gebhart/patrepeval huggingface dataset:
Inhibition of Hypoxanthine-Guanine Phosphoribosyltransferase by Acyclic Nucleoside Phosphonates: A New Class of Antimalarial Therapeutics (2009)

The purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite, Plasmodium falciparum. Acyclic nucleoside phosphonates (ANPs) are analogues of the nucleotide product of the reaction, comprising a purine base joined by a linker to a phosphonate moiety. K(i) values for 19 ANPs were determined for Pf HGXPRT and the corresponding human enzyme, HGPRT. Values for Pf HGXPRT were as low as 100 nM, with selectivity for the parasite enzyme of up to 58. Structures of human HGPRT in complex with three ANPs are reported. On binding, a large mobile loop in the free enzyme moves to partly cover the active site. For three ANPs, the IC(50) values for Pf grown in cell culture were 1, 14, and 46 microM, while the cytotoxic concentration for the first compound was 489 microM. These results provide a basis for the design of potent and selective ANP inhibitors of Pf HGXPRT as antimalarial drug leads.
A bacterial amber suppressor in Saccharomyces cerevisiae is selectively recognized by a bacterial aminoacyl-tRNA synthetase. (1990)

Little is known about the conservation of determinants for the identities of tRNAs between organisms. We showed previously that Escherichia coli tyrosine tRNA synthetase can charge the Saccharomyces cerevisiae mitochondrial tyrosine tRNA in vivo, even though there are substantial sequence differences between the yeast mitochondrial and bacterial tRNAs. The S. cerevisiae cytoplasmic tyrosine tRNA differs in sequence from both its yeast mitochondrial and E. coli counterparts. To test whether the yeast cytoplasmic tyrosyl-tRNA synthetase recognizes the E. coli tRNA, we expressed various amounts of an E. coli tyrosine tRNA amber suppressor in S. cerevisiae. The bacterial tRNA did not suppress any of three yeast amber alleles, suggesting that the yeast enzymes retain high specificity in vivo for their homologous tRNAs. Moreover, the nucleotides in the sequence of the E. coli suppressor that are not shared with the yeast cytoplasmic tyrosine tRNA do not create determinants which are efficiently recognized by other yeast charging enzymes. Therefore, at least some of the determinants that influence in vivo recognition of the tyrosine tRNA are specific to the cell compartment and organism. In contrast, expression of the cognate bacterial tyrosyl-tRNA synthetase together with the bacterial suppressor tRNA led to suppression of all three amber alleles. The bacterial enzyme recognized its substrate in vivo, even when the amount of bacterial tRNA was less than about 0.05% of that of the total cytoplasmic tRNA.
Identification of Transcription Factor Binding Sites Important in the Regulation of the Human Interleukin-5 Gene (1997)

This study identifies three regions of the human interleukin (IL)-5 promoter involved in binding nuclear factors from activated T cells. DNase I footprinting and mobility shift assays with nuclear proteins from the human T cell clone, SP-B21, demonstrated protein interactions with each of these response elements (REs), located between positions -79 and -45 (RE-I), -123 and -92 (RE-II), and -170 and -130 (RE-III). Two of these regions, RE-II and RE-III, have not previously been described to regulate IL-5 expression in T cells. The RE-II site was shown to be critical for inducible IL-5 promoter activity in transient transfection assays in D10.G4.1 T cells, while the RE-III site functions as a negative regulatory element. The activity of the RE-II site was specifically inhibited by cyclosporin A, and transfection assays with IL-5 constructs containing mutations in the RE-II site showed greatly reduced reporter gene activity. We have defined the sequence involved in stimulation-dependent transcription and have identified constitutive as well as inducible DNA-binding protein complexes that bind to RE-II. Antibodies against at least two members of the nuclear factor of activated T cells (NFAT) family of transcription factors are capable of binding to the IL-5 RE-II complexes, although they can be distinguished from previously identified NFAT-specific complexes by several characteristics.
Dicing Up RNAs (2001)

What do stRNAs and siRNAs have in common apart from their small size and their ability to regulate gene expression? The enzyme Dicer it seems, according to a Perspective by
 Ambros
 discussing new findings by
 HutvA gner
 et al .
 and Knight and Bass. Dicer cleaves larger dsRNA precursors into stRNAs and siRNAs. stRNAs regulate gene expression during worm development by preventing the mRNAs they bind to from being translated. siRNAs inactivate gene expression by binding to and degrading target mRNAs.
RFID Application in Hospitals: A Case Study on a Demonstration RFID Project in a Taiwan Hospital (2006)

After manufacturing and retail marketing, healthcare is considered the next home for Radio Frequency Identification (RFID). Although in its infancy, RFID technology has great potential in healthcare to significantly reduce cost, and improve patient safety and medical services. However, the challenge will be to incorporate RFID into medical practice, especially when relevant experience is limited. To explore this issue, we conducted a case study that demonstrated RFID integration into the medical world at one Taiwan hospital. The project that was studied, the Location-based Medicare Service project, was partially subsidized by the Taiwan government and was aimed at containing SARS, a dangerous disease that struck Taiwan in 2003. Innovative and productive of several significant results, the project established an infrastructure and platform allowing for other applications. In this paper we describe the development strategy, design, and implementation of the project. We discuss our findings pertaining to the collaborative development strategy, device management, data management, and value generation. These findings have important implications for developing RFID applications in healthcare organizations.
Noninvasive Diagnosis of Renal-Allograft Rejection by Measurement of Messenger RNA for Perforin and Granzyme B in Urine (2001)

Measurement of mRNA encoding cytotoxic proteins in urinary cells offers a noninvasive means of diagnosing acute rejection of renal allografts.
Inhibition of TGFβ1 by Anti-TGFβ1 Antibody or Lisinopril Reduces Thyroid Fibrosis in Granulomatous Experimental Autoimmune Thyroiditis (2002)

In this study, a murine model of granulomatous experimental autoimmune thyroiditis (G-EAT) was used to determine the role of TGFbeta1 in fibrosis initiated by an autoimmune inflammatory response. The fibrotic process was evaluated by staining thyroid tissue for collagen, alpha-smooth muscle actin, TGFbeta1, and angiotensin-converting enzyme (ACE), and measuring serum thyroxine in mice given anti-TGFbeta1 or the ACE inhibitor lisinopril. The role of particular inflammatory cells in fibrosis was tested by depletion experiments, and the cytokine profile in thyroids was examined by RT-PCR. Neutralization of TGFbeta1 by anti-TGFbeta1 or lisinopril resulted in less collagen deposition and less accumulation of myofibroblasts, and levels of active TGFbeta1 and ACE were reduced in thyroids of treated mice compared with those of untreated controls. Other profibrotic molecules, such as platelet-derived growth factor, monocyte chemotactic protein-1, and IL-13, were also reduced in thyroids of anti-TGFbeta1- and lisinopril-treated mice compared with those of controls. Confocal microscopy showed that CD4(+) T cells and macrophages expressed TGFbeta1. Fibrosis was reduced by injection of anti-CD4 mAb on day 12, when G-EAT was very severe (4-5+). Together, these results suggest a critical role for TGFbeta1 in fibrosis initiated by autoimmune-induced inflammation. Autoreactive CD4(+) T cells may contribute to thyroid fibrosis through production of TGFbeta1. This G-EAT model provides a new model to study how fibrosis associated with autoimmune damage can be inhibited.
Progress toward oligonucleotide therapeutics: pharmacodynamic properties (1993)

Although many issues remain to be resolved, recent progress suggests that oligonucleotides may have therapeutic potential. The first therapeutic oligonucleotide, ISIS 2105, an oligonucleotide designed to treat genital warts, has completed Phase I clinical trials and is undergoing Phase II testing. Conceptually, oligonucleotides may interact with nucleic acid or nonnucleic acid receptors; however, rational design of oligonucleotide drugs to interact with nucleic acid receptors is significantly simpler because the factors that determine affinity and selectivity are better understood. Recent progress demonstrates that this information can be coupled to rapid advances in the medicinal chemistry of oligonucleotides to create new generations of oligonucleotide drugs with dramatically improved properties. The purposes of this review are to place oligonucleotide therapeutics in the context of modern molecular drug discovery and to summarize progress in understanding the pharmacodynamic properties of oligonucleotides designed to bind to nucleic acid receptors. The pharmacokinetic and toxicologic properties of oligonucleotides have been reviewed recently (1-4). The activities of oligonucleotides that bind to nonnucleic acid receptors will be considered in future reviews.
Chimerism Analysis Following Nonmyeloablative Stem Cell Transplantation (2006)

Molecular monitoring of hematopoietic chimerism has become a routine diagnostic approach in patients after allogeneic stem cell transplantation. Chimerism testing permits the documentation and surveillance of engraftment and facilitates early detection of impending graft rejection. In patients transplanted for treatment of malignant hematological disorders, monitoring of chimerism can provide an early indication of incipient disease relapse. The investigation of chimerism has therefore become an indispensable tool for the management of patients during the posttransplant period. Growing use of nonmyeloablative conditioning, which is associated with prolonged duration of mixed hematopoietic chimerism, has further increased the clinical importance of chimerism analysis. At present, the most commonly used technical approaches to the investigation of chimerism include microsatellite analysis by polymerase chain reaction and, in the gender-mismatched transplant setting, fluorescence in situ hybridization analysis of sex chromosomes. The investigation of chimerism within specific leukocyte subsets isolated from peripheral blood or bone marrow samples by flow-sorting or magnetic bead-based techniques provides more specific information on processes underlying the dynamics of donor/recipient chimerism. Moreover, cell subset-specific analysis permits the assessment of impending complications at a significantly higher sensitivity, thus providing a basis for earlier treatment decisions.
A Novel Positive Feedback Loop Mediated by the Docking Protein Gab1 and Phosphatidylinositol 3-Kinase in Epidermal Growth Factor Receptor Signaling (2000)

The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR) we tested the ability of Gab1 to associate with and modulate signaling by this receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that overexpression of Gab1 potentiates EGF-induced activation of the mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via the EGFR. The PH domain of Gab1 was shown to bind specifically to phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3 kinase, and is required for activation of Gab1-mediated enhancement of EGFR signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma membrane in response to EGF and is required for efficient tyrosine phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1 PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR.
Parallel Gene Expression Profiling of Mantle Cell Lymphoma – How Do We Transform ´Omics Data into Clinical Practice (2007)

DNA microarray technology has been a valuable tool to provide a global view of the changes in gene expression that characterize different types of B cell lymphomas, both in relation to clinical parameters but also in comparison with the non-malignant counterparts. The number of transcripts that can be analyzed on an array has dramatically increased, and now most commercially available arrays cover the whole genome, enabling overall analysis of the transcriptome.The backside of collecting this massive amount of information is that even after strict data filtering, it is impossible to do follow-up studies on all findings. Down-stream analysis is time-consuming and when performing confirmatory experiments on the protein level, the experiments are in most cases restricted to proteins recognized by commercially available reagents. Furthermore, since gene expression data is a comparative method not only are the experimental set-up but also the characteristics of both the sample and reference crucial for our ability to answer the questions posed. Thus, initial care must be taken in the design of the experiment and the preparation of the samples.The aim of this review is to discuss the progress in mantle cell lymphoma research enabled by gene expression analysis and to pinpoint the difficulties in making efficient use of the generated data to provide a fast and accurate clinical diagnosis, efficient stratification of patients into disease sub-groups and improved therapy.
Stimulation of growth hormone synthesis by glucose in islets of Langerhans isolated from transgenic mice. (1986)

To examine further the mechanism by which the synthesis of proteins translated on the rough endoplasmic reticulum is regulated in pancreatic beta-cells, the synthesis of growth hormone in islets from transgenic mice carrying the metallothionein-rat growth hormone gene fusion was studied. High glucose (17 mM) stimulated the synthesis and secretion of an apparently normally processed growth hormone. The stimulation of synthesis of growth hormone was less efficient than the stimulation of insulin synthesis in these islets, whereas the stimulation of release of labeled growth hormone paralleled that of insulin. These results are consistent with the hypothesis that signal recognition particle-mediated mechanism(s) may be involved in regulating the translational efficiency of secreted proteins in isolated islets (Welsh, M., Scherberg, N., Gilmore, R., and Steiner, D. F. (1986) Biochem. J. 235, 459-467). Furthermore, in the beta-cells, growth hormone follows the normal regulated pathway of secretory granule transport and exocytosis.
The Wound Hormones of Plants. V. The Synthesis of Some Analogs of Traumatic Acid (1941)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Wound Hormones of Plants. V. The Synthesis of Some Analogs of Traumatic AcidJames English Jr.Cite this: J. Am. Chem. Soc. 1941, 63, 4, 941–943Publication Date (Print):April 1, 1941Publication History Published online1 May 2002Published inissue 1 April 1941https://pubs.acs.org/doi/10.1021/ja01849a012https://doi.org/10.1021/ja01849a012research-articleACS PublicationsRequest reuse permissionsArticle Views217Altmetric-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-Alertsclose Get e-Alerts
Intermolecular Amidation of Unactivated sp2 and sp3 C−H Bonds via Palladium-Catalyzed Cascade C−H Activation/Nitrene Insertion (2006)

This communication describes the Pd(OAc)2-catalyzed intermolecular amidation reactions of unactivated sp2 and sp3 C-H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group were amidated with excellent chemo- and regioselectivities. It is noteworthy that reactive C-X bonds were well-tolerated and a variety of primary amides can be effective nucleophiles for the Pd-catalyzed C-H amidation reactions. For the reaction of unactivated sp3 C-H bonds, beta-amidation of 1 degrees sp3 C-H bonds versus 2 degrees C-H bonds is preferred. The catalytic reaction is initiated by chelation-assisted cyclopalladation involving C-H bond activation. Preliminary mechanistic study suggested that the persulfate oxidation of primary amides should generate reactive nitrene species, which then reacted with the cyclopalladated complex.
The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses (2000)

The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5-1 microM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89-168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5-1 microM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection.
Distribuição do Rendimento entre as Famílias Portuguesas Uma Análise com Base numa Matriz de Contabilidade Social e Regional para 1999 (2005)

A Matriz de Contabilidade Social e Regional (MCSR) reúne num único quadro os fluxos e as interdependências existentes entre os diferentes processos que ocorrem numa economia, sendo enfatizados os aspectos distributivos, nomeadamente entre famílias de diferentes regiões e de distintos grupos sociais. Tendo por base uma MCSR construída para Portugal para o ano de 1999, analisase o processo de distribuição do rendimento entre diversos tipos de famílias, desagregadas por região de residência e por principal fonte de rendimento. Através dos multiplicadores contabilísticos, calculados a partir da MCSR, pretende-se captar os efeitos (directos e indirectos) duma variação exógena sobre o rendimento dos diferentes tipos de famílias. Por um lado, tem-se por objectivo verificar quais os grupos de famílias que mais e menos beneficiam de choques exógenos sobre o seu rendimento. Por outro lado, pretende-se quantificar a distribuição inter-regional e inter-social do rendimento, uma vez que, quando existe um aumento no rendimento das famílias duma dada região e grupo social, esse aumento não tem impacto apenas nesse grupo e nessa região, mas vai difundir-se social e espacialmente.
Approaches to Improve the Oral Bioavailability and Effects of Novel Anticancer Drugs Berberine and Betulinic Acid (2014)

Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA.
Immunosuppressive roles for IL-10 and IL-4 in human infection. In vitro modulation of T cell responses in leprosy (1993)

IL-10 and IL-4 have been shown to exert an inhibitory effect on cell-mediated immune responses. Our previous studies of leprosy demonstrated that IL-10 and IL-4 mRNA were preferentially expressed in lesions from lepromatous patients, those immunologically unresponsive individuals that manifest widespread infection. To define more precisely the regulatory roles of these two cytokines in the immune response to infection, we studied in vitro responses to Mycobacterium leprae. M. leprae triggered IL-10 release from PBMC of patients and healthy donors; the predominant source of the IL-10 was found to be monocytes/macrophages. Stimulation of PBMC in the presence of neutralizing anti-IL-10 mAb indicated that endogenous IL-10 production inhibits PBMC proliferation and release of TNF-alpha, GM-CSF, and IFN-gamma. Paradoxically, studies using neutralizing anti-IL-4 mAb indicated that endogenous IL-4 production enhances PBMC proliferative responses most strikingly in lepromatous patients. We found that rIL-4 expanded CD8+ T cells from lepromatous patients in vitro. CD8+ T cells from lepromatous patients have been shown to suppress CD4+ T cell responses, in part by the release of IL-4. Our study indicated that endogenous IL-4 production inhibited IL-10 secretion and, concomitantly, increased TNF-alpha and GM-CSF release. The present data suggest that, on balance, IL-4 and IL-10 contribute to immunosuppression in human infectious disease.
A Bacterial Effector Acts as a Plant Transcription Factor and Induces a Cell Size Regulator (2007)

Pathogenicity of many Gram-negative bacteria relies on the injection of effector proteins by type III secretion into eukaryotic cells, where they modulate host signaling pathways to the pathogen's benefit. One such effector protein injected by Xanthomonas into plants is AvrBs3, which localizes to the plant cell nucleus and causes hypertrophy of plant mesophyll cells. We show that AvrBs3 induces the expression of a master regulator of cell size, upa20, which encodes a transcription factor containing a basic helix-loop-helix domain. AvrBs3 binds to a conserved element in the upa20 promoter via its central repeat region and induces gene expression through its activation domain. Thus, AvrBs3 and likely other members of this family provoke developmental reprogramming of host cells by mimicking eukaryotic transcription factors.