gebhart/patrepeval huggingface dataset:
A novel phosphatidylinositol 3-kinase inhibitor, ZSTK474 exerted antitumor activity against human tumor xenografts by oral administration (2005)

1691 Phosphatidylinositol 3-kinase (PI3K) is a promising molecular target of cancer therapy since it is a key enzyme playing important roles in various biological pathways such as cell survival, vesicle transport and cytoskeletal rearrangement and is also known to be involved in tumorigenesis. However, little anticancer agents targeting PI3K have been developed yet. We synthesized thousands of s-triazine derivatives and found by cell-based screening 2-(2-difluoromethylbenzoimidazol-1-yl)-4, 6-dimorpholino-1, 3, 5-triazine (ZSTK474) with potent antiproliferative activity. To predict the mode of action of ZSTK474, we exploited the COMPARE analysis based on the chemosensitivity database of a panel of 39 human cell lines. It revealed that ZSTK474 significantly correlated with LY294002 and wortmannin, suggesting that ZSTK474 inhibits PI3K. Then, we biochemically confirmed that ZSTK474 inhibited PI3K at concentrations of 10-100 nM. The inhibition was reversible as was the case of LY294002. Concerning the structure activity relationship, the difluoromethyl group of ZSTK474 was important for inhibiting both cell growth and PI3K. Furthermore, PI3K-inhibitory activities of several s-triazine derivatives significantly correlated with their growth-inhibitory activities. These results suggested that ZSTK474 inhibited cell proliferation through inhibiting PI3K activity. The computer-aided molecular modeling of PI3K-ZSTK474 complex revealed that ZSTK474 could bind to the ATP-binding site of PI3K, and that overall arrangement of ZSTK474 at the site was similar to that of ATP, but not of LY294002. We investigated the effects of ZSTK474 on the cellular signaling pathways and examined its anti tumor activity. ZSTK474 decreased the PDGF-dependent membrane ruffling of murine embryonic fibroblast cells, in which the PDGF-dependent generation of phosphatidylinositol-3,4,5-triphosphate was also reduced. ZSTK474 inhibited the phosphorylation of PI3K-downstream components, Akt and glycogen synthase kinase-3beta, and it decreased the cyclin D1 level. ZSTK474 showed potent antitumor activity by oral administration against murine solid tumors and human cancer xenografts. Severe body weight loss or serious bone marrow toxicity was not observed during the daily oral administrations for more than 10 days. The reduction of the Akt-phosphorylation and the cyclin D1 level in the tumor following ZSTK474 administration was confirmed. In conclusion, we found a novel PI3K inhibitor ZSTK474, and demonstrated its potent antitumor efficacy by oral administration without serious toxicity. ZSTK474 could be orally administered and showed favorable pharmacokinetic properties, which can be great advantages for clinical cancer treatment. ZSTK474 is a promising new anticancer agent for development toward clinical investigation.
From Feedforward to Recurrent LSTM Neural Networks for Language Modeling (2015)

Language models have traditionally been estimated based on relative frequencies, using count statistics that can be extracted from huge amounts of text data. More recently, it has been found that neural networks are particularly powerful at estimating probability distributions over word sequences, giving substantial improvements over state-of-the-art count models. However, the performance of neural network language models strongly depends on their architectural structure. This paper compares count models to feedforward, recurrent, and long short-term memory (LSTM) neural network variants on two large-vocabulary speech recognition tasks. We evaluate the models in terms of perplexity and word error rate, experimentally validating the strong correlation of the two quantities, which we find to hold regardless of the underlying type of the language model. Furthermore, neural networks incur an increased computational complexity compared to count models, and they differently model context dependences, often exceeding the number of words that are taken into account by count based approaches. These differences require efficient search methods for neural networks, and we analyze the potential improvements that can be obtained when applying advanced algorithms to the rescoring of word lattices on large-scale setups.
Securing Dynamic Distributed Storage Systems Against Eavesdropping and Adversarial Attacks (2011)

We address the problem of securing distributed storage systems against eavesdropping and adversarial attacks. An important aspect of these systems is node failures over time, necessitating, thus, a repair mechanism in order to maintain a desired high system reliability. In such dynamic settings, an important security problem is to safeguard the system from an intruder who may come at different time instances during the lifetime of the storage system to observe and possibly alter the data stored on some nodes. In this scenario, we give upper bounds on the maximum amount of information that can be stored safely on the system. For an important operating regime of the distributed storage system, which we call the bandwidth-limited regime, we show that our upper bounds are tight and provide explicit code constructions. Moreover, we provide a way to short list the malicious nodes and expurgate the system.
Preserved epitope‐specific T cell activation by recombinant Bet v 1‐MBP fusion proteins (1998)

Using crude preparations of recombinant fusion proteins of Bet v 1 with MBP, multiple T cell epitopes were identified in Bet v 1. As T cell activation is preserved in this system, the generation of recombinant allergens with TH1-inducing proteins as fusion partners might be considered as a T-cell targeted approach for specific immunotherapy.
Leflunomide Aventis Pharma. (2001)

Hoechst Marion Roussel (HMR; now Aventis Pharma) launched leflunomide (HWA-486), an immunomodulator and a disease-modifying antirheumatic drug (DMARD), for the treatment of rheumatoid arthritis (RA) in the US in late 1998 [310118]. By August 2000, the compound had been launched extensively across all of Latin America and in all major European countries [380046]. The compound is also under preclinical investigationfor the prevention of transplant rejection [279727], [304402]. In 1998, HMR filed for approvalfor RA in Europe [279727]. In September 1998, the FDA approved leflunomide for the treatment of active RA in adults and it was launched shortly thereafter [298204], [299258], [310118]. In September 1999, the EU Commission accepted the view of the Committee for Proprietary Medicinal Products, published in May 1999 [326040], [337534], and gave approval for the use of leflunomide in RA in adults [339128]. Lehman Brothers has reported that EU launch was delayed by rare side effects including pancytopenia [354434]. In August 1998, the Arthritis Advisory Committee unanimously recommended that leflunomide be contraindicatedfor pregnancy, and that a pregnancy registry should be established to monitor possible teratogenic effects of the drug [296187]. Kyorin had a licence to develop leflunomide in Japan. Product approval was scheduled for 1998 [159079], but no development has been reported since 1994. Preclinical studies in an animal model of experimental allergic encephalomyelitis (EAE) have shown leflunomide to be a powerful immunosuppressant which may have potential in diseases such as multiple sclerosis [187881]. Leflunomide is rapidly processed in vivo to its active metabolite, A-771726 (RS-61980) [202941], [253615]. In 1996, leflunomide was designated as one of HMR's nine top-priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].
Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation (2008)

CD8(+) T cells recognize peptide fragments of endogenously synthesized antigens of cancers or viruses, presented by MHC I molecules. Such antigen presentation requires the generation of peptides in the cytosol, their passage to the endoplasmic reticulum, loading of MHC I with peptides, and transport of MHC I-peptide complexes to the cell surface. Heat-shock protein (hsp) 90 is a cytosolic chaperone known to associate with peptide and peptide precursors of MHC I epitopes. We report here that treatment of cells with hsp90 inhibitors leads to generation of "empty" MHC I caused by inhibited loading of MHC I with peptides. Inhibition of hsp90 does not inhibit synthesis of MHC I, nor does it affect the activity of proteasomes. Hsp90-inhibited cells, such as proteasome-inhibited cells, are poor stimulators of T lymphocytes. The role of hsp90 in presentation of an ovalbumin epitope is shown to be at a postproteasomal step: hsp90 associates with N-terminally extended precursors of the SIINFEHL epitope, and such peptides are depleted from hsp90 preparations in hsp90-inhibited cells. Inhibition of hsp90 in the antigen donor cell compromises their ability to cross-prime. Conversely, stressed cells expressing elevated hsp90 levels show a heat-shock factor-dependent, enhanced ability to cross-prime. These results demonstrate a substantial role for hsp90 in chaperoning of antigenic peptides in direct and indirect presentation. The introduction of a stress-inducible component in these pathways has significant implications for their modulation during fever and infection.
Dynamic tactile sensing: perception of fine surface features with stress rate sensing (1993)

Dynamic tactile sensing, which is defined as sensing during motion for perception of high spatial and temporal frequencies, is presented. Applications include sensing fine surface features and textures and monitoring contact conditions for dextrous manipulation. One type of dynamic tactile sensor, the stress rate sensor, is described in detail. It uses piezoelectric polymer transducers to measure the changes in stress induced in the sensor's rubber skin as it traverses small surface features and textures. The signals are interpreted with the aid of a solid mechanics model of the contact interaction and a linear deconvolution filter. Experimental verification of the sensor's performance, including the detection of surface features only 6.5 mu m high, are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Using transparent compression to improve SSD-based I/O caches (2010)

Flash-based solid state drives (SSDs) offer superior performance over hard disks for many workloads. A prominent use of SSDs in modern storage systems is to use these devices as a cache in the I/O path. In this work, we examine how transparent, online I/O compression can be used to increase the capacity of SSD-based caches, thus increasing the costeffectiveness of the system. We present FlaZ, an I/O system that operates at the block-level and is transparent to existing file-systems. To achieve transparent, online compression in the I/O path and maintain high performance, FlaZ, provides support for variable-size blocks, mapping of logical to physical blocks, block allocation, and cleanup. FlaZ, mitigates compression and decompression overheads that can have a significant impact on performance by leveraging modern multicore CPUs. We implement FlaZ, in the Linux kernel and evaluate it on a commodity server with multicore CPUs, using TPC-H, PostMark, and SPECsfs. Our results show that compressed caching trades off CPU cycles for I/O performance and enhances SSD efficiency as a cache by up to 99%, 25%, and 11% for each workload, respectively.
Studies of protein hydration in aqueous solution by direct NMR observation of individual protein-bound water molecules (1989)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStudies of protein hydration in aqueous solution by direct NMR observation of individual protein-bound water moleculesGottfried Otting and Kurt WuethrichCite this: J. Am. Chem. Soc. 1989, 111, 5, 1871–1875Publication Date (Print):March 1, 1989Publication History Published online1 May 2002Published inissue 1 March 1989https://pubs.acs.org/doi/10.1021/ja00187a050https://doi.org/10.1021/ja00187a050research-articleACS PublicationsRequest reuse permissionsArticle Views983Altmetric-Citations249LEARN 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
Principles of Digital Dynamic-Range Compression (2005)

This article provides an overview of dynamic-range compression in digital hearing aids. Digital technology is becoming increasingly common in hearing aids, particularly because of the processing flexibility it offers and the opportunity to create more-effective devices. The focus of the paper is on the algorithms used to build digital compression systems. Of the various approaches that can be used to design a digital hearing aid, this paper considers broadband compression, multi-channel filter banks, a frequency-domain compressor using the FFT, the side-branch design that separates the filtering operation from the frequency analysis, and the frequency-warped version of the side-branch approach that modifies the analysis frequency spacing to more closely match auditory perception. Examples of the compressor frequency resolution, group delay, and compression behavior are provided for the different design approaches.
Clomipramine in the treatment of rapid (premature) ejaculation (1999)

Twenty-three premature ejaculators (PEs) and 11 control subjects were administered 25 mg of clomipramine in a double-blind, placebo-controlled, crossover design study. During 2-week trials, subjects took either the drug or the placebo 4 to 6 hours prior to sexual activity. Daily diary data revealed that, for both groups, orgasmic latency was significantly increased when taking the clomipramine. For the PEs, the average increase in orgasmic latency during intercourse was from less than 1 minute to more than 3.5 minutes. Subjects also participated in two laboratory sessions while on the drug and placebo. During these lab sessions they were exposed to erotic videos with and without the addition of vibrotactile stimulation to the penis. Results from the laboratory data support those from the diaries. Specifically, PEs were significantly less likely to reach orgasm during the lab sessions while on the clomipramine than while on the placebo. Further, they reported a significantly greater sense of control over their orgasm while on the drug. The results of this study, along with previous research, strongly support the value of low doses of clomipramine in the treatment of premature ejaculation, specifically when taken on an as-needed basis as little as 4 hours prior to sexual activity. It is important to note, however, that the beneficial effects of the drug were not uniform across clinical subjects. In this study, those PEs with the shortest orgasmic latencies while on the placebo were the least likely to substantially improve while on the drug. Additional research is necessary to determine whether changes in the timing and dosage of the clomipramine administration can extend the benefits of the drug to those with the shortest latencies.
Mass Production of Genetically Modified <em>Aedes aegypti</em> for Field Releases in Brazil (2014)

New techniques and methods are being sought to try to win the battle against mosquitoes. Recent advances in molecular techniques have led to the development of new and innovative methods of mosquito control based around the Sterile Insect Technique (SIT)(1-3). A control method known as RIDL (Release of Insects carrying a Dominant Lethal)(4), is based around SIT, but uses genetic methods to remove the need for radiation-sterilization(5-8). A RIDL strain of Ae. aegypti was successfully tested in the field in Grand Cayman(9,10); further field use is planned or in progress in other countries around the world. Mass rearing of insects has been established in several insect species and to levels of billions a week. However, in mosquitoes, rearing has generally been performed on a much smaller scale, with most large scale rearing being performed in the 1970s and 80s. For a RIDL program it is desirable to release as few females as possible as they bite and transmit disease. In a mass rearing program there are several stages to produce the males to be released: egg production, rearing eggs until pupation, and then sorting males from females before release. These males are then used for a RIDL control program, released as either pupae or adults(11,12). To suppress a mosquito population using RIDL a large number of high quality male adults need to be reared(13,14). The following describes the methods for the mass rearing of OX513A, a RIDL strain of Ae. aegypti (8), for release and covers the techniques required for the production of eggs and mass rearing RIDL males for a control program.
Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1 (2017)

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC<sub>50</sub> = 12 nM, D<sub>max</sub> = 96%) with excellent selectivity against a related kinase IKKε, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.
Novel tetracyclic spiropiperidines. 1. 3-Aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidines] as potential antidepressants (1981)

A series of 3-aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine] derivatives was synthesized and evaluated pharmacologically for potential psychotropic activity. Potent antidepressant-like activity was noted throughout the series, as assessed by tetrabenazine (TBZ) ptosis prevention in mice and potentiation of 5-hydroxytryptophan (5-HTP) induced behavioral effects in rats. A possible therapeutic advantage of the title compounds appears to be the overall low anticholinergic potential in comparison with the classic tricyclic antidepressants. Several congeners with nuclear halogen substitution also exhibited CNS stimulant properties, as evidenced by their ability to induce a dopamine agonist-like stereotypy and to increase the spontaneous motor activity in mice.
Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases (2007)

Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nepsilon2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this "gain of function phenotype" could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
Combination of a Fusogenic Glycoprotein, Prodrug Activation, and Oncolytic Herpes Simplex Virus for Enhanced Local Tumor Control (2006)

We have previously developed an oncolytic herpes simplex virus-1 based on a clinical virus isolate, which was deleted for ICP34.5 to provide tumor selected replication and ICP47 to increase antigen presentation as well as tumor selective virus replication. A phase I/II clinical trial using a version of this virus expressing granulocyte macrophage colony-stimulating factor has shown promising results. The work reported here aimed to develop a version of this virus in which local tumor control was further increased through the combined expression of a highly potent prodrug activating gene [yeast cytosine deaminase/uracil phospho-ribosyltransferase fusion (Fcy::Fur)] and the fusogenic glycoprotein from gibbon ape leukemia virus (GALV), which it was hoped would aid the spread of the activated prodrug through the tumor. Viruses expressing the two genes individually or in combination were constructed and tested, showing (a) GALV and/or Fcy::Fur expression did not affect virus growth; (b) GALV expression causes cell fusion and increases the tumor cell killing at least 30-fold in vitro and tumor shrinkage 5- to 10-fold in vivo; (c) additional expression of Fcy::Fur combined with 5-fluorocytosine administration improves tumor shrinkage further. These results indicate, therefore, that the combined expression of the GALV protein and Fcy::Fur provides a highly potent oncolytic virus with improved capabilities for local tumor control. It is intended to enter the GALV/Fcy::Fur expressing virus into clinical development for the treatment of tumor types, such as pancreatic or lung cancer, where local control would be anticipated to be clinically advantageous.