1,094 research outputs found
Deriving a Provisional Tolerable Intake for Intravenous Exposure to Silver Nanoparticles Released from Medical Devices
Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL05) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 μg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general
Comparing the hierarchy of keywords in on-line news portals
The tagging of on-line content with informative keywords is a widespread
phenomenon from scientific article repositories through blogs to on-line news
portals. In most of the cases, the tags on a given item are free words chosen
by the authors independently. Therefore, relations among keywords in a
collection of news items is unknown. However, in most cases the topics and
concepts described by these keywords are forming a latent hierarchy, with the
more general topics and categories at the top, and more specialised ones at the
bottom. Here we apply a recent, cooccurrence-based tag hierarchy extraction
method to sets of keywords obtained from four different on-line news portals.
The resulting hierarchies show substantial differences not just in the topics
rendered as important (being at the top of the hierarchy) or of less interest
(categorised low in the hierarchy), but also in the underlying network
structure. This reveals discrepancies between the plausible keyword association
frameworks in the studied news portals
Master Equation for the Motion of a Polarizable Particle in a Multimode Cavity
We derive a master equation for the motion of a polarizable particle weakly
interacting with one or several strongly pumped cavity modes. We focus here on
massive particles with complex internal structure such as large molecules and
clusters, for which we assume a linear scalar polarizability mediating the
particle-light interaction. The predicted friction and diffusion coefficients
are in good agreement with former semiclassical calculations for atoms and
small molecules in weakly pumped cavities, while the current rigorous quantum
treatment and numerical assessment sheds a light on the feasibility of
experiments that aim at optically manipulating beams of massive molecules with
multimode cavities.Comment: 30 pages, 5 figure
The Proper Splicing of RNAi Factors Is Critical for Pericentric Heterochromatin Assembly in Fission Yeast
Heterochromatin preferentially assembles at repetitive DNA elements, playing roles in transcriptional silencing, recombination suppression, and chromosome segregation. The RNAi machinery is required for heterochromatin assembly in a diverse range of organisms. In fission yeast, RNA splicing factors are also required for pericentric heterochromatin assembly, and a prevailing model is that splicing factors provide a platform for siRNA generation independently of their splicing activity. Here, by screening the fission yeast deletion library, we discovered four novel splicing factors that are required for pericentric heterochromatin assembly. Sequencing total cellular RNAs from the strongest of these mutants, cwf14Δ, showed intron retention in mRNAs of several RNAi factors. Moreover, introducing cDNA versions of RNAi factors significantly restored pericentric heterochromatin in splicing mutants. We also found that mutations of splicing factors resulted in defective telomeric heterochromatin assembly and mis-splicing the mRNA of shelterin component Tpz1, and that replacement of tpz1+ with its cDNA partially rescued heterochromatin defects at telomeres in splicing mutants. Thus, proper splicing of RNAi and shelterin factors contributes to heterochromatin assembly at pericentric regions and telomeres
Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain
Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational mo difications in histones are pivotal in regulating transcription. Here, we report th at phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signa l-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 ( p - S10H3) as well as fos transcription, a down-stream effect of p -S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p -S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain
Growth and puberty in a 2-year open-label study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder
Background: Stimulant medications for the treatment of
attention-deficit/hyperactivity disorder have a history of
safe and effective use; however, concerns exist that they
may adversely affect growth trajectories in children and
adolescents.
Objective: The objective of this study was to evaluate the
longer-term effects of lisdexamfetamine dimesylate on
weight, height, body mass index and pubertal development
in children and adolescents with attention-deficit/hyperactivity disorder.
Methods: Children and adolescents aged 6–17 years with
attention-deficit/hyperactivity disorder took open-label
lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this
open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and selfreported pubertal status using Tanner staging.
Results: The safety analysis population comprised all
enrolled participants (N = 314) and 191 (60.8%) completed
the study. Weight decrease was reported as a treatmentemergent adverse event in 63 participants (20.1%) and two
participants (0.6%) discontinued the study as a result of
treatment-emergent adverse events of weight decrease
A Co-Opted DEAD-Box RNA Helicase Enhances Tombusvirus Plus-Strand Synthesis
Replication of plus-strand RNA viruses depends on recruited host factors that aid several critical steps during replication. In this paper, we show that an essential translation factor, Ded1p DEAD-box RNA helicase of yeast, directly affects replication of Tomato bushy stunt virus (TBSV). To separate the role of Ded1p in viral protein translation from its putative replication function, we utilized a cell-free TBSV replication assay and recombinant Ded1p. The in vitro data show that Ded1p plays a role in enhancing plus-strand synthesis by the viral replicase. We also find that Ded1p is a component of the tombusvirus replicase complex and Ded1p binds to the 3′-end of the viral minus-stranded RNA. The data obtained with wt and ATPase deficient Ded1p mutants support the model that Ded1p unwinds local structures at the 3′-end of the TBSV (−)RNA, rendering the RNA compatible for initiation of (+)-strand synthesis. Interestingly, we find that Ded1p and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is another host factor for TBSV, play non-overlapping functions to enhance (+)-strand synthesis. Altogether, the two host factors enhance TBSV replication synergistically by interacting with the viral (−)RNA and the replication proteins. In addition, we have developed an in vitro assay for Flock house virus (FHV), a small RNA virus of insects, that also demonstrated positive effect on FHV replicase activity by the added Ded1p helicase. Thus, two small RNA viruses, which do not code for their own helicases, seems to recruit a host RNA helicase to aid their replication in infected cells
Genome wide mapping reveals PDE4B as an IL-2 induced STAT5 target gene in activated human PBMCs and lymphoid cancer cells
IL-2 is the primary growth factor for promoting survival and proliferation of activated T cells that occurs following engagement of the Janus Kinase (JAK)1-3/and Signal Transducer and Activator of Transcription (STAT) 5 signaling pathway. STAT5 has two isoforms: STAT5A and STAT5B ( commonly referred to as STAT5) which, in T cells, play redundant roles transcribing cell cycle and survival genes. As such, inhibition of STAT5 by a variety of mechanisms can rapidly induce apoptosis in certain lymphoid tumor cells, suggesting that it and its target genes represent therapeutic targets to control certain lymphoid diseases. To search for these molecules we aligned IL-2 regulated genes detected by Affymetrix gene expression microarrays with the STAT5 cistrome identified by chip-on-ChIP analysis in an IL-2-dependent human leukemia cell line, Kit225. Select overlapping genes were then validated using qRT(2)PCR medium-throughput arrays in human PHA-activated PBMCs. Of 19 putative genes, one key regulator of T cell receptor signaling, PDE4B, was identified as a novel target, which was readily up-regulated at the protein level (3 h) in IL-2 stimulated, activated human PBMCs. Surprisingly, only purified CD8+ primary T-cells expressed PDE4B, but not CD4+ cells. Moreover, PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for pharmaceutical intervention for certain lymphoid diseases
Changes in male rat urinary protein profile during puberty: a pilot study
BACKGROUND:
Androgen-dependent proteins (lipocalins) circulate in blood of male rats and mice and, being small (~ 18 kDa), pass freely into glomerular filtrate. Some are salvaged in proximal nephrons but some escape in urine. Several organic molecules can bind to these proteins causing, where salvage occurs, nephropathy including malignancy in renal cortex. In urine, both free lipocalins and ligands contribute to an increasingly-recognised vital biological role in social communication between adults, especially in the dark where reliance is on smell and taste. Crystal structure of the first-characterised lipocalin of male rats, alpha2u-globulin, has been determined and peptide sequences for others are available, but no study of occurrence during early puberty has been made. We have followed temporal occurrence in urine of juveniles (n = 3) for non-invasive pilot study by high resolution gradient mini-gel electrophoresis, tryptic digest of excised protein bands, and LC-MS/MS of digest to identify peptide fragments and assign to specific lipocalins. Study objective refers directly to external availability for social communication but also indirectly to indicate kinetics of circulating lipocalins to which some xenobiotics may bind and constitute determinants of renal disease.
RESULTS:
Mini-gels revealed greater lipocalin complexity than hitherto recognised, possibly reflecting post-translational modifications. Earliest patterns comprised rat urinary protein 1, already evident in Sprague-Dawley and Wistar strains at 36 and 52 days, respectively. By 44 and 57 days major rat protein (alpha2u-globulin) occurred as the progressively more dominant protein, though as two forms with different electrophoretic mobility, characterised by seven peptide sequences. No significant change in urinary testosterone had occurred in Wistars when major rat protein became evident, but testosterone surged by 107 days concomitant with the marked abundance of excreted lipocalins.
CONCLUSIONS:
Qualitative temporal changes in the composition of excreted lipocalins early in puberty, and apparent increase in major urinary protein as two resolvable forms, should catalyse systematic non-invasive study of urinary lipocalin and testosterone dynamics from early age, to illuminate this aspect of laboratory rodent social physiology. It could also define the potential temporal onset of nephrotoxic ligand risk, applicable to young animals used as toxicological models
The Grizzly, April 15, 1988
Greek Week\u27s Coming! • Sorority Songfest Sunday • Letters: Visser to Goofley: Kiss Dirt!; Code: Honor; Billing Miffs Student; Professor Nagy Responds to Tiryak Forum; Red Cross Congratulates UC Donators • Mid East Forum Scheduled • Take Women\u27s Studies! • 1988-89 RAs Announced • Men\u27s Track Races to 5-0 • LAX Hopes to Lift Level of Play Against West Chester • Women\u27s Outdoor Places Fourth • Baseball Hopes to Turn Season Around vs. Widener • Race-rafters Rollick • Underclassmen Pitching Power Carrying Softballers • Hallinger Takes Third • Strong Sailing for U.C. • The Grizzly\u27s Senior Sports Spotlight Salutes Kris Carr • Women Students Rule • Tommy Conwell in Concert Rumbles Ursinus • Portrait of an Artist • STAR Ambassadors Shinehttps://digitalcommons.ursinus.edu/grizzlynews/1211/thumbnail.jp
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