Translocation of PEGylated quantum dots across rat alveolar epithelial cell monolayers

Farnoosh Fazlollahi1,8, Arnold Sipos1,2, Yong Ho Kim1,2, Sarah F Hamm-Alvarez6, Zea Borok1–3, Kwang-Jin Kim1,2,5–7, Edward D Crandall1,2,4,8 1Will Rogers Institute Pulmonary Research Center, 2Department of Medicine, 3Department of Biochemistry and Molecular Biology, 4Department of Pathology, 5Department of Physiology and Biophysics, 6Department of Pharmacology and Pharmaceutical Sciences, 7Department of Biomedical Engineering, 8Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA Background: In this study, primary rat alveolar epithelial cell monolayers (RAECM) were used to investigate transalveolar epithelial quantum dot trafficking rates and underlying transport mechanisms. Methods: Trafficking rates of quantum dots (PEGylated CdSe/ZnS, core size 5.3 nm, hydrodynamic size 25 nm) in the apical-to-basolateral direction across RAECM were determined. Changes in bioelectric properties (ie, transmonolayer resistance and equivalent active ion transport rate) of RAECM in the presence or absence of quantum dots were measured. Involvement of endocytic pathways in quantum dot trafficking across RAECM was assessed using specific inhibitors (eg, methyl-ß-cyclodextrin, chlorpromazine, and dynasore for caveolin-, clathrin-, and dynamin-mediated endocytosis, respectively). The effects of lowering tight junctional resistance on quantum dot trafficking were determined by depleting Ca2+ in apical and basolateral bathing fluids of RAECM using 2 mM EGTA. Effects of temperature on quantum dot trafficking were studied by lowering temperature from 37°C to 4°C. Results: Apical exposure of RAECM to quantum dots did not elicit changes in transmonolayer resistance or ion transport rate for up to 24 hours; quantum dot trafficking rates were not surface charge-dependent; methyl-ß-cyclodextrin, chlorpromazine, and dynasore did not decrease quantum dot trafficking rates; lowering of temperature decreased transmonolayer resistance by approximately 90% with a concomitant increase in quantum dot trafficking by about 80%; and 24 hours of treatment of RAECM with EGTA decreased transmonolayer resistance by about 95%, with increased quantum dot trafficking of up to approximately 130%. Conclusion: These data indicate that quantum dots do not injure RAECM and that quantum dot trafficking does not appear to take place via endocytic pathways involving caveolin, clathrin, or dynamin. We conclude that quantum dot translocation across RAECM takes place via both transcellular and paracellular pathways and, based on comparison with our prior studies, interactions of nanoparticles with RAECM are strongly dependent on nanoparticle composition and surface properties. Keywords: alveolar epithelial barrier, transport, paracellular pathways, endocytosi

Oxidation of Cellular Amino Acid Pools Leads to Cytotoxic Mistranslation of the Genetic Code

Aminoacyl-tRNA synthetases use a variety of mechanisms to ensure fidelity of the genetic code and ultimately select the correct amino acids to be used in protein synthesis. The physiological necessity of these quality control mechanisms in different environments remains unclear, as the cost vs benefit of accurate protein synthesis is difficult to predict. We show that in Escherichia coli, a non-coded amino acid produced through oxidative damage is a significant threat to the accuracy of protein synthesis and must be cleared by phenylalanine-tRNA synthetase in order to prevent cellular toxicity caused by mis-synthesized proteins. These findings demonstrate how stress can lead to the accumulation of non-canonical amino acids that must be excluded from the proteome in order to maintain cellular viability

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells. Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β. Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity

The quality of options in strategic decision making: a study about creativity and completeness in business decision making

A qualidade das decisões estratégicas dos empresários está diretamente relacionada à capacidade que eles demonstram para encontrar alternativas criativas quando enfrentam os problemas de suas empresas. Essas alternativas podem ser geradas intuitivamente, utilizando heurísticas. As pesquisas sobre geração de alternativas têm indicado consistentemente que as pessoas não são eficientes nessa atividade. As explicações para esse fato, contidas na literatura sobre decisão, não são conclusivas e permitem especulações a respeito. Para explorar essa questão e relacioná-la ao administrador brasileiro, foi idealizado um experimento com 174 alunos de quatro cursos de MBA para avaliar a originalidade e a completude das alternativas. O experimento e a respectiva análise basearam-se na confluência da pesquisa experimental, oriunda da psicologia cognitiva da decisão, com as visões da ciência da decisão organizacional tradicional e o novo campo de estudo das decisões intuitivas ou naturalísticas. Para mensurar a criatividade das alternativas apresentadas durante o experimento, empregou-se o conceito de árvore hierárquica, que demonstrou ser uma poderosa ferramenta para a tipologia de alternativas. O resultado desse experimento confirmou o baixo desempenho em geração de alternativas dos gerentes e, ao mesmo tempo, indicou que, provavelmente, a etapa de geração de alternativas isolada da etapa de escolha pode melhorar a qualidade das alternativas. A heurística, por sua vez, não demonstrou influenciar o conjunto de alternativas geradas. _________________________________________________________________________________________ ABSTRACT: The quality of strategic decisions of executives is directly related to the ability they have to find creative alternatives when facing business problems. These alternatives could be generated intuitively, using heuristics. On the other hand, the researches on alternatives generation have consistently indicated that people are not efficient on this duty. The argument for that, contained in the decision’s literature, is not conclusive and it allows speculation about it. To explore this issue and relate it to the Brazilian Administration, an experiment was designed for 174 students of four courses of MBA. The experiment and the analysis were resulted from the confluence between the experimental research from decision cognitive psychology with science’s vision of the traditional organizational decision and the new field of study on naturalistic or intuitive decisions. To measure the creativity of the alternatives presented during the experiment, the concept of hierarchical tree was utilized and it has proved a powerful tool to the typology of alternatives. The result of this experiment confirmed the poor performance in alternatives generation by managers and at the same time, indicated that probably, the generation of options isolated of analysis can produce better quality of alternatives. The heuristic, do not demonstrated any influence on options generated

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Sensorimotor-inspired Tactile Feedback and Control Improve Consistency of Prosthesis Manipulation in the Absence of Direct Vision

The lack of haptically aware upper-limb prostheses forces amputees to rely largely on visual cues to complete activities of daily living. In contrast, able-bodied individuals inherently rely on conscious haptic perception and automatic tactile reflexes to govern volitional actions in situations that do not allow for constant visual attention. We therefore propose a myoelectric prosthesis system that reflects these concepts to aid manipulation performance without direct vision. To implement this design, we built two fabric-based tactile sensors that measure contact location along the palmar and dorsal sides of the prosthetic fingers and grasp pressure at the tip of the prosthetic thumb. Inspired by the natural sensorimotor system, we use the measurements from these sensors to provide vibrotactile feedback of contact location and implement a tactile grasp controller that uses automatic reflexes to prevent over-grasping and object slip. We compare this system to a standard myoelectric prosthesis in a challenging reach-to-pick-and-place task conducted without direct vision; 17 able-bodied adults took part in this single-session between-subjects study. Participants in the tactile group achieved more consistent high performance compared to participants in the standard group. These results indicate that the addition of contact-location feedback and reflex control increases the consistency with which objects can be grasped and moved without direct vision in upper-limb prosthetics.Comment: Accepted to IROS 202

Fisher-Tropsch Synthesis on Alumina Supported Iron-Nickel Catalysts: Effect of Preparation Methods

Two 40 % Fe/60 % Ni/Al2O3 catalysts were prepared using incipient wetness (catalyst A) and co-precipitation (catalyst B), and the activity and selectivity to light olefins in Fischer-Tropsch Synthesis (FTS) has been studied in a fixed-bed reactor under different operating conditions. These conditions were: temperature 220–270 °C, Pressure 1–15 bar, H2/CO molar ratio 1–3 and gas hourly space velocity (GHSV) 1600–5600 h–1. The optimum operating conditions were found for each catalyst and were used to study catalytic performance after stabilization. The results showed that these catalysts were highly stable and retained activity and selectivity for 240 h. The results also showed that the incipient wetness catalyst had a higher activity, higher selectivity to light olefin and C5+ products and lower selectivity to methane and water-gas shift (WGS) activity after stabilization. Also, it was found that higher iron dispersion enhances the negative effects of water such as low CO conversion, low olefin selectivity and higher methane and CO2 selectivity