A dose-controlled system for air-liquid interface cell exposure and application to zinc oxide nanoparticles

<p>Abstract</p> <p>Background</p> <p>Engineered nanoparticles are becoming increasingly ubiquitous and their toxicological effects on human health, as well as on the ecosystem, have become a concern. Since initial contact with nanoparticles occurs at the epithelium in the lungs (or skin, or eyes), <it>in vitro </it>cell studies with nanoparticles require dose-controlled systems for delivery of nanoparticles to epithelial cells cultured at the air-liquid interface.</p> <p>Results</p> <p>A novel air-liquid interface cell exposure system (ALICE) for nanoparticles in liquids is presented and validated. The ALICE generates a dense cloud of droplets with a vibrating membrane nebulizer and utilizes combined cloud settling and single particle sedimentation for fast (~10 min; entire exposure), repeatable (<12%), low-stress and efficient delivery of nanoparticles, or dissolved substances, to cells cultured at the air-liquid interface. Validation with various types of nanoparticles (Au, ZnO and carbon black nanoparticles) and solutes (such as NaCl) showed that the ALICE provided spatially uniform deposition (<1.6% variability) and had no adverse effect on the viability of a widely used alveolar human epithelial-like cell line (A549). The cell deposited dose can be controlled with a quartz crystal microbalance (QCM) over a dynamic range of at least 0.02-200 μg/cm². The cell-specific deposition efficiency is currently limited to 0.072 (7.2% for two commercially available 6-er transwell plates), but a deposition efficiency of up to 0.57 (57%) is possible for better cell coverage of the exposure chamber.</p> <p>Dose-response measurements with ZnO nanoparticles (0.3-8.5 μg/cm²) showed significant differences in mRNA expression of pro-inflammatory (IL-8) and oxidative stress (HO-1) markers when comparing submerged and air-liquid interface exposures. Both exposure methods showed no cellular response below 1 μg/cm²ZnO, which indicates that ZnO nanoparticles are not toxic at occupationally allowed exposure levels.</p> <p>Conclusion</p> <p>The ALICE is a useful tool for dose-controlled nanoparticle (or solute) exposure of cells at the air-liquid interface. Significant differences between cellular response after ZnO nanoparticle exposure under submerged and air-liquid interface conditions suggest that pharmaceutical and toxicological studies with inhaled (nano-)particles should be performed under the more realistic air-liquid interface, rather than submerged cell conditions.</p

Cluster analysis of higher-education competitiveness in selected European countries

The subject of research in this paper is higher-education competitiveness on account of its impact on the enhancement of social and economic competitiveness, as well as on the growth of human capital and creation of social knowledge. The purpose of this paper is to group the selected European countries according to higher-education competitiveness, by means of the hierarchical cluster analysis method, with a special focus on the position of Serbia. Higher-education competitiveness in the chosen countries is analysed by means of three indicators of competitiveness: the ratio of the number of students per number of inhabitants, the number of students per number of employed, as well as the amount of budgetary funds allocated per student. The research results indicate different higher-education competitiveness in the analysed countries and also the fact that, according to this analysis, Serbia is in the group of countries with low competitiveness of higher education

Scary Barbie: An Extremely Energetic, Long-Duration Tidal Disruption Event Candidate Without a Detected Host Galaxy at z = 0.995

We report multi-wavelength observations and characterization of the ultraluminous transient AT 2021lwx (ZTF20abrbeie; aka ``Barbie'') identified in the alert stream of the Zwicky Transient Facility (ZTF) using a Recommender Engine For Intelligent Transient Tracking (REFITT) filter on the ANTARES alert broker. From a spectroscopically measured redshift of 0.995, we estimate a peak observed pseudo-bolometric luminosity of log (L$_{\text{max}} / [\text{erg}/\text{s}]$) = 45.7 from slowly fading ztf-$\it{g}$ and ztf-$r$ light curves spanning over 1000 observer-frame days. The host galaxy is not detected in archival Pan-STARRS observations ($g > 23.3$ mag), implying a lower limit to the outburst amplitude of more than 5 mag relative to the quiescent host galaxy. Optical spectra from Lick and Keck Observatories exhibit strong emission lines with narrow cores from the H Balmer series and ultraviolet semi-forbidden lines of Si III] $\lambda$1892, C III] $\lambda$1909, and C II] $\lambda$2325. Typical nebular lines in AGN spectra from ions such as [O II] and [O III] are not detected. These spectral features, along with the smooth light curve that is unlike most AGN flaring activity, and the luminosity that exceeds any observed or theorized supernova, lead us to conclude that AT 2021lwx is most likely an extreme tidal disruption event (TDE). Modeling of ZTF photometry with MOSFiT suggests that the TDE was between a $\approx 14 M_{\odot}$ star and a supermassive black hole of mass $M_{\text{BH}} \sim$ $10^{8} M_{\odot}$. Continued monitoring of the still-evolving light curve along with deep imaging of the field once AT 2021lwx has faded can test this hypothesis and potentially detect the host galaxy.Comment: 15 pages, 4 figures, 1 Table; Version as published in The Astrophysical Journal Letters. Observations of AT 2021lwx published in the paper can be found at https://bsubraya.github.io/research

Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m−2), 5-FU (400 mg m−2), leucovorin (40 mg m−2) and epirubicin (60 mg m−2) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance

The association of hydration status with physical signs, symptoms and survival in advanced cancer-The use of Bioelectrical Impedance Vector Analysis (BIVA) technology to evaluate fluid volume in palliative care: An observational study

Background Hydration in advanced cancer is a controversial area; however, current hydration assessments methods are poorly developed. Bioelectrical impedance vector analysis (BIVA) is an accurate hydration tool; however its application in advanced cancer has not been explored. This study used BIVA to evaluate hydration status in advanced cancer to examine the association of fluid status with symptoms, physical signs, renal biochemical measures and survival. Materials and methods An observational study of 90 adults with advanced cancer receiving care in a UK specialist palliative care inpatient unit was conducted. Hydration status was assessed using BIVA in addition to assessments of symptoms, physical signs, performance status, renal biochemical measures, oral fluid intake and medications. The association of clinical variables with hydration was evaluated using regression analysis. A survival analysis was conducted to examine the influence of hydration status and renal failure. Results The hydration status of participants was normal in 43 (47.8%), 'more hydrated' in 37 (41.1%) and 'less hydrated' in 10 (11.1%). Lower hydration was associated with increased symptom intensity (Beta = -0.29, p = 0.04) and higher scores for physical signs associated with dehydration (Beta = 10.94, p = 0.02). Higher hydration was associated with oedema (Beta = 2.55, p<0.001). Median survival was statistically significantly shorter in 'less hydrated' patients (44 vs. 68 days; p = 0.049) and in pre-renal failure (44 vs. 100 days; p = 0.003). Conclusions In advanced cancer, hydration status was associated with clinical signs and symptoms. Hydration status and pre-renal failure were independent predictors of survival. Further studies can establish the utility of BIVA as a standardised hydration assessment tool and explore its potential research application, in order to inform the clinical management of fluid balance in patients with advanced cancer

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion

Measurement of functional microcirculatory geometry and velocity distributions using automated image analysis

This study describes a new method for analyzing microcirculatory videos. It introduces algorithms for quantitative assessment of vessel length, diameter, the functional microcirculatory density distribution and red blood-cell (RBC) velocity in individual vessels as well as its distribution. The technique was validated and compared to commercial software. The method was applied to the sublingual microcirculation in a healthy volunteer and in a patient during cardiac surgery. Analysis time was reduced from hours to minutes compared to previous methods requiring manual vessel identification. Vessel diameter was detected with high accuracy (>80%, d > 3 pixels). Capillary length was estimated within 5 pixels accuracy. Velocity estimation was very accurate (>95%) in the range [2.5, 1,000] pixels/s. RBC velocity was reduced by 70% during the first 10 s of cardiac luxation. The present method has been shown to be fast and accurate and provides increased insight into the functional properties of the microcirculation