Assessing cellular toxicities in fibroblasts upon exposure to lipid-based nanoparticles: a high content analysis approach

Lipid-based nanoparticles (LNPs) are widely used for the delivery of drugs and nucleic acids. Although most of them are considered safe, there is confusing evidence in the literature regarding their potential cellular toxicities. Moreover, little is known about the recovery process cells undergo after a cytotoxic insult. We have previously studied the systemic effects of common LNPs with different surface charge (cationic, anionic, neutral) and revealed that positively charged LNPs ((+)LNPs) activate pro-inflammatory cytokines and induce interferon response by acting as an agonist of Toll-like receptor 4 on immune cells. In this study, we focused on the response of human fibroblasts exposed to LNPs and their cellular recovery process. To this end, we used image-based high content analysis (HCA). Using this strategy, we were able to show simultaneously, in several intracellular parameters, that fibroblasts can recover from the cytotoxic effects of (+)LNPs. The use of HCA opens new avenues in understanding cellular response and nanotoxicity and may become a valuable tool for screening safe materials for drug delivery and tissue engineering.     

Artificial Dim Light at Night during Pregnancy Can Affect Hormonal and Metabolic Rhythms in Rat Offspring

Artificial light at night (ALAN) is considered an environmental risk factor that can interfere with the circadian control of the endocrine system and metabolism. We studied the impact of ALAN during pregnancy on the hormonal and biochemical parameters in rat pups at postnatal (P) days P3, P10, and P20. Control dams (CTRL) were kept in a standard light-dark regime, and ALAN dams were exposed to dim ALAN (<2 lx) during the whole pregnancy. A plasma melatonin rhythm was found in all CTRL groups, whereas in ALAN pups, melatonin was not rhythmic at P3, and its amplitude was lowered at P10; no differences were found between groups at P20. Plasma corticosterone was rhythmic at P20 in both groups, with decreased mesor in ALAN pups. Plasma thyroid hormones exhibited an inconsistent developmental pattern, and vasopressin levels were suppressed at the beginning of the dark phase at P20 in ALAN compared to CTRL. Glucose and cholesterol showed significant daily rhythms in CTRL but not in ALAN offspring at P3. Exposure to ALAN during pregnancy disturbed the development of daily rhythms in measured hormones and metabolites, suggesting that ALAN during pregnancy can act as an endocrine disruptor that can interfere with the normal development of the progeny.     

An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer’s Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model

Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.     

A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease—Identifying Those at the Greatest Risk

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.     

The pin power distribution in theVVER-1000 mock-up on the LR-0 research reactor

The pin power density distribution in reactor is an important quantity, necessary for the adequate assessment of fuel conditions and of core structures and pressure vessel radiation embrittlement as well.The paper shows the detailed comparison of calculated and experimentally determined pin by pin power distribution. To verify the reliability of measured data used for comparison with calculated data, the symmetrically located pins were measured. The calculations have been done with deterministic and Monte Carlo approach. The effect of different data libraries used for calculations are discussed as well.     

Thermal scatter treatment of iron in transport of photons and neutrons

The present paper deals with measured as well as calculated energy spectra of neutron and photon beams from the AKR-2 experimental reactor after having passed through Fe layers and Fe/H₂O combined layers. The experiment results are compared with calculations presented in various nuclear data libraries, such as, ENDF/B VI.2., ENDF/B VII., BROND 3, JENDL 3.3 and JEFF 3.1. Two models were used to calculate the neutron transport. The first takes into account the atomic structure of the material, whereas the other neglects the effect of inter-atomic bonds assuming the atomic nucleus behaviour to follow the free gas model.     

Determination of AKR-2 leakage beam and verification at iron and water arrangements

In this paper computational procedures and the experimental determination of the AKR-2 (Technical University Dresden) beam parameters are described. The calculations were performed using the MCNPX code (Pelowitz, 2002) and the nuclear data libraries ENDF/B VI.2., ENDF/B VII.0., JEFF 3.1., JENDL 3.3 and BROND 3. The nuclear data were processed using the NJOY code (MacFarlane and Muir, 1994). The measurements were performed with a two-parameter stilbene spectrometer (Bures et al., 2002).     

Consistent Viewing and Interaction for Multiple Users in Projection-Based VR Systems

In projection-based Virtual Reality (VR) systems, typically only one headtracked user views stereo images rendered from the correct view position. For other users, who are presented a distorted image, moving with the first user's head motion, it is difficult to correctly view and interact with 3D objects in the virtual environment. In close-range VR systems, such as the Virtual Workbench, distortion effects are especially large because objects are within close range and users are relatively far apart. On these systems, multi-user collaboration proves to be difficult. In this paper, we analyze the problem and describe a novel, easy to implement method to prevent and reduce image distortion and its negative effects on close-range interaction task performance. First, our method combines a shared camera model and view distortion compensation. It minimizes the overall distortion for each user, while important user-personal objects such as interaction cursors, rays and controls remain distortion-free. Second, our method retains co-location for interaction techniques to make interaction more consistent. We performed a user experiment on our Virtual Workbench to analyze user performance under distorted view conditions with and without the use of our method. Our findings demonstrate the negative impact of view distortion on task performance and the positive effect our method introduces. This indicates that our method can enhance the multi-user collaboration experience on close-range, projection-based VR systems.     

Particle Distribution and Separation in Continuous Casting Tundish

The tundish as a part of a continuous casting machine combines the discontinuous ladle metallurgy with the continuous solidification of slabs in the mould. The tundish plays a major role in the challenging task of “clean steel” production. That means the smallest number of inclusions and high cleanliness in all steel grades after changing the conditions at the inlet of the tundish. Inclusions hinder the metal forming process and lead often to fatigue. The cleanliness of steels is important to fulfil the customer's requirements. In the present study inclusion removal was simulated in a 1:3 scaled water model of a single‐strand tundish for the production of stainless steels with a particle counter. The particle counter is capable of counting a large number of particles with a wide range of diameters. The separation rate for particle diameters from d_P = 1 ‐ 250 μm was determined with a counter for the water model tundish. With similarity conditions for the particles this deposition rate can be transformed to the melt flow in a steel tundish. The separation rate was measured for different flow rates in the water model tundish. A larger flow rate decreased the separation rate. Additionally, the separation rate for the tundish fitted with an impact pad was measured and showed a significant increase of separation for particles with a smaller diameter. Furthermore, the particle distribution in the tundish for different size groups of particles was investigated with and without an impact pad. Numerical simulations were carried out with the finite‐volume commercial code FLUENT using the realizable k‐ε turbulence model. A special boundary condition for the separation of particles at the surface was implemented.