28 research outputs found
Finding the Cell Center by a Balance of Dynein and Myosin Pulling and Microtubule Pushing: A Computational Study
By comparing computer modeling predictions with observations, we conclude that strong dynein and weaker myosin-generated forces pull the microtubules inward competing with microtubule plus-ends pushing the microtubule aster outward and that the balance of these forces positions the centrosome at the cell center
Epithelial Proinflammatory Response and Curcumin-Mediated Protection from Staphylococcal Toxic Shock Syndrome Toxin-1
Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-ÎșB-dependent transcription in HVECs that was associated with increased expression of TNF- α, MIP-3α, IL-6 and IL-8. Curcumin, an antagonist of NF-ÎșB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-α was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-ÎșB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe
Co-delivery of natural metabolic inhibitors in a self-microemulsifying drug delivery system for improved oral bioavailability of curcumin
Recent years have seen a rapid rise in the use of electronic cigarettes (e-cigarettes), especially among teens and young adults, including a significant minority who have never smoked âtraditionalâ cigarettes. Response to this surging use has so far been mixed, with popular claims about e-cigarettesâ health benefits as a smoking cessation tool pitted against growing concern about new âgatewaysâ to nicotine dependence among young non-smokers, and the ârenormalizationâ of smoking behavior. In January 2015, California Public Health Department called for a major campaign to educate young Californians about e-cigarettes. The effectiveness of such a campaign requires nuanced understanding of the meanings and use of e-cigarettes (popularly known as âvapingâ) among this group, yet detailed knowledge is lacking. Our in-progress study explores vape culture among young people aged 18-22 in Stockton. Our proposed presentation would report initial findings from at least three focus group discussions with selfidentified âcasualâ and â committedâ vapers. Including Pacific students, Delta students, and those not engaged in higher education. Major themes that will be highlighted include the varied appeals of vaping, the characterization of vape culture as a âcommunityâ, and the social acceptance and restraints experienced by vapers
Folic Acid Functionalized Nanoparticles for Enhanced Oral Drug Delivery
The oral absorption of drugs that have poor bioavailability
can
be enhanced by encapsulation in polymeric nanoparticles. Transcellular
transport of nanoparticle-encapsulated drug, possibly through transcytosis,
is likely the major mechanism through which nanoparticles improve
drug absorption. We hypothesized that the cellular uptake and transport
of nanoparticles can be further increased by targeting the folate
receptors expressed on the intestinal epithelial cells. The objective
of this research was to study the effect of folic acid functionalization
on transcellular transport of nanoparticle-encapsulated paclitaxel,
a chemotherapeutic with poor oral bioavailability. Surface-functionalized
polyÂ(d,l-lactide-<i>co</i>-glycolide)
(PLGA) nanoparticles loaded with paclitaxel were prepared by the interfacial
activity assisted surface functionalization technique. Transport of
paclitaxel-loaded nanoparticles was investigated using Caco-2 cell
monolayers as an in vitro model. Caco-2 cells were found to express
folate receptor and the drug efflux protein, p-glycoprotein, to high
levels. Encapsulation of paclitaxel in PLGA nanoparticles resulted
in a 5-fold increase in apparent permeability (<i>P</i><sub>app</sub>) across Caco-2 cells. Functionalization of nanoparticles
with folic acid further increased the transport (8-fold higher transport
compared to free paclitaxel). Confocal microscopic studies showed
that folic acid functionalized nanoparticles were internalized by
the cells and that nanoparticles did not have any gross effects on
tight junction integrity. In conclusion, our studies indicate that
folic acid functionalized nanoparticles have the potential to enhance
the oral absorption of drugs with poor oral bioavailability
Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans
Furan, a possible human carcinogen,
is found in heat treated foods
and tobacco smoke. Previous studies have shown that humans are capable
of converting furan to its reactive metabolite, <i>cis</i>-2-butene-1,4-dial (BDA), and therefore may be susceptible to furan
toxicity. Human risk assessment of furan exposure has been stymied
because of the lack of mechanism-based exposure biomarkers. Therefore,
a sensitive LC-MS/MS assay for six furan metabolites was applied to
measure their levels in urine from furan-exposed rodents as well as
in human urine from smokers and nonsmokers. The metabolites that result
from direct reaction of BDA with lysine (BDA-<i>N</i><sup>α</sup>-acetyllysine) and from cysteine-BDA-lysine cross-links
(<i>N</i>-acetylcysteine-BDA-lysine, <i>N</i>-acetylcysteine-BDA-<i>N</i><sup>α</sup>-acetyllysine, and their sulfoxides)
were targeted in this study. Five of the six metabolites were identified
in urine from rodents treated with furan by gavage. BDA-<i>N</i><sup>α</sup>-acetyllysine, <i>N</i>-acetylcysteine-BDA-lysine,
and its sulfoxide were detected in most human urine samples from three
different groups. The levels of <i>N</i>-acetylcysteine-BDA-lysine
sulfoxide were more than 10 times higher than that of the corresponding
sulfide in many samples. The amount of this metabolite was higher
in smokers relative to that in nonsmokers and was significantly reduced
following smoking cessation. Our results indicate a strong relationship
between BDA-derived metabolites and smoking. Future studies will determine
if levels of these biomarkers are associated with adverse health effects
in humans
Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis
Humans are exposed to furan, a toxicant and possible
human carcinogen,
through multiple sources including diet and tobacco smoke. The urinary
metabolites of furan are derived from the reaction of its toxic metabolite
with protein nucleophiles and are biomarkers of exposure and potential
harm. An established isotopic dilution liquid-chromatography mass
spectrometry method was used to measure these biomarkers in urine
from users of e-cigarettes, cannabis, and/or combustible tobacco with/without
reduced nicotine levels. Amounts of furan mercapturic acid metabolites
were higher in these individuals relative to nonsmokers, indicating
that they may be at risk for potential furan-derived toxicities
Extended effects of evening meal carbohydrate-to-fat ratio on fasting and postprandial substrate metabolism
TSST-1 induces IL-8 and activates NF-ÎșB from HVEC with minimal toxicity.
<p>HVEC were exposed to TSST-1 (10â500 ”g/ml) for 6 h, then cell viability (A) and IL-8 production (B) were determined. Viability was determined using an MTT assay. IL-8 was measured from culture supernatants by ELISA and expressed as fold increase in IL-8 production compared to media only control (TSST-1 0 ”g/ml). Data presented are representative of three independent experiments done in triplicate, mean ± SD. * denotes p<0.05 compared to media only control.</p