gebhart/patrepeval huggingface dataset:
Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation (2005)

Angiogenic therapy with individual growth factors or "master switch" genes is being evaluated for treatment of advanced coronary artery disease. In this study, we investigated the efficacy and mechanism of PR39, a gene capable of activating VEGF and fibroblast growth factor (FGF)-2-dependent pathways. PR39 enhances hypoxia-inducible factor-1alpha (HIF-1alpha)-dependent gene expression by selectively inhibiting proteasome degradation of this transcription factor. In addition, PR39 also stimulates expression of the FGF receptors (FGFR)-1 and syndecan-4. In a pig model of chronic myocardial ischemia, we used angiography, MRI, and microsphere regional blood flow to evaluate the efficacy of intramyocardial adenoviral protein arginine-rich peptide (Ad-PR39) injections. Ad-PR39 improved collateral scores, regional perfusion, and regional function in a dose-dependent manner. Local VEGF, VEGFR-1, VEGFR-2, syndecan, and FGFR-1 levels were 16-75% upregulated after Ad-PR39 injections as assessed by real-time PCR, suggesting upregulation of VEGF and FGF pathways. PR39 is an angiogenic peptide that improves perfusion and function of ischemic myocardium, at least in part, through collateral formation. The dual mechanism, i.e., stimulation of HIF-1alpha and FGF receptor expression, likely accounts for the functional benefits of PR39.
Fluoride ion as a base in organic synthesis (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleFluoride ion as a base in organic synthesisJames H. ClarkCite this: Chem. Rev. 1980, 80, 5, 429–452Publication Date (Print):October 1, 1980Publication History Published online1 May 2002Published inissue 1 October 1980https://pubs.acs.org/doi/10.1021/cr60327a004https://doi.org/10.1021/cr60327a004research-articleACS PublicationsRequest reuse permissionsArticle Views5485Altmetric-Citations574LEARN 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
Phase-Shifting Gabor Holographic Microscopy (2010)

A new lensless microscopy method able to recover the complex wavefront diffracted by a sample from a set of inline recorded holograms is presented. It is based on a modified Gabor-like setup where a condenser lens and a spatial light modulator (SLM) are inserted in a classical Gabor configuration. The condenser lens provides the sample's spectrum at the system Fourier plane while the SLM allows phase shifting modulation of the central spot (DC term) of the sample's spectrum. As consequence, the proposed imaging system recovers the complex amplitude distribution of the diffracted sample wavefront without an additional reference beam. Experimental results validate the proposed method and expand the Gabor method applicability beyond cases of weak diffraction assumption.
2,5-DialkyItetrahydrofurans, Common Components of the Cuticular Lipids of Lepidoptera (1998)

Abstract In more than 50 lepidopteran species 2,5-dialkyltetrahydrofurans were identified as com­ponents of the cuticular lipids. The chain length of these compounds varies between C 25 and C 37 and both cis-and trans-compounds are present. In addition, previously unknown 2-alkyl-5-(1-hydroxyalkyl)tetrahydrofurans were found in some species. The identification procedure and synthesis of representative compounds are reported.
Pathway analysis of primary central nervous system lymphoma (2008)

Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a "CNS signature." Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true "CNS signature" because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.
Control of asparagine-linked oligosaccharide chain processing: studies on bovine pancreatic ribonuclease B. An in vitro system for the processing of exogenous glycoproteins. (1984)

To gain an understanding of why the polymannose-type oligosaccharide chain of bovine pancreatic ribonuclease B is not processed to a complex-type chain in vivo, the processing of this glycoprotein was studied in two cell-free systems. Addition of native 125I-ribonuclease B to rat liver Golgi membranes in the presence of UDP-GlcNAc resulted in the conversion of the high mannose chain to a complex type as evidenced by the acquisition of resistance to digestion with endoglucosaminidase H. Processing was linearly dependent on time and on the amount of Golgi membranes. Omission of UDP-GlcNAc from the reaction mixtures completely abolished processing of the glycoprotein. Product identification studies confirmed that the formation of ribonuclease that was resistant to digestion with endoglucosaminidase H was accompanied by the appearance of a complex-type oligosaccharide that contained one or more terminal beta-GlcNAc residues. In vitro processing of 125I-ribonuclease B that had been denatured by reduction and alkylation revealed that the rate of complex chain formation was only slightly greater than that observed with the native enzyme. In contrast to the results obtained with the heterologous rat liver system, Golgi membranes from bovine pancreas failed to process native ribonuclease B to the complex form. However, bovine pancreas Golgi membranes did readily process the denatured form of the enzyme. The presence of a factor in bovine pancreas that binds only to native ribonuclease B and thereby prevents its oligosaccharide chain from being processed was considered to be unlikely on the basis of gel filtration studies and mixing experiments. These findings indicate that some aspect of the conformation of native ribonuclease B prevents one or more of the processing enzymes of bovine pancreas from acting on the oligosaccharide chain. In addition, the substrate specificity of this processing enzyme(s) differs markedly from its counterpart in rat liver. These two factors, conformation of the substrate and specificity of the processing enzymes, apparently combine to produce the high mannose oligosaccharide chain of ribonuclease B observed in vivo.
Modifying the stereochemistry of an enzyme-catalyzed reaction by directed evolution (2003)

Aldolases have potential as tools for the synthesis of stereochemically complex carbohydrates. Here, we show that directed evolution can be used to alter the stereochemical course of the reaction catalyzed by tagatose-1,6-bisphosphate aldolase. After three rounds of DNA shuffling and screening, the evolved aldolase showed an 80-fold improvement in k(cat)/K(m) toward the non-natural substrate fructose 1,6-bisphosphate, resulting in a 100-fold change in stereospecificity. (31)P NMR spectroscopy was used to show that, in the synthetic direction, the evolved aldolase catalyzes the formation of carbon-carbon bonds with unnatural diastereoselectivity, where the >99:<1 preference for the formation of tagatose 1,6-bisphosphate was switched to a 4:1 preference for the diastereoisomer, fructose 1,6-bisphosphate. This demonstration is of considerable significance to synthetic chemists requiring efficient syntheses of complex stereoisomeric products, such as carbohydrate mimetics.
In vitro selection of RNA epitopes using autoimmune patient serum (1993)

Nucleotide-specific autoimmune epitopes have not been precisely defined despite the fact that certain kinds of DNA and RNA species are known to bind autoantibodies. Our laboratory has used nucleic acid epitope libraries, consisting of randomized RNA pools, to select specific RNA conformers recognized by antibodies, including a peptide-specific antibody. In the present study, serum from a patient with systemic lupus erythematosus was used to select ligands from an RNA epitope library. The selected RNA contained sequences that were found to be similar to regions within the U1 small nuclear RNA, previously shown to react with autoantibodies. Furthermore, the selected RNA epitopes were able to inhibit autoantibody reactivity with specific regions of U1 RNA, thus demonstrating their immunologic cross-reactivity with the natural RNA epitope. Although the origins of nucleic acid-binding autoantibodies are not understood, the identification of these defined U1 RNA epitopes, in regions of the RNA where cell proteins are not known to bind, is most compatible with models of immunologic cross-reactivity or with direct presentation to the immune system rather than with anti-Id models. These experiments demonstrate that RNA epitope libraries may be used to reveal the fine specificity of autoimmune recognition and provide a useful approach to study RNA-protein interactions.
The active site residue Valine 867 in human telomerase reverse transcriptase influences nucleotide incorporation and fidelity (2007)

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, contains conserved motifs common to retroviral reverse transcriptases and telomerases. Within the C motif of hTERT is the Leu866-Val867-Asp868-Asp869 tetrapeptide that includes a catalytically essential aspartate dyad. Site-directed mutagenesis of Tyr183 and Met184 residues in HIV-1 RT, residues analogous to Leu866 and Val867, revealed that they are key determinants of nucleotide binding, processivity and fidelity. In this study, we show that substitutions at Val867 lead to significant changes in overall enzyme activity and telomere repeat extension rate, but have little effect on polymerase processivity. All Val867 substitutions examined (Ala, Met, Thr) led to reduced repeat extension rates, ranging from approximately 20 to 50% of the wild-type rate. Reconstitution of V867M hTERT and telomerase RNAs (TRs) with mutated template sequences revealed the effect on extension rate was associated with a template copying defect specific to template A residues. Furthermore, the Val867 hTERT mutants also displayed increased nucleotide incorporation fidelity, implicating Val867 as a determinant of telomerase fidelity. These findings suggest that by evolving to have a valine at position 867, the wild-type hTERT protein may have partially compromised polymerase fidelity for optimal and rapid repeat synthesis.
Three-dimensional degradable porous polymer-ceramic matrices for use in bone repair (1996)

A degradable polymer-ceramic matrix for use as a bone graft material is described. The fabrication method used produces 3-dimensional macroporous matrices which are structurally similar to cancellous bone in their porosity, mechanically similar to cancellous bone in compressive elastic modulus and chemically comparable to the mineral matrix of bone in that they contain hydroxyapatite (HA). A 50:50 copolymer of poly(lactide/glycolide) (PLAGA) reinforced by a particulate calcium phosphate ceramic, HA, was used to create a matrix composed of polymeric microspheres. The channels between these spheres were pores approximately 100 microns in diameter. Four polymer/ceramic ratios were used in matrix fabrication: 1:0, 1:1, 2.5:1, and 5:1. The mechanical behavior of the material was found to vary with ceramic content. Increased levels of HA resulted in increased compressive elastic moduli. Prior to polymer degradation, moduli ranged from a high of 1459 MPa (50% HA) to a low of 293 MPa (0% HA). Degradation studies over a 6-week period showed that 0 and 16.7% HA-containing matrices lost up to 50% of their original weight, while the 28.6 and 50% IIA-containing matrices lost up to 20% of their original weight. Increased HA matrix content translated into decreased rates of matrix degradation. Environmental scanning electron microscopy (ESEM) confirmed that the polymer matrix contained pores that were interconnected during degradation. Viewed via ESEM, 10% HA containing matrices completely degraded by 6 weeks, while 50% HA matrices remained relatively stable. These studies indicate that the porous 3-dimensional polymer/ceramic matrix may potentially be useful as a synthetic material for bone repair.
Bcl-2 leads to expression of anti-DNA B cells but no nephritis: a model for a clinical subset (1999)

Transgenic mice expressing anti-DNA antibodies have been extensively studied as a model for understanding B cell regulation in systemic lupus erythematosus (SLE). BALB/c mice transgenic for the R4A-gamma2b heavy chain of an anti-double-stranded DNA (dsDNA) antibody produce two populations of high-affinity anti-dsDNA B cells, one deleted, and the other anergized. We generated double-transgenic BALB / c mice expressing both the R4A-gamma2b heavy chain and the anti-apoptotic bcl-2 gene in the B cell compartment to study whether bcl-2 overexpression differentially affected anergic and deleted B cells. The double-transgenic mice (R4A/bcl-2) express elevated serum titers of both high- and low-affinity anti-dsDNA antibodies and display rescue of autoreactive B cells that are normally either deleted or anergized. Despite the presence of anti-dsDNA antibodies in their serum, R4A/bcl-2-transgenic mice do not develop nephritis, demonstrating that overexpression of bcl-2 is not by itself sufficient to allow disease progression. This phenotype resembles that of some SLE patients who have high titers of anti-DNA antibodies without nephritis.
Abstract 4630: Integrin αVα6 is expressed on multiple solid tumors and is a potential therapeutic target for auristatin-based antibody-drug conjugates (2012)

Abstract Antibody-drug conjugates (ADCs) are designed to deliver a targeted, potent payload directly to the tumor cell. This targeted cytoxicity can greatly augment the antitumor activity of a naked antibody and reduce the off target toxicity of free drug. Cancers of the head and neck, pancreas, bladder, lung, ovary and breast show frequent expression of integrin α6, suggesting they may be amenable to therapeutic targeting with an anti-integrin β6 ADC. We identified a therapeutic antibody that is optimal for drug delivery by screening a large panel of anti-integrin β6 ADCs on antigen-positive tumor lines. Monoclonal antibody 15H3 showed consistent potency as an ADC on solid tumor cell lines representative of the target indications. The ADC activity of 15H3 was detectable using either monomethyl auristatin E with a protease-cleavable linker (vcMMAE) or monomethyl auristatin F (mcMMAF), which requires antibody degradation. 15H3 was selected as the lead and humanized for in vivo testing. Humanized 15H3 (h15H3) retained all the properties of the mouse parental antibody, including the ability to cross-bind multiple species (human, monkey, rat, and mouse integrin α6). In vitro analysis showed that h15H3-vcMMAE and h15H3-mcMMAF internalize within a few hours and result in antigen-specific cytotoxicity of carcinoma lines. In vivo studies of integrin-α6 positive xenografts demonstrated antitumor activity. Our data suggest that integrin β6 is a promising potential ADC target for antigen-positive solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4630. doi:1538-7445.AM2012-4630
Response to high osmotic conditions and elevated temperature in Saccharomyces cerevisiae is controlled by intracellular glycerol and involves coordinate activity of MAP kinase pathways (2003)

In the yeast Saccharomyces cerevisiae, response to an increase in external osmolarity is mediated by the HOG (high osmolarity glycerol) MAP kinase pathway. HOG pathway mutant strains display osmosensitive phenotypes. Recently evidence has been obtained that the osmosensitivity of HOG pathway mutants is reduced during growth at elevated temperature (37 degrees C). A notable exception is the ste11ssk2ssk22 mutant, which displays hypersensitivity to osmotic stress at 37 degrees C. This paper reports that overexpression of FPS1 or GPD1 (encoding the glycerol transport facilitator and glycerol-3-phosphate dehydrogenase, respectively, and both affecting intracellular glycerol levels) reduces the hypersensitivity to osmotic stress of ste11ssk2ssk22 at 37 degrees C. Although in this particular HOG pathway mutant a correlation between suppression of the phenotype and glycerol content could be demonstrated, the absolute level of intracellular glycerol per se does not determine whether a strain is osmosensitive or not. Rather, evidence was obtained that the glycerol level may have an indirect effect, viz. by influencing signalling through the PKC (protein kinase C) MAP kinase pathway, which plays an important role in maintenance of cellular integrity. In order to validate the data obtained with a HOG pathway mutant strain for wild-type yeast cells, MAP kinase signalling under different growth conditions was examined in wild-type strains. PKC pathway signalling, which is manifest at elevated growth temperature by phosphorylation of MAP kinase Mpk1p, is rapidly lost when cells are shifted to high external osmolarity conditions. Expression of bck1-20 or overexpression of WSC3 in wild-type cells resulted in restoration of PKC signalling. Both PKC and HOG signalling, cell wall phenotypes and high osmotic stress responses in wild-type cells were found to be influenced by the growth temperature. The data taken together indicate the intricate interdependence of growth temperature, intracellular glycerol, cell wall structure and MAP kinase signalling in the hyperosmotic stress response of yeast.
Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. (1997)

Members of the phosphatidylinositol (PI) 3-kinase gene family, including the ataxia telangiectasia gene and the DNA-dependent protein kinase (DNA-PK), are involved in regulating cellular radiosensitivity. We have investigated two structurally unrelated PI 3-kinase inhibitors, wortmannin and LY294002, to determine whether they inhibit DNA-PK and increase cellular radiosensitivity. The PI 3-kinase inhibitors wortmannin and LY294002 were effective radiosensitizers of human tumor cells, with sensitizer enhancement ratios (at 10% survival) of 2.8 and 1.9, respectively, in SW480 cells. Wortmannin and LY294002 inhibited the kinase activity of purified DNA-PK and inactivated cellular DNA-PK kinase activity. Inhibition of cellular DNA-PK activity occurred at the same concentrations of wortmannin that caused radiosensitization, and this correlation was found in a range of tumor cell lines. However, cells deficient in either DNA-PK (scid cells) or the ataxia telangiectasia protein were also partly sensitized to radiation by wortmannin, indicating the involvement of more than one protein kinase in the mechanism of action of wortmannin. Wortmannin also affected the G2-M checkpoint. SW480 cells had a reversible G2-M delay of 20 h following irradiation. However, wortmannin-treated SW480 cells had a prolonged G2-M delay; more than 75% of cells were arrested in G2 at 50 h postirradiation. This suggests the accumulation of significant unrepaired DNA damage following inhibition of PI 3-kinase family members. Therefore, PI 3-kinase inhibitors may represent a new class of radiosensitizers that inhibit the repair of DNA damage.
Human tumor necrosis factor mutants with preferential binding to and activity on either the R55 or R75 receptor (1994)

Previously, we reported that the cytotoxic activity of human (h) tumor necrosis factor (TNF) on murine (m) L929 cells requires the integrity of three loops (positions 30-36, 84-88 and 138-150) which cluster around the interface between each two subunits of the trimeric hTNF structure. The collection of hTNF mutants was further characterized by their activity on various human cell systems as well as by their binding to the two types of hTNF receptor (R), R55 and R75. It turned out that two amino acids (Leu29 and Arg32) were specifically involved in hR75 binding, as Leu29-->Ser (L29S) and Arg32-->Trp (R32W) mutant molecules had largely lost binding to hR75, but not to hR55. In order to screen for more highly R55-specific mutants, nine other amino acids were inserted at these two positions; only the substitutions L29G and L29Y showed an increased differential binding as compared to L29S, while no further improvement was found with mutations at position 32 compared to R32W. Biological assays mediated either by hR55 or hR75 confirmed the results obtained by physical binding to purified receptors. A similar substitution in mTNF, Arg32-->Tyr, also resulted in a preferential loss of binding to hR75 and a large decrease in mR75-mediated bioactivity. Except for the double mutant L29S-R32W, all other tested amino acid substitutions in the loops at positions 30-36 or 84-88 of hTNF led to a substantial loss of affinity for both receptors and a concomitant reduction of biological activity. In the loop at positions 138-150, the non-conservative replacement of Glu by Lys at position 146 (E146K) resulted in an even lower binding to R75 as compared to R32W, while binding on and bioactivity through R55 was only slightly reduced. Remarkably, a reversed differential binding was observed after substitution at position 143 in hTNF; replacing Asp by non-conservative residues such as Tyr, Phe or Asn resulted in a much larger decrease in binding to R55 than to R75. In conclusion, receptor-specific mutants such as R32W, E146K and D143N can be used to study the function either of R55 or R75 on different human cell types. In vivo, we presume that the R55-specific mutants will retain antitumor activity in the absence of R75-dependent, severe side effects.