gebhart/patrepeval huggingface dataset:
Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane (2012)

Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier--the glomerular basement membrane (GBM)--can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities).
Automated and interactive composition of ubiquitous applications (2012)

Application composition refers to the creation of applications by using Web Services and resources such as mobile devices, displays, and various augmented everyday objects as building blocks. This approach is especially useful for ubiquitous applications which focus on supporting users' needs and everyday activities. This thesis proposes to compose these applications by choosing the appropriate set of resources and services and their configuration as dictated by the users themselves, together with their needs and other contexts. This thesis studies automated and interactive application composition. The first approach enables the system to act upon users' needs and intentions, while the second enables users themselves to specify their needs and achieve their goals. The research was carried out by designing, implementing and evaluating eight prototypes for automated and interactive application composition. The evaluation methods used included performance analysis and user experiments. The main results include (1) the design and implementation of automated composition mechanisms which rely on evolutionary computing and genetic algorithms, (2) a detailed performance analysis of these mechanisms using synthesized datasets and in a real networking environment; (3) the design and implementation of interactive application composition prototypes which rely on graphical and physical (i.e. touch-based) user interfaces for mobile devices and utilize various contexts; (4) an evaluation of these prototypes in a series of user experiments. The evaluation studied the following issues: users' attitudes towards an automated composition system which makes decisions on their behalf; users' attitudes towards a context-aware composition interface; and the issue of balancing user control and system autonomy.
Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. (1994)

We have established long-term cultures of several cell lines stably and uniformly expressing human immunodeficiency virus type 1 (HIV-1) in order to (a) identify naturally processed HIV-1 peptides recognized by cytotoxic T lymphocytes (CTL) from HIV-1-seropositive individuals and (b) consider the hypothesis that naturally occurring epitope densities on HIV-infected cells may limit their lysis by CTL. Each of two A2-restricted CD8+ CTL specific for HIV-1 gag or reverse transcriptase (RT) recognized a single naturally processed HIV-1 peptide in trifluoroacetic acid (TFA) extracts of infected cells: gag 77-85 (SLYNTVATL) or RT 476-484 (ILKEPVHGV). Both processed peptides match the synthetic peptides that are optimally active in cytotoxicity assays and have the consensus motif described for A2-associated peptides. Their abundances were approximately 400 and approximately 12 molecules per infected Jurkat-A2 cell, respectively. Other synthetic HIV-1 peptides active at subnanomolar concentrations were not present in infected cells. Except for the antigen processing mutant line T2, HIV-infected HLA-A2+ cell lines were specifically lysed by both A2-restricted CTL, although infected Jurkat-A2 cells were lysed more poorly by RT-specific CTL than by gag-specific CTL, suggesting that low cell surface density of a natural peptide may limit the effectiveness of some HIV-specific CTL despite their vigorous activity against synthetic peptide-treated target cells.
New Bacterial Species Associated with Chronic Periodontitis (2003)

Recent investigations of the human subgingival oral flora based on ribosomal 16S cloning and sequencing have shown many of the bacterial species present to be novel species or phylotypes. The purpose of the present investigation was to identify potential periodontal pathogens among these newly identified species and phylotypes. Species-specific ribosomal 16S primers for PCR amplification were developed for detection of new species. Associations with chronic periodontitis were observed for several new species or phylotypes, including uncultivated clones D084 and BH017 from the Deferribacteres phylum, AU126 from the Bacteroidetes phylum, Megasphaera clone BB166, clone X112 from the OP11 phylum, and clone I025 from the TM7 phylum, and the named species Eubacterium saphenum, Porphyromonas endodontalis, Prevotella denticola, and Cryptobacterium curtum. Species or phylotypes more prevalent in periodontal health included two uncultivated phylotypes, clone W090 from the Deferribacteres phylum and clone BU063 from the Bacteroidetes, and named species Atopobium rimae and Atopobium parvulum.
Basophil/mast cell precursors in human peripheral blood (1983)

Semisolid (methylcellulose) hemopoietic cultures revealed the presence of histamine-containing granulocyte colonies derived from precursors (CFU-C) present in human peripheral blood. Light microscopy and histochemical studies of cells in individual histamine-containing colonies demonstrated homogeneous populations of metachromatic basophil/mast cells (BMC) at various stages of maturation. By inverted microscopy, pure BMC colonies were more often found to have the overall appearance of the previously described "eosinophil" (type II), rather than "neutrophil-macrophage" (type I), colony type. Histamine-positive colonies constituted 58% (50/86) of all (type I and type II) granulocyte colonies in repeated cultures from a patient with systemic mastocytosis (SM), and 19% (13/67) of colonies in cultures from 8 patients with chronic myeloid leukemia (CML); this was in contrast to 8% (12/153) of colonies in cultures from 4 patients with urticaria pigmentosa (UP) and 6 normal controls (p less than 0.0001). Calculated frequency of BMC CFU-C was approximately 1 per 2 X 10(6) in normal and 1 per 2 X 10(5) nucleated cells in SM peripheral blood. Taking colony size into account, histamine content per cell in histamine-positive type II colonies in SM cultures was 1.1 +/- 0.19 pg, compared to 0.29 +/- 0.08 pg in CML and less than or equal to 0.10 in normals and UP. Electron microscopy (EM) of individual colonies revealed electron-dense granules with ultrastructural features of BMC in histamine-positive, but not histamine-negative, colonies. Use of these methods may help to further clarify the nature of BMC precursors and the regulation of their proliferation in bone marrow disorders and allergic states.
Regiocontrolled nucleophilic addition to selectively activated p-quinone diimines: alternative preparation of a key intermediate employed in the preparation of the CC-1065 left-hand subunit (1990)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRegiocontrolled nucleophilic addition to selectively activated p-quinone diimines: alternative preparation of a key intermediate employed in the preparation of the CC-1065 left-hand subunitDale L. Boger and Hamideh ZarrinmayehCite this: J. Org. Chem. 1990, 55, 4, 1379–1390Publication Date (Print):February 1, 1990Publication History Published online1 May 2002Published inissue 1 February 1990https://pubs.acs.org/doi/10.1021/jo00291a059https://doi.org/10.1021/jo00291a059research-articleACS PublicationsRequest reuse permissionsArticle Views1003Altmetric-Citations34LEARN 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
Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics (2015)

Here, we investigated the influence of the variable fragment (Fv) of IgG antibodies on the binding to the neonatal Fc receptor (FcRn) as well as on FcRn-dependent pharmacokinetics (PK). FcRn plays a key role in IgG homeostasis, and specific manipulation in the crystallizable fragment (Fc) is known to affect FcRn-dependent PK. Although the influence of the antigen-binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism is hitherto only poorly understood. Therefore, we analyzed the two IgG1 antibodies, briakinumab and ustekinumab, that have similar Fc parts but different terminal half-lives in human and systematically engineered variants of them with cross-over exchanges and varied charge distribution. Using FcRn affinity chromatography, molecular dynamics simulation, and in vivo PK studies in human FcRn transgenic mice, we provide evidence that the charge distribution on the Fv domain is involved in excessive FcRn binding. This excessive binding prevents efficient FcRn-IgG dissociation at physiological pH, thereby reducing FcRn-dependent terminal half-lives. Furthermore, we observed a linear correlation between FcRn column retention times of the antibody variants and the terminal half-lives in vivo. Taken together, our study contributes to a better understanding of the FcRn-IgG interaction, and it could also provide profound potential in FcRn-dependent antibody engineering of the variable Fab region.
Intraretinal oxygen levels before and after photoreceptor loss in the RCS rat. (2000)

There was no significant tissue hypoxia during photoreceptor degeneration in the dystrophic RCS rat. The changes in intraretinal oxygen distribution are consistent with the loss of outer retinal oxygen uptake but the preservation of inner retinal oxygen metabolism.
DNA-based approaches to the treatment of allergies. (2002)

Although excellent pharmacological treatments for allergies exist, they do not change the underlying pathogenesis of allergic diseases and do not cure the disease. Only allergen-specific immunotherapy, the injection of small but increasing amounts of allergen, has been shown to change a pre-existing allergic Th2 immune response to a non-allergic Th1 response. However, since injection of allergen is associated with the risk of allergic and sometimes even life-threatening anaphylactic reactions, immunotherapy is no longer used as extensively as in the past. In the search for a novel immunotherapy having a low risk-to-benefit ratio, immunostimulatory CpG motif DNA sequences have recently been shown to provide an excellent tool for designing safer and more efficient forms of allergen immunotherapy. These DNA-based immunotherapeutics include allergen gene vaccines, immunization with allergen-DNA conjugates and immunomodulation with immunostimulatory oligodeoxynucleotides. All three DNA-based immunotherapeutics have been shown to be very effective in animal models of allergic diseases and, at present, allergen-DNA conjugates are being tested for their safety and efficacy in allergic patients. This review describes the preclinical findings and the data of the first clinical trials in allergic patients of DNA-based immunotherapeutics for allergic disorders.
Effect of surface roughness on the efficiency of self-healing polymers (2013)

A shape memory polymer (SMP) is a smart material capable of maintaining two distinct shapes depending on its temperature. A SMP is soft at temperatures above its glass transition temperature but hard below it. When copolyester thermoplastic additives are dispersed in a SMP, it becomes a SMP-based particulate composite capable of self-healing at both the molecular level and the structural level. This makes it very desirable for industrial applications. Upon damage to the composite, the surfaces at the damage interface have to come into contact for efficient healing; the shape memory effect, coupled with a confined recovery (healing) process, ensures this. This study examined the effect of the surface roughness at the damage interface on the efficiency of the healing process. Also studied was the effect of the compressive stress at the point of contact during the healing process on the healing efficiency. The particulate composite (CP-PSMP) consisted of polystyrene shape memory polymer (PSMP) as the matrix and copolyester thermoplastic additives (CP) as the reinforcement. Compressive programming at 10 % pre-strain was performed on the CP-PSMP, which was then tested for its pre-flexural strength. Next, the surfaces were varied using sandpapers of different embedded particle diameters, and the CP-PSMP was healed at 10 MPa using the close-then-heal (CTH) self-healing mechanism. The recovered flexural strength was then obtained and the healing efficiency computed as a fraction of the recovered flexural strength to the pre-healing flexural strength. Healing efficiencies were found to be higher for CP-PSMP with smoother surfaces. The highest healing efficiency of 39 % was found in CP-PSMP with average and root-mean-squared roughness profile parameters, Ra and Rq, of 0.425 and 0.617 μm respectively. Another set of tests revealed that healing was more efficient at higher compressive stresses. Efficiencies at higher compressive stresses (20 – 80 MPa) ranged from 78 % to 118 %. Next, the effects of sanding on healing efficiency was examined by comparing the healing efficiencies of two sets of CP-PSMP with similar Ra and Rq values—one of which was treated with sandpaper. The sanded CP-PSMP samples were 24 % more efficient in healing.
An engineered Escherichia coli tyrosyl–tRNA synthetase for site-specific incorporation of an unnatural amino acid into proteins in eukaryotic translation and its application in a wheat germ cell-free system (2002)

Tyrosyl-tRNA synthetase (TyrRS) from Escherichia coli was engineered to preferentially recognize 3-iodo-L-tyrosine rather than L-tyrosine for the site-specific incorporation of 3-iodo-L-tyrosine into proteins in eukaryotic translation systems. The wild-type TyrRS does not recognize 3-iodo-L-tyrosine, because of the bulky iodine substitution. On the basis of the reported crystal structure of Bacillus stearothermophilus TyrRS, three residues, Y37, Q179, and Q195, in the L-tyrosine-binding site were chosen for mutagenesis. Thirty-four single amino acid replacements and 16 of their combinations were screened by in vitro biochemical assays. A combination of the Y37V and Q195C mutations changed the amino acid specificity in such a way that the variant TyrRS activates 3-iodo-L-tyrosine 10-fold more efficiently than L-tyrosine. This engineered enzyme, TyrRS(V37C195), was tested for use in the wheat germ cell-free translation system, which has recently been significantly improved, and is now as productive as conventional recombinant systems. During the translation in the wheat germ system, an E. coli suppressor tRNA(Tyr) was not aminoacylated by the wheat germ enzymes, but was aminoacylated by the E. coli TyrRS(V37C195) variant with 3-iodo-l-tyrosine. After the use of the 3-iodotyrosyl-tRNA in translation, the resultant uncharged tRNA could be aminoacylated again in the system. A mass spectrometric analysis of the produced protein revealed that more than 95% of the amino acids incorporated for an amber codon were iodotyrosine, whose concentration was only twice that of L-tyrosine in the translation. Therefore, the variant enzyme, 3-iodo-L-tyrosine, and the suppressor tRNA can serve as an additional set orthogonal to the 20 endogenous sets in eukaryotic in vitro translation systems.
Evaluation of the New AxSYM Cyclosporine Assay: Comparison with TDx Monoclonal Whole Blood and Emit Cyclosporine Assays (1999)

Cyclosporine (CsA) is a cyclic undecapeptide that has potent immunosuppressive activity, but its narrow therapeutic range and variable pharmacokinetics in humans make monitoring of CsA mandatory (1). The generally accepted whole-blood therapeutic ranges of CsA (with specific assay) are 100–200 μg/L for renal transplant patients and 150–250 μg/L for cardiac, hepatic, and pancreatic transplant patients during the maintenance phase (2)(3), whereas slightly higher ranges are recommended during the induction phase. The CsA metabolites arising from oxidative pathways (4) cross-react in immunoassays (5)(6), leading to results higher than those by HPLC. Trough concentrations of metabolite AM1, the major metabolite in human blood (1)(4), can exceed those of the parent drug (1). For metabolites AM1, AM9, and AM4N, immunosuppressive activity is <10% of that observed for CsA (7)(8), and at least in rats, various CsA metabolites are not nephrotoxic (9). Thus CsA itself, rather than its metabolites, is the major pharmacologically active substance (10), and specific analytical methods are recommended (3)(11)(12). HPLC is specific but time-consuming and labor-intensive; it also displays the highest between-center CV (1). Three major immunoassays based on different CsA monoclonal antibodies were developed by Abbott, IncStar, and Syva Laboratories: a fluorescence polarization immunoassay (FPIA; for the TDx analyzer), a Cyclo-Trac RIA, and an Emit, respectively (13)(14). All of these immunoassays yield slightly higher concentrations than does HPLC, with FPIA concentrations high by 20–30% (15). The results can be summarized as HPLC < Emit < RIA < TDx.

Very recently, a new monoclonal CsA FPIA assay was introduced by Abbott Laboratories for the AxSYM analyzer; it was aimed at reducing metabolite cross-reactivity further and, therefore, at correlating better with HPLC. We first evaluated the analytical performances of this new assay by comparing it with the …
Homocysteine and Diabetic Retinopathy (2007)

Plasma total homocysteine concentration may be a useful biomarker and/or a novel risk factor for increased risk of diabetic retinopathy in people with type 2 diabetes.
Pharmacokinetics of (−)−folinic acid after oral and intravenous administration of the racemate. (1989)

1. A pharmacokinetic study of the natural (-)-isomer of folinic acid ((-)-5 CHOTHF) and of total (-)-folates was performed in 12 healthy subjects after i.v. and oral administration of the racemic form of folinic acid. 2. After a 25 mg i.v. injection, (-)-5 CHOTHF kinetics were described by a biexponential function. The mean steady state volume of distribution (Vss) was 161; systemic and renal clearances averaged 335 and 53 ml min-1, respectively. After the same oral dose, (-)-5 CHOTHF was rapidly absorbed. Plasma concentrations of unchanged drug were much lower than those achieved after i.v. administration but in nine subjects, the disposition kinetics were also biexponential. Absolute bioavailability was only 4% as a consequence of a significant intestinal first pass effect. 3. AUC and t1/2Z values for total (-)-folates were similar after both routes of administration, indicating that the drug was fully absorbed. However the AUC of the active metabolite after i.v. dosage was only half that after oral dosage. 4. The amounts of total (-)-folates excreted in urine after both routes of administration were not significantly different and averaged one third of the dose after 24 h, whereas excretion of (-)-5 CHOTHF was three times less after oral treatment than after parenteral treatment. 5. Oral administration is a more suitable route for folinic acid therapy because more of the active metabolite is produced than after parenteral injection.
Enhancing Effects of Agelasphin-11 on Natural Killer Cell Activities of Normal and Tumor-Bearing Mice. (1996)

Agelasphin-11 (AGL-11), a novel alpha-galactosylceramide isolated from an extract of a marine sponge, Agelas mauritianus, markedly prolonged the life span of mice intraperitoneally inoculated with B16 cells. Since AGL-11 did not show any direct cytotoxic activity against B16 cells, this compound is considered to be a biological response modifier (BRM). We focused on the enhancing effect of this compound on in vivo natural killer (NK) cell activity because several BRMs have already been determined to enhance the in vivo natural killer (NK) cell activity. When we evaluated the enhancing activity of AGL-11 using normal mice, AGL-11 enhanced in vivo NK cell activity more potently than Poly I:C, which is a positive control. In addition, we examined the effect of this compound on the NK cell activity of tumor-bearing mice, and found that AGL-11 recovers the reduced NK cell activity in a tumor-bearing condition to a higher level than that of normal mice. These results suggest that AGL-11 shows antitumor activity by the activation of antitumor effector cells such as NK cells.
Long-Term Outcome and Relative Risk in Women With Atypical Squamous Cells of Undetermined Significance (1999)

Few studies have compared long-term follow-up and risk for invasive cancer in women with atypical squamous cells of undetermined significance (ASCUS). We conducted a 6-year review of pathology files for 651 women in whom ASCUS had been diagnosed in 1992. Data collected included patient demographics, follow-up diagnoses, time between follow-up examinations, and procedures performed. At follow-up, high-grade squamous intraepithelial lesions (HSIL) had developed in 9.0% of the women, and invasive cancer in none. Previous cervical history did not affect risk for an HSIL. Although the average time to first follow-up was 6.18 months, in 20.9% of the women the diagnosis of HSIL was not established until after 2.0 years. For individual pathologists, the percentage of HSILs ranged from 0% to 18.8%. Thus women with ASCUS who are followed up regularly are at low risk for development of invasive cancer.
Ligand binding and gene control characteristics of tandem riboswitches in Bacillus anthracis (2007)

Most riboswitches are composed of a single metabolite-binding aptamer and a single expression platform that function together to regulate genes in response to changing metabolite concentrations. In rare instances, two aptamers or sometimes two complete riboswitches reside adjacent to each other in untranslated regions (UTRs) of mRNAs. We have examined an example of a tandem riboswitch in the Gram-positive bacterium Bacillus anthracis that includes two complete riboswitches for thiamine pyrophosphate (TPP). Unlike other complex riboswitch systems described recently, tandem TPP riboswitches do not exhibit cooperative ligand binding and do not detect two different types of metabolites. In contrast, both riboswitches respond independently to TPP and are predicted to function in concert to mimic the more "digital" gene control outcome observed when two aptamers bind ligands cooperatively. Our findings further demonstrate that simple gene control elements made only of RNA can be assembled in different architectures to yield more complex gene control outcomes.