gebhart/patrepeval huggingface dataset:
Synthesis and biological activities of a phosphorodithioate analog of 2′, 5′-oligoadenylate (1995)

To enhance the resistance of 2-5A (pppA2'p5'A2'p5'A) to degradation by exo- and endonucleases, a phosphorodithioate analog was synthesized using a solid-phase phosphite triester approach with N6-benzoyl-5'-O-dimethoxytrityl-3'-O-t-butyldimethylsilyladenosine 2'-[S-(beta-thiobenzoylethyl)-pyrrolidinophosphorothioamidit e]. 5'-Monophosphorylation was accomplished with 2-[2-(4,4'-dimethoxytrityloxy)-ethylsulfonyl]ethyl-(2-cyanoe thyl)-(N,N- diisopropyl)-phosphoramidite. The resulting product, p5'A2'(s2p)- 5'A2'(s2p)5'A, was approximately 10-fold less effective as an activator of purified human recombinant 2-5A-dependent RNase than was 2-5A itself. This loss of activation ability was related directly to the loss of binding ability of the phosphorodiothioate analog. As predicted, p5'A2'(s2p)5'A2' (s2p)5'A was stable to snake venom phosphodiesterase and the nucleolytic activities of both human lymphoblastoid CEM cell extracts and human serum, under conditions that led to facile degradation of parent 2-5A. This nuclease stability permitted the observation of the CEM cell extracts and human serum phosphatase activity which led to 5'-dephosphorylation of p5'A2'(s2p)5'A2'(s2p)5'A.
Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on AAV hairpin DNA (1996)

Both the Rep68 and Rep78 proteins of adeno-associated virus type 2 (AAV) bind to AAV terminal repeat hairpin DNA and can mediate site-specific nicking in vitro at the terminal resolution site (trs) within the terminal repeats. To define the regions of the Rep proteins required for these functions, a series of truncated Rep78 derivatives was created. Wild-type and mutant proteins were synthesized by in vitro translation and analyzed for AAV hairpin DNA binding, trs endonuclease activity, and interaction on hairpin DNA. Amino-terminal deletion mutants which lacked the first 29 or 79 amino acid residues of Rep78 did not bind hairpin DNA, which is consistent with our previous identification of a DNA-binding domain in this region. Progressive truncation of the carboxyl-terminal region of Rep78 did not eliminate hairpin DNA binding until the deletion reached amino acid 443. The electrophoretic mobility of the Rep-specific protein-DNA complexes was inversely related to the molecular weight of the Rep derivative. Analysis of the C-terminal deletion mutants by the trs endonuclease assay identified a region (amino acids 467 to 476) that is essential for nicking but is not necessary for DNA binding. When endonuclease-positive, truncated Rep proteins that bound hairpin DNA were mixed with full-length Rep78 or Rep68 protein in electrophoretic mobility shift assays, a smear of protein-DNA complexes was observed. This smear migrated at an intermediate position with respect to the bands generated by the proteins individually. An antibody recognizing only the full-length protein produced a novel supershift band when included in a mixed binding assay containing Rep68 and a truncated Rep mutant. These experiments suggest that the Rep proteins can form hetero-oligomers on the AAV hairpin DNA.
Place Versus Response Learning Revisited: Tests of Blocking on the Radial Maze. (2005)

Neurobiological and behavioral research indicates that place learning and response learning occur simultaneously, in parallel. Such findings seem to conflict with theories of associative learning in which different cues compete for learning. The authors conducted place+response training on a radial maze and then tested place learning and response learning separately by reconfiguring the maze in various ways. Consistent with the effects of manipulating place and response systems in the brain (M. G. Packard & J. L. McGaugh, 1996), well-trained rats showed strong place learning and strong response learning. Three experiments using associative blocking paradigms indicated that prior response learning interferes with place learning. Blocking and related tests can be used to better understand how memory systems interact during learning.
TGF‐β–induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring (2007)

Transforming-growth factor-beta (TGF-beta) is a pleiotrophic growth factor that is synthesized by many cells in the body. This growth factor is chemotactic for fibroblasts, stimulates fibroblast proliferation, and increases the synthesis of a number of extracellular matrix proteins including collagens. The TGF-beta activator protein is a transacting factor, which binds to the TGF-beta element in the distal promoter of the COL1A1 collagen gene and induces transcription of this gene. Although transient TGF-beta 1 activity participates in repair and regeneration of tissues, persistent TGF-beta 1 function affects excessive fibrosis and ultimately scarring of both skin and internal organs. Scarring of internal organ (e.g., liver and lung) results in a loss of function and ultimately death may occur. The central issue of this review is that phosphorothioate double-stranded decoys or other decoys decrease procollagen gene expression, procollagen synthesis, and collagen during fibrogenesis. The rationale is that the decoys containing the TGF-beta element or other gene transcription regulatory CIS-elements bind the transacting proteins preventing the latter from binding to the CIS-element in the 5'-flanking region of the natural gene resulting in transcription inhibition. We will, in part, focus on aspects involved in TGF-beta 1-induced fibrosis that occur during fibrogenesis and the use of the dsTGF-beta element containing oligodeoxynucleotide decoys to control excessive collagen synthesis, and deposition resulting from persistent TGF-beta. In our model of regulation of collagen synthesis, these double-stranded oligo decoys act as promoter competitors, binding to the activator protein either in the cytoplasm or in the nucleus. The significance of the proposed studies is that these novel natural antifibrotics will mimic the effect of glucocorticoids on collagen synthesis during fibrogenesis without the unwanted side effects of these steroids. Based on our previous studies on the molecular mechanisms by which glucocorticoids selectively decrease collagen synthesis, designed phosphorothioate oligodeoxynucleotides resistant to nuclease action will mimic the effects of glucocorticoids at the molecular, cellular, and in vivo levels of collagen synthesis. However, the glucocorticoids significantly inhibit noncollagen protein synthesis. Both the single-stranded and double-stranded oligodeoxynucleotide specifically decrease collagen synthesis without an inhibitory effect on noncollagen protein synthesis. In this review, we will specifically ask if TGF-beta-induced collagen synthesis is inhibited in cell culture and in vivo by using the double-stranded oligodeoxynucleotide decoys, will this inhibit fibrogenesis and ultimately scarring?
ChemInform Abstract: A Convenient, Solvent Free and High Yielding Synthesis of Bicyclo‐Heterocyclic Compounds. (2008)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones (1994)

A 4.6 kb Staphylococcus aureus DNA fragment containing DNA gyrase-like genes (grlA and grlB) was cloned and sequenced. The proteins GrlA and GrlB exhibit more than 30% identity with E. coli DNA topoisomerase IV subunits and with the gyrase subunits from S. aureus and Escherichia coli. The combined E. coli cell extracts of GrlA and GrlB overproducing strains catalysed ATP-dependent relaxation and decatenation specific to DNA topoisomerase IV. The temperature-sensitive phenotype of Salmonella typhimurium parC and parE mutants was complemented by the S. aureus grlA and grlB genes, when the two genes were co-expressed. These results show that GrlA and GrlB are the subunits of S. aureus DNA topoisomerase IV. The GyrA subunit of DNA gyrase has been previously defined as a primary target of quinolones based on genetic and biochemical experiments essentially carried out in E. coli. Single-point mutations occurring in the 'quinolone resistance-determining region' (QRDR) of GyrA were found in bacteria exhibiting quinolone resistance, the most common mutation being a substitution of Ser-83 on the E. coli GyrA sequence. We analysed eight S. aureus fluoroquinolone-resistant clinical isolates and observed that mutations in the QRDR of GyrA are not present in the low-quinolone-resistant isolates. In contrast, Ser-80 of GrlA, which corresponds to Ser-83 of E. coli GyrA, is substituted to Phe or Tyr in both high- and low-quinolone-resistant isolates. We propose that DNA topoisomerase IV is a primary target of fluoroquinolones in S. aureus.
Slanted hole array beam profiler (SHArP)—a high-resolution portable beam profiler based on a linear aperture array (2006)

We demonstrate a novel high-resolution portable beam profiler based on a slanted linear array of small apertures, termed a slanted hole array beam profiler (SHArP). The apertures are directly fabricated on a metal-coated CMOS imaging sensor. With a single linear scan, the aperture array can establish a virtual grid of sampling points for beam profiling. With our prototype, we demonstrate beam profiling of Gaussian beams over an area of 66.5 microm x 66.5 microm with a resolution of 0.8 microm (compare with the CMOS pixel size of 10 microm). The resolution can be improved into the range of submicrometers by fabricating smaller apertures. The good correspondence between the measured and calculated beam profiles proves the fidelity of our new beam profiling scheme.
p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. (2003)

We identified and characterized two new ING family genes, p29ING4 and p28ING5,coding for two proteins of 249 and 240 amino acids, respectively. Both p29ING4 and p28ING5 proteins have a plant homeodomain finger motif also found in other ING proteins, and which is common in proteins involved in chromatin remodeling. p29ING4 or p28ING5 overexpression resulted in a diminished colony-forming efficiency, a decreased cell population in S phase, and the induction of apoptosis in a p53-dependent manner. Both p29ING4 and p28ING5 activate the p21/waf1 promoter, and induce p21/WAF1 expression. p29ING4 and p28ING5 enhance p53 acetylation at Lys-382 residues, and physically interact with p300, a member of histone acetyl transferase complexes, and p53 in vivo. These results indicate that p29ING4 and p28ING5 may be significant modulators of p53 function.
Affinity as a Tool in Life Science (2008)

The use of affinity-based tools has become invaluable as a platform for basic research and in the development of drugs and diagnostics. Applications include affinity chromatography and affinity tag fusions for efficient purification of proteins as well as methods to probe the protein network interactions on a whole-proteome level. A variety of selection systems has been described for in vitro evolution of affinity reagents using combinatorial libraries, which make it possible to create high-affinity reagents to virtually all biomolecules, as exemplified by generation of therapeutic antibodies and new protein scaffold binders. The strategies for high-throughput generation of affinity reagents have also opened up the possibility of generating specific protein probes on a whole-proteome level. Recently, such affinity proteomics have allowed the detailed analysis of human protein expression in a comprehensive manner both in normal and disease tissue using tissue microarrays and confocal microscopy.
Host Inflammation Increases Alloimmunization to Transfused Red Blood Cells. (2005)

Abstract Background: Alloimmunization to RBC is a serious sequelae of transfusion, which can result in hemolytic transfusion reactions and difficulty identifying compatible units for future transfusion. Although any given unit of RBC contains numerous alloantigens, only 6% of transfusion recipients mount a measurable alloantibody response. The factors that determine whether a given transfusion recipient will generate antibodies remains undetermined. Activation of the innate immune system through inflammation is known to have a significant effect on immune responses in other settings. Accordingly, we hypothesized that recipient inflammation would modulate humoral responses to transfused RBC. Methods: Hen egg lysozyme (HEL) is a well studied antigen. In order to convert HEL into a model blood group antigen, we utilized transgenic mHEL mice, which express HEL on the surface of RBC as a transmembrane protein. Leukoreduced mHEL RBC were transfused into B10. BR recipient mice (H-2k MHC haplotype). To induce host inflammation, recipient mice received an intraperitoneal injection of poly(I:C), which is a double-stranded RNA that mimics inflammation commonly seen with viral infection. The inflammatory effects of poly (I:C) were confirmed by observing activation of macrophages using flow cytometry. Plasma was obtained from recipient mice 7 and 14 days post-transfusion, and anti-HEL antibody titers and isotypes were determined by HEL specific ELISA. Results: Inflammation of mice with poly (I:C) resulted in a significant increase in the magnitude of anti-HEL IgG synthesis. Whereas mice receiving mHEL RBC alone had only a weak anti-HEL IgG response, treatment with poly (I:C) prior to transfusion resulted in a 15 fold increase in anti-HEL IgG (p value =.0003). In addition, whereas IgG1 and IgG3 were the predominant anti-HEL IgG subtypes in mice receiving mHEL RBC alone, IgG3 and IgG2b predominated in mice treated with poly (I:C) prior to mHEL transfusion. Thus, treatment of transfusion recipients with an agent that mimics inflammation commonly seen in viral infections significantly increased humoral immunity and altered IgG subtype composition. Discussion: The findings reported here demonstrate that host inflammation with a viral-like agent increases alloimmunization to transfused RBC and suggests that co-existing infections in humans may increase humoral immunization to transfused RBC. In addition, since different IgG subtypes have different hemolytic potentials, the observed deviation may influence the clinical significance of alloantibody formation. These findings provide the rational basis for possible intervention using immunomodulatory agents to prevent alloimmunization or to divert the response to a non-hemolytic IgG subtype.
Tetrapeptide inhibitors of protein farnesyltransferase: amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation. (1992)

Protein farnesyltransferase from rat brain transfers farnesyl residues to cysteine residues in tetrapeptides that conform to the sequence CA1A2X, where C is cysteine, A1 and A2 are aliphatic amino acids, and X is methionine or serine. When the A2 residue is aromatic [e.g., phenylalanine as in Cys-Val-Phe-Met (CVFM)], the tetrapeptide continues to bind to the enzyme, but it can no longer accept a farnesyl group, and it becomes a pure inhibitor. The current studies show that this resistance to farnesylation also requires a positive charge on the cysteine amino group. Derivatization of this group with acetyl, octanoyl, or cholic acid residues or extension of the peptide with an additional amino acid restores the ability of phenylalanine-containing peptides to accept a farnesyl residue. The same result was obtained when the amino group of cysteine was deleted (mercaptopropionyl-VFM). These data suggest that the positive change on the cysteine amino group acts in concert with an aromatic residue in the A2 position to render peptides resistant to farnesylation by the rat brain enzyme.
Alternating .alpha.,.beta.-oligothymidylates with alternating (3'.fwdarw.3')- and (5'.fwdarw.5')-internucleotidic phosphodiester linkages as models for antisense oligodeoxyribonucleotides (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAlternating .alpha.,.beta.-oligothymidylates with alternating (3'.fwdarw.3')- and (5'.fwdarw.5')-internucleotidic phosphodiester linkages as models for antisense oligodeoxyribonucleotidesMasakazu Koga, Michael F. Moore, and Serge L. BeaucageCite this: J. Org. Chem. 1991, 56, 12, 3757–3759Publication Date (Print):June 1, 1991Publication History Published online1 May 2002Published inissue 1 June 1991https://pubs.acs.org/doi/10.1021/jo00012a001https://doi.org/10.1021/jo00012a001research-articleACS PublicationsRequest reuse permissionsArticle Views124Altmetric-Citations25LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Inhibitors of Aldo-Keto Reductases AKR1C1-AKR1C4 (2011)

The AKR1C aldo-keto reductases (AKR1C1-AKR1C4) are enzymes that interconvert steroidal hormones between their active and inactive forms. In this manner, they can regulate the occupancy and trans-activation of the androgen, estrogen and progesterone receptors. The AKR1C isoforms also have important roles in the production and inactivation of neurosteroids and prostaglandins, and in the metabolism of xenobiotics. They thus represent important emerging drug targets for the development of agents for the treatment of hormone-dependent forms of cancer, like breast, prostate and endometrial cancers, and other diseases, like premenstrual syndrome, endometriosis, catamenial epilepsy and depressive disorders. We present here the physiological roles of these enzymes, along with their structural properties and an overview of the recent developments regarding their inhibitors. The most important strategies of inhibitor design are described, which include the screening of banks of natural compounds (like cinnamic acids, flavonoids, jasmonates, and related compounds), the screening of and structural modifications to non-steroidal anti-inflammatory drugs, the substrate-inspired design of steroidal and nonsteroidal inhibitors, and computer-assisted structure-based inhibitor design.
Functional interaction of paramyxovirus glycoproteins: identification of a domain in Sendai virus HN which promotes cell fusion (1996)

The cell fusion activity of most paramyxoviruses requires coexpression of a fusion protein (F) and a hemagglutinin-neuraminidase protein (HN) which are derived from the same virus type. To define the domain of the HN protein which interacts with the F protein in a type-specific manner a series of chimeric HN proteins between two different paramyxoviruses, Sendai virus (SN) and human parainfluenza virus type 3 (PI3), was constructed and coexpressed with the SN-F protein by using the vaccinia virus T7 RNA polymerase transient-expression system. Quantitative assays were used to evaluate cell surface expression as well as fusion-promoting activities of the chimeric HN molecules. A chimeric HN protein [SN(140)] containing 140 N-terminal amino acids derived from SN-HN and the remainder (432 amino acids) derived from PI3-HN was found to promote cell fusion with the SN-F protein. In contrast, a second chimeric HN with 137 amino acids from SN-HN at the N terminus could not promote fusion with SN-F, even though the protein was expressed on the cell surface. A construct in which the PI3-HN cytoplasmic tail and transmembrane domain were substituted for those of SN in the SN(140) chimera still maintained the ability to promote cell fusion. These results indicate that a region including only 82 amino acids in the extracellular domain, adjacent to the transmembrane domain of the SN-HN protein, is important for interaction with the SN-F protein and promotion of cell fusion.
Interactions between p300 and Multiple NF-Y Trimers Govern Cyclin B2 Promoter Function (2003)

The CCAAT box is one of the most common elements in eukaryotic promoters and is activated by NF-Y, a conserved trimeric transcription factor with histone-like subunits. Usually one CCAAT element is present in promoters at positions between -60 and -100, but an emerging class of promoters harbor multiple NF-Y sites. In the triple CCAAT-containing cyclin B2 cell-cycle promoter, all CCAAT boxes, independently from their NF-Y affinities, are important for function. We investigated the relationships between NF-Y and p300. Chromatin immunoprecipitation analysis found that NF-Y and p300 are bound to the cyclin B2 promoter in vivo and that their binding is regulated during the cell cycle, positively correlating with promoter function. Cotransfection experiments determined that the coactivator acts on all CCAAT boxes and requires a precise spacing between the three elements. We established the order of in vitro binding of the three NF-Y complexes and find decreasing affinities from the most distal Y1 to the proximal Y3 site. Binding of two or three NF-Y trimers with or without p300 is not cooperative, but association with the Y1 and Y2 sites is extremely stable. p300 favors the binding of NF-Y to the weak Y3 proximal site, provided that a correct distance between the three CCAAT is respected. Our data indicate that the precise spacing of multiple CCAAT boxes is crucial for coactivator function. Transient association to a weak site might be a point of regulation during the cell cycle and a general theme of multiple CCAAT box promoters.
Detection of TNT and Picric Acid on Surfaces and in Seawater by Using Photoluminescent Polysiloles. (2001)

Nitroaromatic explosives can be detected in a simple and rapid method by the quenching of the photoluminescence of fluorescent polysiloles. Quenching is achieved by electron transfer from the conduction band of the polysiloles to electron-poor molecules such as picric acid, nitrobenzene, 2,4-dinitrotoluene (DNT), and 2,4,6-trinitrotoluene (TNT). Dilute polymer solutions can also be employed as a forensic spray-on reagent to visualize TNT or picric acid residues under a UV lamp (see picture of the print of a nitrile-gloved hand that had been in contact with TNT).