gebhart/patrepeval huggingface dataset:
Development of Drug Delivery Systems for Macromolecular Drugs (1996)

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.
Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway (1997)

T cell-dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met-encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38(+)CD77(+) tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.
Severe combined immunodeficiency. A model disease for molecular immunology and therapy (2005)

Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.
Cultura de innovación es competitividad (2014)

La cultura de Innovacion es cuando la innovacion es parte de la identidad automatica, sistematica y observable de una organizacion. Los resultados de esta cultura conllevan el lanzamiento de nuevos productos y servicios, la reaccion y aprendizaje rapido a las respuestas de los clientes.
Cycloadditions as a Method for Oligonucleotide Conjugation (2006)

There is a large requirement in modern molecular biology for the production of specifically conjugated oligonucleotides. For instance, oligonucleotides may be conjugated to fluorescent labels to allow sequence specific detection following a biological assay. A number of methods exist for the conjugation of oligonucleotides and mainly rely on the use of a nucleophile attached to the oligonucleotide reacting with reactive species to form the desired product. A new approach to achieve oligonucleotide conjugations is to use cycloadditions. This review covers the growing use of cycloadditions for labelling of oligonucleotides at various positions within the sequence and the advantages over existing techniques. A number of different dienes have been reported and each is reviewed. Finally, the use of these conjugated oligonucleotides is reported with a view, to demonstrate the advantages of using cycloaddition for the conjugations.
Actions of Aprataxin in Multiple DNA Repair Pathways (2007)

Mutations in the Aptx gene lead to a neurological disorder known as ataxia oculomotor apraxia-1. The product of Aptx is Aprataxin (Aptx), a DNA-binding protein that resolves abortive DNA ligation intermediates. Aprataxin catalyzes the nucleophilic release of adenylate groups covalently linked to 5' phosphate termini, resulting in termini that can again serve as substrates for DNA ligases. Here we show that Aprataxin acts preferentially on adenylated nicks and double-strand breaks rather than on single-stranded DNA. Moreover, we show that whereas the catalytic activity of Aptx resides within the HIT domain, the C-terminal zinc finger domain provides stabilizing contacts that lock the enzyme onto its high affinity AMP-DNA target site. Both domains are therefore required for efficient AMP-DNA hydrolase activity. Additionally, we find a role for Aprataxin in base excision repair, specifically in the removal of adenylates that arise from abortive ligation reactions that take place at incised abasic sites in DNA. We suggest that Aprataxin may have a general proofreading function in DNA repair, removing DNA adenylates as they arise during single-strand break repair, double-strand break repair, and in base excision repair.
A Facile Formation of Dibenzo [a,d] cycloheptenylium Ion by Decarbonylation. Color Reactions of the Cyheptamide Metabolites (1971)

Treatment with concentrated sulfuric acid of different 10-hydroxylated metabolites of the anticonvulsant cyheptamide results in intensely colored products. These have been identified as dibenzo-[a,d]cycloheptenylium ions.
Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice (2003)

Deficiency of acyl CoA:cholesterol acyltransferase 2 (ACAT2) in mice results in a reduction in cholesterol ester synthesis in the small intestine and liver, which in turn limits intestinal cholesterol absorption, hepatic cholesterol gallstone formation, and the accumulation of cholesterol esters in the plasma lipoproteins. Here we examined the contribution of ACAT2-derived cholesterol esters to atherosclerosis by crossing ACAT2-deficient (ACAT2(-/-)) mice with apolipoprotein (apo) E-deficient (ApoE(-/-)) mice, an atherosclerosis-susceptible strain that has impaired apoE-mediated clearance of apoB-containing lipoproteins. ACAT2(-/-) ApoE(-/-) mice and ACAT2(+/+) ApoE(-/-) (control) mice had similar elevations of plasma apoB and total plasma lipids; however, the lipid cores of the apoB-containing lipoproteins in ACAT2(-/-) ApoE(-/-) mice contained primarily triglycerides rather than cholesterol esters. At 30 wk of age, only the control mice had significant atherosclerosis, which was nearly absent in ACAT2(-/-) ApoE(-/-) mice. ACAT2 deficiency in the apoE-deficient background also led to a compensatory increase in the activity of lecithincholesterol acyltransferase, the major plasma cholesterol esterification enzyme, which increased high-density lipoprotein cholesterol esters. Our results demonstrate the crucial role of ACAT2-derived cholesterol esters in the development of atherosclerosis in mice and suggest that triglyceride-rich apoB-containing lipoproteins are not as atherogenic as those containing cholesterol esters. Our results also support the rationale of pharmacological inhibition of ACAT2 as a therapy for atherosclerosis.
Novel ultrahigh-density flash memory with a stacked-surrounding gate transistor (S-SGT) structured cell (2003)

In order to overcome the limitation of cell area of 4F/sup 2/ per bit in conventional NAND flash memory cells, stacked-surrounding gate transistor (S-SGT) structured cell is proposed. This newly structured cell achieves a cell area of 4F/sup 2//N per bit, where N is the number of stacked memory cells in one silicon pillar, without using multibit per memory cell technology. The S-SGT structured cell consisting of two stacked memory cells in one silicon pillar achieves a cell area per bit of less than 50% of the smallest reported NAND structured cell. The novel S-SGT structured cells are fabricated by vertical self-aligned processes using a 0.2 /spl mu/m design rule. The S-SGT structured cell can be programmed and erased by uniform injection and uniform emission of Fowler-Nordheim (F-N) tunneling electrons over the whole channel area of the memory cell, respectively, which is the same program and erase mechanism as in conventional NAND structured cell. This high performance S-SGT structured cell is applicable to high-density nonvolatile memories for 16 G/64 G bit Flash memories and beyond.
Chapter 8 Enzyme catalysis in biological fuel cells (2014)

Over the past 10 years, increasing interest in enzymatic catalysts for electrical energy applications has been moti-vated by the ongoing search for nonprecious electrocat-alysts with low cost, a desire to harness biorenewable fuels, and revolutionary advances in biological science and technology. Enzymes are high molecular weight proteins (MW ∼10–100 kDa) produced by RNA translation from the DNA of living organisms. A large class of enzymes are redox active, and are categorized as oxidoreductases (enzyme class (EC) 1).[1] Biological fuel cells were first studied starting in the 1960 s and have received scholarly and scientific atten-tion ever since.[2, 3] However, enzymes have, to a much greater extent, been applied in electrochemical biosensors.[4] Such sensors may be potentiometric or amperometric; in
Catalytic methods for metal carbene transformations (1986)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCatalytic methods for metal carbene transformationsMichael P. DoyleCite this: Chem. Rev. 1986, 86, 5, 919–939Publication Date (Print):October 1, 1986Publication History Published online1 May 2002Published inissue 1 October 1986https://pubs.acs.org/doi/10.1021/cr00075a013https://doi.org/10.1021/cr00075a013research-articleACS PublicationsRequest reuse permissionsArticle Views6152Altmetric-Citations908LEARN 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
Hematopoietic growth factor receptors (1991)

The molecular cloning for most of the hematopoietic growth factor receptors has been achieved over the past few years and revealed that they can by assigned to two discrete receptor families, namely the hematopoietic growth factor superfamily (HRS) and the receptor tyrosine kinase family (RTK). The members of the HRS, including granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R), interleukin 3 receptor (IL-3-R), granulocyte CSF receptor (G-CSF-R) and erythropoietin receptor (Epo-R), share a common binding domain and the absence of a tyrosine kinase domain in their cytoplasmic portion. In some cases (e.g., GM-CSF-R), the high-affinity receptor structure is obtained through the association of the low-affinity binding chain (alpha chain) with an accessory protein (beta chain). It is conceivable that this protein might also represent the common subunit shared by GM-CSF-R and by IL-3-R when they are co-expressed to form the putative GM-CSF-R/IL-3-R complex. Although tyrosine phosphorylation following ligand receptor activation seems to be a common event in the HRS, its role in the signal transduction mechanisms is unknown. Due to the structural analogies among the members of this family any new insight into one particular receptor member, such as its subunit structure and its signal transduction pathways, will be generalizable to the other family members. The subclass III of the RTK family, including the CSF-1-R and c-kit, is characterized by an additional insert into the kinase domain that recognizes and binds protein substrates. Ligand induced activation of the kinase domain and its signaling potential are mediated by receptor oligomerization which stabilizes interactions between adjacent cytoplasmic domains and leads to activation of kinase function by molecular interaction. Interestingly, the receptors included in this subclass are the products of well known cellular proto-oncogenes. A large variety of structural alteration found in receptor-derived oncogene products may lead to constitutive activation of receptor signals that, consequently, result in the subversion of the mechanisms controlling the cell growth.
DNA-Mediated Electron Transfer and Application to 'Biochip' Development (1990)

Abstract : To study the electronic properties of double-stranded DNA as to determining whether this macromolecule can support electron transport processes. This pertains to possibly utilizing the base sequence and secondary structure of DNA as a matrix for developing molecular level electronic components. Toward these goals, we have studied the anisotropic electronic properties of DNA single crystals using reflectance spectroscopy and studied the interactions of transitions metals with double-stranded DNA by X-ray diffraction. We have also synthesized a number of porphyrin and acridine modified DNA molecules, and assembled a photoflash photolysis apparatus for direct study of electron transfer through DNA. In related work, we have shown that the propensity for DNA to adopt specific double helical conformations can be predicted from calculations of solvent accessible surfaces. From this, we were able to obtain diffraction quality single crystals of DNA oligomers in a predictive manner.
Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy (2001)

The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.
Targeted mutation of the Hprt gene in mouse embryonic stem cells. (1988)

The hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene has been mutated in mouse blastocyst-derived embryonic stem cells by site-directed homologous recombination. Embryonic stem cells were electroporated in the presence of a targeting DNA fragment containing two specific features: (i) The targeting DNA contained a promoterless neomycin phosphotransferase (neo) gene that, when located within the endogenous Hprt locus, could be transcribed from the promoter of the target locus. (ii) The targeting fragment had two short regions of homology with the endogenous Hprt gene: one, 132 base pairs long and the other, 1.2 kilobase pairs long. Targeted cells in which the designed homologous recombination event occurred were isolated either by selection with G418 followed by 6-thioguanine or by selection with 6-thioguanine alone. Even though less than 2 kilobases of homology existed between the exogenous and target DNAs, an average of 2.6 embryonic stem cells were successfully targeted for every 10(5) colonies surviving electroporation. Six of the Hprt- cell lines showed homologous recombination. These six lines were further analyzed by nucleotide sequencing a fragment that spans one crossover point after amplification by the polymerase chain reaction. Four lines had the expected sequence, whereas two lines had small deletions abutting the 132-base-pair region of homology.
Direct Cell Cycle Regulation by the Fibroblast Growth Factor Receptor (FGFR) Kinase through Phosphorylation-dependent Release of Cks1 from FGFR Substrate 2 (2004)

Fibroblast growth factors (FGFs) are upstream activators of the mitogen-activated protein kinase pathway and mitogens in a wide variety of cells. However, whether the mitogen-activated protein kinase pathway solely accounts for the induction of cell cycle or antiapoptotic activity of the FGF receptor (FGFR) tyrosine kinase is not clear. Here we report that cell cycle inducer Cks1, which triggers ubiquitination and degradation of p27(Kip1), associates with the unphosphorylated form of FGFR substrate 2 (FRS2), an adaptor protein that is phosphorylated by FGFR kinases and recruits downstream signaling molecules. FGF-dependent activation of FGFR tyrosine kinases induces FRS2 phosphorylation, causes release of Cks1 from FRS2, and promotes degradation of p27(Kip1) in 3T3 cells. Since degradation of p27(Kip1) is a key regulatory step in activation of the cyclin E/A-Cdk complex during the G(1)/S transition of the cell cycle, the results suggest a novel mitogenic pathway whereby FGF and other growth factors that activate FRS2 directly activate cyclin-dependent kinases.
Rapid, sensitive PCR-based detection of mycoplasmas in simulated samples of animal sera (1994)

A fast and simple method to detect mycoplasmal contamination in simulated samples of animal sera by using a PCR was developed. The following five mycoplasma species that are major cell culture contaminants belonging to the class Mollicutes were investigated: Mycoplasma arginini, Acholeplasma laidlawii, Mycoplasma hyorhinis, Mycoplasma orale, and Mycoplasma fermentans. After a concentration step involving seeded sera, genus-specific primers were used to amplify a 717-bp DNA fragment within the 16S rRNA gene of mycoplasmas. In a second step, the universal PCR was followed by amplification of variable regions of the 16S rRNA gene by using species-specific primers, which allowed identification of contaminant mycoplasmas. With this method, 10 fg of purified DNA and 1 to 10 color-changing units of mycoplasmas could be detected. Since the sensitivity of the assay was increased 10-fold when the amplification products were hybridized with an internal mycoplasma-specific 32P-labelled oligonucleotide probe, a detection limit of 1 to 10 genome copies per PCR sample was obtained. This highly sensitive, specific, and simple assay may be a useful alternative to methods currently used to detect mycoplasmas in animal sera.
A murine monoclonal antibody detecting N-acetyl- and N-glycolyl-GM2: characterization of cell surface reactivity. (1986)

Antisera reactive with the ganglioside GM2 were raised by immunizing C57BL/6 mice with the C57BL/6 melanoma JB-RH. Fusion with NS-1 was performed using splenic mononuclear cells from a mouse with high antibody titer. An immunoglobulin M monoclonal antibody (monoclonal antibody 5-3) was identified which was reactive with an antigen that was resistant to heat, trypsin, and Pronase. A panel of purified glycolipids was used to determine the specificity of monoclonal antibody 5-3. Reactivity was restricted to N-acetyl- and N-glycolyl-GM2. No reactivity was detected with asialo-GM2 or other gangliosides. Monoclonal antibody 5-3 was used to define the expression of GM2 on the cell surface of cultured human normal and malignant cells. Reactivity was seen with cell lines derived from 8 of 8 astrocytomas, 5 of 5 neuroblastomas, 7 of 9 sarcomas, 4 of 18 human melanomas, 2 of 4 murine melanomas, 4 of 37 epithelial cancers and with 0 of 6 skin fibroblast and 0 of 2 brain fibroblast lines. GM2, like GD2 and GD3, appears to be a differentiation antigen largely restricted to cells of neuroectodermal origin.
Soluble forms of CD40 inhibit biologic responses of human B cells (1992)

We have expressed the CD40 surface Ag as both a soluble 28-kDa molecule and a 57-kDa Fc fusion protein containing the human IgG1 Fc region. Soluble CD40 and the Fc fusion protein inhibited the proliferative response of anti-IgM-activated human B cells to the CD40 mAb G28-5. Similarly, G28-5- and IL-4-induced IgE secretion from PBMC depleted of T cells was effectively blocked by both forms of soluble CD40. Although the soluble constructs of CD40 had only a minimal inhibitory effect on IL-4-mediated proliferation of anti-IgM-activated B cells, IL-4-induced soluble CD23 shedding from both PBMC and T cells depleted of PBMC, and IgE secretion from PBMC, were significantly reduced in a concentration-dependent manner when soluble CD40 was present in the culture. The data presented demonstrate that both soluble forms of the CD40 molecule are biologically active, and suggest that the ligand for CD40 is inducible in IL-4-stimulated cultures and that it mediates both shedding of sCD23 and IgE secretion.
Phase II Trial of Systemic Continuous Fluorouracil and Subcutaneous Recombinant Interferon Alfa-2b for Treatment of Hepatocellular Carcinoma (2003)

Continuous IV FU and thrice-weekly SC rIFNalpha2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.