gebhart/patrepeval huggingface dataset:
Bay-43-9006 (2002)

The Ras/Raf/MEK pathway is a signaling module that controls cell growth and survival. Activation of this pathway results in a cascade of events from the cell surface to the nucleus ultimately affecting cellular proliferation, apoptosis, differentiation and transformation. Raf is a serine/threonine kinase that is a downstream effector enzyme of Ras. When activated, Raf goes on to activate MEK1 and MEK2 kinases which in turn phosphorylate and activate ERK1 and ERK2 which translocate to the nucleus where they stimulate pathways required for translation initiation and transcription activation leading to proliferation. Raf kinase has been validated as a potential and attractive target for hyperproliferative disorders such as cancer. Research has recently focused on efforts to discover potent Raf kinase inhibitors and several low-molecular-weight Raf kinase inhibitors have been described. Bis-aryl ureas were identified within this program using medicinal chemistry-directed syntheses or combinatorial libraries. After high-throughput screening of more than 200,000 compounds against recombinant Raf-1 kinase. the orally active Bay-43-9006 was identified as having potent inhibitory activity and was chosen for further development as a treatment for cancer. Bay-43-9006 has exhibited potent in vitro activity against several tumor cell lines and has displayed efficacy in human tumor xenograft models Moreover, results from phase I development in patients with a variety of cancer types indicates promising clinical efficacy for the compound.
Effect of the molecular weight of polyethylene glycol on the bioavailability of indomethacin sustained-release suppositories prepared with solid dispersions. (1987)

Conventional suppositories were prepared by using polyethylene glycol (PEG) alone, and sustained-release suppositories were prepared by using hydroxypropylmethylcellulose phthalate (HP55) -PEG 1000, 2000 and 4000 matrices. The effect of the molecular weight of PEG on the in vitro release characteristic and bioavailability in rabbits of indomethacin (IM) in those suppositories was investigated. The release rate of IM from the conventional and matrix suppositories decreased slightly with increase of the molecular weight of PEG. The bioavailability of the conventional suppositories was independent of the molecular weight of PEG, but the bioavailability of the matrix suppositories decreased with increase of the molecular weight of PEG.
Chiral synthesis of prostaglandins (PGE1) from D-glyceraldehyde (1977)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChiral synthesis of prostaglandins (PGE1) from D-glyceraldehydeGilbert Stork and Takashi TakahashiCite this: J. Am. Chem. Soc. 1977, 99, 4, 1275–1276Publication Date (Print):February 1, 1977Publication History Published online1 May 2002Published inissue 1 February 1977https://pubs.acs.org/doi/10.1021/ja00446a055https://doi.org/10.1021/ja00446a055research-articleACS PublicationsRequest reuse permissionsArticle Views2888Altmetric-Citations140LEARN 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
The Vent-Like Homeobox Gene Ventx2 Is a Novel Candidate for a Human Hematopoietic Regulatory Protein. (2005)

Abstract Identification of the genes which are critically involved in normal and leukemic hematopoiesis is a major goal for experimental and clinical hematology. Recent data indicate that a variety of regulatory molecules active in early development may also play a role in the maintenance of hematopoietic stem cells with repopulating activity. Since it was shown, that the Xvent-2 homeobox gene is part of the BMP-4 signalling pathway in Xenopus it is of particular interest to examine the expression profile and function of the human homologue Ventx2 in hematopoietic development. We first analysed Ventx2 expression by RT-PCR in CD3, CD19 and CD33 cells highly purified by FACS sort from peripheral blood of healthy donors. Expression of Ventx2 was detected in T- and B- as well as differentiated myeloid cells indicating that Ventx2 is expressed in multiple hematopoietic lineages. Furthermore, VENTX2 expression was recurrently detected in bone marrow samples from AML patients at diagnosis as determined by RT-PCR (n=6). In an attempt to characterize the functional relevance of Ventx2 expression for hematopoietic development we retrovirally engineered murine hematopoietic progenitor cells to constitutively express the gene using a MSCV-based retroviral construct with an IRES-EGFP cassette. Successfully transduced cells were injected into lethally irradiated mice or used for in vitro experiments. At the level of the clonogenic progenitor VENTX2 induced a 3fold increase in the number of CFU-G (n=5; p&amp;lt;0.001) compared to the GFP control (62 versus 25 CFU-G, respectively, per 1000 initially plated cells) without increasing the total number of colonies, indicating that VENTX2 promoted granulocytic differentiation in vitro. Re-plating assays confirmed the effect of the homeobox gene with an over 9fold increase in the number of secondary CFU-G (511 vs. 54, respectively, per 1000 initially plated cells). When the effect of VENTX-2 on the frequency of LTC-IC was determined by limiting dilution assay (n=2), no major differences were detected between the homeobox gene and the control arm (453 LTC-IC vs. 801 LTC-IC per 1x106 cells, respectively, p = n.s.). Furthermore, the number of colonies generated per LTC-IC did not significantly differ between the two arms (17 colonies for VENTX2 and 26 colonies for the control). In NOD/SCID mice VENTX2 induced a 2.9fold increase in the proportion of CD15+ mature myeloid cells within the GFP-positive compartment (n=7) compared to the control (n=9)(6.4 % vs. 2.2 %, respectively; p&amp;lt;0.02), translating into 4 x 106 (± 1 x 106) human CD15+ /GFP+ cells per mouse in the VENTX2 group compared to 2x106 cells (± 6 x 105) in the control. These findings characterize VENTX2 as a novel regulatory protein in human hematopoiesis and add information about the role of non-clustered homeobox genes in early blood development.
Manufacturing of recombinant therapeutic proteins in microbial systems (2006)

Recombinant therapeutic proteins have gained enormous importance for clinical applications. The first recombinant products have been produced in E. coli more than 20 years ago. Although with the advent of antibody-based therapeutics mammalian expression systems have experienced a major boost, microbial expression systems continue to be widely used in industry. Their intrinsic advantages, such as rapid growth, high yields and ease of manipulation, make them the premier choice for expression of non-glycosylated peptides and proteins. Innovative product classes such as antibody fragments or alternative binding molecules will further expand the use of microbial systems. Even more, novel, engineered production hosts and integrated technology platforms hold enormous potential for future applications. This review summarizes current applications and trends for development, production and analytical characterization of recombinant therapeutic proteins in microbial systems.
Oligodendrocytes but not astrocytes express apolipoprotein E after injury of rat optic nerve (1989)

Apolipoprotein E (apoE), a lipid-binding glycoprotein involved in transport and metabolism of phospholipids and cholesterol, is synthesized and secreted at elevated rates following transection of mature rat peripheral and central nerves. In the peripheral nervous system (PNS) infiltrating macrophages express apoE during Wallerian degeneration. Following injury of the optic nerve (ON) apoE synthesis is significantly stimulated but the apoE-expressing cells have thus far not been identified. This study used 1 micron and thin cryosections to identify the cellular source of apoE in transected ON. Serial 1 micron frozen sections were stained by avidin-biotin-peroxidase complex immunocytochemistry by using a specific antiserum to apoE and by antibodies that identify different cell types: glial fibrillary acidic protein (GFAP) for astrocytes, 2',3'-cyclic nucleotide-3' phosphodiesterase (CNP) for oligodendrocytes, and ED1 for macrophages. In normal ON both astrocytes and oligodendrocytes were apoE-positive. One week after ON transection oligodendrocytes accounted for the majority of apoE-positive cells, while apoE immunoreactivity had disappeared from astroglial cell bodies and processes. In contrast to the PNS only a few ED1/apoE-positive macrophages were present in ON 7 days after transection. By using immunogold-labeled ultrathin cryosections apoE could be localized in the Golgi apparatus of oligodendrocytes, indicating synthesis by these cells. Our data suggest that oligodendrocyte-derived apoE protein may participate in the redistribution of myelin lipids after CNS injury.
The Sequence Alteration Associated with a Mutational Hotspot in p53 Protects Cells From Lysis by Cytotoxic T Lymphocytes Specific for a Flanking Peptide Epitope (1998)

A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264-272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.264-272 peptide-specific CTLs. Synthetic 27-mer p53 polypeptides covering the antigenic nonamer region 264-272 of p53 were used as proteasome substrates to investigate whether the R to H mutation at the P1' position of the COOH terminus of the epitope affects proteasome-mediated processing of the protein. Analysis of the generated products by tandem mass spectrometry and the kinetics of polypeptide processing in conjunction with CTL assays demonstrate that the R to H mutation alters proteasomal processing of the p53 protein by inhibiting proteolytic cleavage between residues 272 and 273. This prevents the release of the natural CTL epitope that spans flanking residues 264-272 as well as a putative precursor peptide. These results demonstrate that mutation of p53 not only leads to malignant transformation but may also, in some instances, affect immune surveillance and should be considered in the design of cancer vaccines.
Neural Network-Based Face Detection (1999)

Object detection is a fundamental problem in computer vision. For such applications as image indexing, simply knowing the presence or absence of an object is useful. Detection of faces, in particular, is a critical part of face recognition and, and critical for systems which interact with users visually. Techniques for
Microvascular and Neuronal Consequences of Common Carotid Artery Thrombosis and Platelet Embolization in Rats (1993)

The microvascular and neuronal consequences of nonocclusive common carotid artery (CCA) thrombosis were documented in rats. Thrombosis of the CCA was produced by a rose bengal-mediated photochemical insult and regional patterns of blood-brain barrier (BBB) disruption were documented by horseradish peroxidase (HRP) histochemistry at 15 min (n = 12), 4 h (n = 3), 1 day (n = 5) or 7 days (n = 5) after vascular injury. At 15 min and 4 h after thrombosis, multiple foci of BBB disruption were present throughout the thrombosed hemisphere; protein leakage was occasionally detected contralaterally. Extravasated HRP was associated with well-perfused arterioles and arterioles containing luminal platelet aggregates at different stages of degranulation. Evidence for local platelet adhesion and aggregation or endothelial disruption at these sites was not detected. However, HRP-containing endothelial plasmalemmal vesicles were present at leaky sites. Variable degrees of parenchymal injury were documented including dendritic and astrocytic swelling with neuronal necrosis. By 1 day after CCA thrombosis, the overall frequency of permeable sites, more commonly associated with luminal leukocytes and parenchymal necrosis, was reduced. At 7 days, vessels permeable to HRP were associated with tissue necrosis, reactive astrocytes and microglial infiltration. Arteriole wall thickening and leukocyte accumulation within arterioles and venules were also detected. Widespread platelet embolization leading to variable degrees of BBB disruption and tissue injury occurs after CCA thrombosis. Acute abnormalities in vascular permeability are thus hypothesized to play an important role in the acute pathogenesis of cerebrovascular thrombosis. Delayed leukocyte accumulation in this model of embolic infarction may represent a secondary insult to the injured brain.
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets (2011)

Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.
A human leptin mutant induces weight gain in normal mice (1997)

Leptin, a fat secreted hormone, regulates ingestive behaviour and energy balance by binding to a specific receptor. Using site-directed mutagenesis, we screened for single amino acid residues in human leptin which are critical for receptor binding and biological activity. Here we report that one of these mutants has in vivo antagonistic properties. An Arg to Gln substitution at position 128 of human leptin does not affect receptor binding but knocks out biological activity. Repeated injection of R128Q in normal C57BL/6J mice results in a progressive increase in body weight. This demonstrates that R128Q is able to interfere with the negative feedback control of endogenous leptin. This mutant could be of therapeutic use for wasting disorders, such as anorexia and cachexia, where weight gain would be beneficial.
Excitatory synaptic transmission in cultures of rat olfactory bulb (1990)

1. Olfactory bulb neurons were dissociated from neonatal rats and plated at low density on a confluent layer of olfactory bulb astrocytes. Intracellular stimulation of presumptive mitral/tufted (M/T) cells evoked monosynaptic excitatory postsynaptic potentials (EPSPs) in adjacent neurons. Whole-cell recording techniques and a flow-pipe drug delivery system were used to compare EPSPs with voltage-clamp recordings of currents evoked by excitatory amino acids (EAA) including N-acetylaspartylglutamate (NAAG), a putative mitral cell transmitter. 2. Cultured olfactory bulb neurons were morphologically and physiologically distinct. Large pyramidal-shaped neurons were present, which were NAAG immunoreactive; stimulation of these neurons invariably evoked EPSPs, suggesting that they were M/T cells. The majority of small bipolar neurons were glutamic acid decarboxylase (GAD) immunoreactive consistent with granule or periglomerular gamma-aminobutyric acid (GABA)ergic interneurons. 3. Monosynaptic EPSPs between M/T cells could be separated into fast and slow components by the use of EAA receptor antagonists. A fast component with a time-to-peak of 7.7 +/- 1.0 (SE) ms and half-width of 31.8 +/- 7.4 ms was blocked by the non-NMDA receptor antagonist 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX, 2.5 microM). The slow component (time-to-peak = 41.4 +/- 7.2 ms; half-width = 218.9 +/- 40.4 ms) was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5, 100 microM). 4. Under voltage clamp, flow-pipe applications of NAAG (10-1,000 microM) evoked inward currents at a holding potential of -60 mV in Mg-free solutions.(ABSTRACT TRUNCATED AT 250 WORDS)
Structural and Immunological Characterization of Recombinant Pan b 1, a Major Allergen of Northern Shrimp, <b><i>Pandalus borealis</i></b> (2012)

A recombinant tropomyosin from P. borealis was generated that can be used in diagnostics and further studies on tropomyosin allergenicity and specific immunotherapy.
Separate GTP Binding and GTPase Activating Domains of a Gα Subunit (1993)

Most members of the guanosine triphosphatase (GTPase) superfamily hydrolyze guanosine triphosphate (GTP) quite slowly unless stimulated by a GTPase activating protein or GAP. The alpha subunits (G alpha) of the heterotrimeric G proteins hydrolyze GTP much more rapidly and contain an approximately 120-residue insert not found in other GTPases. Interactions between a G alpha insert domain and a G alpha GTP-binding core domain, both expressed as recombinant proteins, show that the insert acts biochemically as a GAP. The results suggest a general mechanism for GAP-dependent hydrolysis of GTP by other GTPases.
Assessing THK523 selectivity for tau deposits in Alzheimer’s disease and non–Alzheimer’s disease tauopathies (2014)

The results of this study suggest that (18)F-THK523 selectively binds to paired helical filament tau in AD brains but does not bind to tau lesions in non-AD tauopathies, or to α-synuclein in PD brains.
Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing’s Sarcoma and Prostate Carcinoma (2012)

FLI1 and ERG, the major ETS transcription factors involved in rearrangements in the Ewing's sarcoma family of tumors (ESFT) and in prostate carcinomas (PCa), respectively, belong to the same subfamily, having 98% sequence identity in the DNA binding domain. We therefore decided to investigate whether the aberrant transcription factors in both malignancies have some common downstream targets. We crossed a publicly available list of all putative EWSR1-FLI1 target genes in ESFT with our microarray expression data on 24 PCa and 6 non-malignant prostate tissues (NPT) and choose four genes among the top-most differentially expressed between PCa with (PCa ERG+) and without (PCa ETS-) ETS fusion genes (HIST1H4L, KCNN2, ECRG4 and LDOC1), as well as four well-validated direct targets of the EWSR1-FLI1 chimeric protein in ESFT (NR0B1, CAV1, IGFBP3 and TGFBR2). Using quantitative expression analysis in 16 ESFT and seven alveolar rhabdomyosarcomas (ARMS), we were able to validate the four genes previously described as direct targets of the EWSR1-FLI1 oncoprotein, showing overexpression of CAV1 and NR0B1 and underexpression of IGFBP3 and TGFBR2 in ESFT as compared to ARMS. Although none of these four genes showed significant expression differences between PCa ERG+ and PCa ETS-, CAV1, IGFBP3 and TGFBR2 were less expressed in PCa in an independent series of 56 PCa and 15 NPT, as also observed for ECRG4 and LDOC1, suggesting a role in prostate carcinogenesis in general. On the other hand, we demonstrate for the first time that both HIST1H4L and KCNN2 are significantly overexpressed in PCa ERG+ and that ERG binds to the promoter of these genes. Conversely, KCNN2 was found underexpressed in ESFT relative to ARMS, suggesting that the EWSR1-ETS oncoprotein may have the opposite effect of ERG rearrangements in PCa. We conclude that aberrant ETS transcription factors modulate target genes differently in ESFT and PCa.
Carbon monoxide‐induced vasorelaxation and the underlying mechanisms (1997)

1. Carbon monoxide (CO) induced a concentration-dependent relaxation of isolated rat tail artery tissues which were precontracted with phenylephrine or U-46619. This vasorelaxing effect of CO was independent of the presence of the intact endothelium. 2. The CO-induced vasorelaxation was partially inhibited by the blockade of either the cyclicGMP pathway or big-conductance calcium-activated K (KCa) channels. When both the cyclicGMP pathway and KCa channels were blocked, the CO-induced vasorelaxation was completely abolished. 3. Incubation of vascular tissues with hemin, in order to enhance the endogenous production of CO, suppressed the phenylephrine-induced vasocontraction in a time- and concentration-dependent manner. The hemin-induced suppression of the vascular contractile response to phenylephrine was abolished after the vascular tissues were co-incubated with either oxyhaemoglobin or zinc protoporphyrin-IX, suggesting an induced endogenous generation of CO from vascular tissues. 4. The effect of hemin incubation on vascular contractility did not involve the endogenous generation of nitric oxide. 5. Our results suggest that CO may activate both a cyclicGMP signalling pathway and KCa channels in the same vascular tissues, and that the endogenously generated CO may significantly affect the vascular contractile responses.
Distributed Convex Optimization for Electric Vehicle Aggregators (2016)

One of the main challenges for electric vehicle (EV) aggregators is the definition of a control infrastructure that scales to large EV numbers. This paper proposes a new optimization framework for achieving computational scalability based on the alternating directions method of multipliers, which allows for distributing the optimization process across several servers/cores. We demonstrate the performance and versatility of our framework by applying it to two relevant aggregator objectives: 1) valley filling; and 2) cost-minimal charging with grid capacity constraints. Our results show that the solving time of our approach scales linearly with the number of controlled EVs and outperforms the centralized optimization benchmark as the fleet size becomes larger.