ohmic electrical contacts throughout all junctions in the CNT/metal-catalyst/graphene-film system. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
CAPI: A Coherent Accelerator Processor Interface (2015)

Heterogeneous computing systems combine different types of compute elements that share memory. A specific class of heterogeneous systems discussed in this paper pairs traditional general-purpose processing cores and accelerator units. While this arrangement enables significant gains in application performance, device driver overheads and operating system code path overheads can become prohibitive. The I/O interface of a processor chip is a well-suited attachment point from a system design perspective, in that standard server models can be augmented with application-specific accelerators. However, traditional I/O attachment protocols introduce significant device driver and operating system software latencies. With the Coherent Accelerator Processor Interface (CAPI), we enable attaching an accelerator as a coherent CPU peer over the I/O physical interface. The CPU peer features consist of a homogeneous virtual address space across the CPU and accelerator, and hardware-managed caching of this shared data on the I/O device. This attachment method greatly increases the opportunities for acceleration due to the much shorter software path length required to enable its use compared to a traditional I/O model.
Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity (1992)

A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).
Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. (2001)

Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clinical trials, including in breast cancer. R115777 inhibited growth of MCF-7 cells in vitro with an IC(50) of 0.31 +/- 0.25 microM. Exposure of MCF-7 cells to increasing concentrations of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concentrations >1 microM. After continuous exposure to 2 microM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered p.o. twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated versus control (% T/C) = 63% at day 21]. Greater inhibition was observed at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting volume. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat shock protein 40, or N-Ras were detectable. In addition, significant increases in apoptotic index and p21(WAF1/CIP1) expression were observed, concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclinical antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and/or response.