Iron content of ferritin modulates its uptake by intestinal epithelium: implications for co-transport of prions

The spread of Chronic Wasting Disease (CWD) in the deer and elk population has caused serious public health concerns due to its potential to infect farm animals and humans. Like other prion disorders such a sporadic Creutzfeldt-Jakob-disease of humans and Mad Cow Disease of cattle, CWD is caused by PrP-scrapie (PrPSc), a β-sheet rich isoform of a normal cell surface glycoprotein, the prion protein (PrPC). Since PrPSc is sufficient to cause infection and neurotoxicity if ingested by a susceptible host, it is important to understand the mechanism by which it crosses the stringent epithelial cell barrier of the small intestine. Possible mechanisms include co-transport with ferritin in ingested food and uptake by dendritic cells. Since ferritin is ubiquitously expressed and shares considerable homology among species, co-transport of PrPSc with ferritin can result in cross-species spread with deleterious consequences. We have used a combination of in vitro and in vivo models of intestinal epithelial cell barrier to understand the role of ferritin in mediating PrPSc uptake and transport. In this report, we demonstrate that PrPSc and ferritin from CWD affected deer and elk brains and scrapie from sheep resist degradation by digestive enzymes, and are transcytosed across a tight monolayer of human epithelial cells with significant efficiency. Likewise, ferritin from hamster brains is taken up by mouse intestinal epithelial cells in vivo, indicating that uptake of ferritin is not limited by species differences as described for prions. More importantly, the iron content of ferritin determines its efficiency of uptake and transport by Caco-2 cells and mouse models, providing insight into the mechanism(s) of ferritin and PrPSc uptake by intestinal epithelial cells

Paradoxical Role of Prion Protein Aggregates in Redox-Iron Induced Toxicity

Imbalance of iron homeostasis has been reported in sporadic Creutzfeldt-Jakob-disease (sCJD) affected human and scrapie infected animal brains, but the contribution of this phenotype to disease associated neurotoxicity is unclear.Using cell models of familial prion disorders, we demonstrate that exposure of cells expressing normal prion protein (PrP(C)) or mutant PrP forms to a source of redox-iron induces aggregation of PrP(C) and specific mutant PrP forms. Initially this response is cytoprotective, but becomes increasingly toxic with time due to accumulation of PrP-ferritin aggregates. Mutant PrP forms that do not aggregate are not cytoprotective, and cells show signs of acute toxicity. Intracellular PrP-ferritin aggregates induce the expression of LC3-II, indicating stimulation of autophagy in these cells. Similar observations are noted in sCJD and scrapie infected hamster brains, lending credence to these results. Furthermore, phagocytosis of PrP-ferritin aggregates by astrocytes is cytoprotective, while culture in astrocyte conditioned medium (CM) shows no measurable effect. Exposure to H(2)O(2), on the other hand, does not cause aggregation of PrP, and cells show acute toxicity that is alleviated by CM.These observations suggest that aggregation of PrP in response to redox-iron is cytoprotective. However, subsequent co-aggregation of PrP with ferritin induces intracellular toxicity unless the aggregates are degraded by autophagosomes or phagocytosed by adjacent scavenger cells. H(2)O(2), on the other hand, does not cause aggregation of PrP, and induces toxicity through extra-cellular free radicals. Together with previous observations demonstrating imbalance of iron homeostasis in prion disease affected brains, these observations provide insight into the mechanism of neurotoxicity by redox-iron, and the role of PrP in this process

A size-extensive state-specific multi-reference many-body approach using incomplete model spaces

We present a size-extensive and size-consistent state-specific multi-reference coupled-cluster approach based on an incomplete model space (IMS) and also discuss simplifications if the IMS is quasi-complete. Methods such as perturbation theory or CEPA-like schemes follow naturally as suitable approximants. Intermediate normalization for the wave-operator, Ω is abandoned in the formalism and suitable excitations, defined as open and quasi-open - which excite out of the IMS by their action on at least one of the model functions - are incorporated in Ω. The effective operator W, leading to the energy on diagonalization, is a closed connected operator

Конструкція контролера нечіткої логіки для управління напругою, частотою, струмом та потужністю ізольованої мікромережі на основі трифазної розподіленої генерації

Сьогоднішні екологічно чисті технології, пов'язані з мікромережами, наближаються до розумної системи наномереж. Вона задовольняє попит на електроенергію у всьому світі шляхом належного використання відновлюваних джерел енергії та систем накопичення енергії. Проте, управління електростанцією з використанням мікромереж перейшло на рівень, який вимагає складного і плавного контролю у взаємодії з мережею, включаючи розподілену операцію ізоляції. Динаміка навантаження і похибки є загальними проблемами, що впливають на профіль частоти, напруги та потужності мікромережі, яка є відповідальною за пошкодження навантаження та системи енергопостачання. У статті запропоновано конструкцію надійного контролера нечіткої логіки (FLC) для регулювання характеристик трифазної ізольованої мікромережі. Характеристики запропонованого FLC досліджували за різних умов навантаження, надійність яких оцінювали у стані несправності. Досліджувані характеристики мікромережі забезпечують високе відстеження та надійну роботу запропонованого FLC.Today’s clean technologies related to microgrids are approaching towards the smart nanogrid system. It fulfils the demand of the electricity throughout the world by proper using of renewable energy sources and energy storage systems. Still, the microgrid (MG) power plant control has enriched to a level that it will require complicated and smooth control in the grid interaction including distributed islanding operation. The load dynamics and uncertainties are the common issues which hampers the frequency, voltage and power profile of the MG that is responsible to damage the load and power system. The design of robust fuzzy logic controller (FLC) has been proposed in this research article to regulate the performances of three-phase islanded MG. The performance of the proposed FLC has been examined under different loading condition whose robustness has been evaluated under faulty condition. The investigated performances of the MG ensure high tracking and robust performance of the proposed FLC

A Robust Controller for Multilevel Distributed Generation Based Islanded Microgrid

The power requirement throughout the world is continuously increasing due to the technological development and change in human life. The unplanned uses of the fossil fuel to fulfill the electric demand hampers the future resources that will make resource threat for the future generation. Non-renewable energy sources are the alternative of fossil fuel that increases the possibility of the microgrid (MG) technology that not only reduces the excess pressure on fossil fuel but also produces clean energy. The control of proper operation of the MG is essential for maintaining stable voltage, current and power delivery. The stable profile of the performance of MG may be greatly hampered due to the presence of load dynamics as well as uncertainties that is responsible to damage the system. This chapter represents an improved design of fuzzy logic control approach to regulate the stable and tracking performance of the MG against different faults and uncertainties

Generation of Oxygenating Fluorinated Methacrylamide Chitosan Microparticles to Increase Cell Survival and Function in Large Liver Spheroids

Despite advances in the development of complex culture technologies, the utility, survival, and function of large 3D cell aggregates, or spheroids, are impeded by mass transport limitations. The incorporation of engineered microparticles into these cell aggregates offers a promising approach to increase spheroid integrity through the creation of extracellular spaces to improve mass transport. In this study, we describe the formation of uniform oxygenating fluorinated methacrylamide chitosan (MACF) microparticles via a T-shaped microfluidic device, which when incorporated into spheroids increased extracellular spacing and enhanced oxygen transport via perfluorocarbon substitutions. The addition of MACF microparticles into large liver cell spheroids supported the formation of stable and large spheroids (\u3e500 μm in diameter) made of a heterogeneous population of immortalized human hepatoma (HepG2) and hepatic stellate cells (HSCs) (4 HepG2/1 HSC), especially at a 150:1 ratio of cells to microparticles. Further, as confirmed by the albumin, urea, and CYP3A4 secretion amounts into the culture media, biological functionality was maintained over 10 days due to the incorporation of MACF microparticles as compared to controls without microparticles. Importantly, we demonstrated the utility of fluorinated microparticles in reducing the number of hypoxic cells within the core regions of spheroids, while also promoting the diffusion of other small molecules in and out of these 3D in vitro models

Cervical Pessary versus Expectant Management for the Prevention of Delivery Prior to 36 Weeks in Women with Placenta Previa: A Randomized Controlled Trial.

Objective  This multicenter randomized controlled trial compared cervical pessary (CP) versus expectant management (EM) in women with placenta previa between 22.0 and 32.0 in prolonging gestation until ≥ 36.0 weeks gestation. Study Design  This study took place from November 2016 to June 2018. Women were randomized to receive either the Bioteque CP or EM. The pessary was removed at ≥ 36.0 weeks unless indicated. The primary outcome was gestational age (GA) at delivery, with secondary outcomes including need for transfusion, number and duration of antepartum admissions, type of delivery, and neonatal outcomes. A total of 140 patients were needed to show a 3-week prolongation of pregnancy in the pessary group; however, the trial was stopped early due to budgetary issues. Results  Of the 33 eligible women, 17 were enrolled. Although not statistically significant, the mean GA at delivery in the CP group was greater than women in the EM group (36.5 ± 1.23 vs. 36.0 ± 2.0; p  = 0.1673). The number and duration of antepartum admissions was greater in the EM group (2.7 ± 0.58 vs. 16.0 ± 22.76 days; p  = 0.1264) as well. Conclusion  Although the study was underpowered to determine the primary outcome, safety and feasibility of CP in pregnancies complicated with previa were demonstrated

Cervical Pessary versus Expectant Management for the Prevention of Delivery Prior to 36 Weeks in Women with Placenta Previa: A Randomized Controlled Trial

Objective  This multicenter randomized controlled trial compared cervical pessary (CP) versus expectant management (EM) in women with placenta previa between 22.0 and 32.0 in prolonging gestation until ≥ 36.0 weeks' gestation. Study Design  This study took place from November 2016 to June 2018. Women were randomized to receive either the Bioteque CP or EM. The pessary was removed at ≥ 36.0 weeks unless indicated. The primary outcome was gestational age (GA) at delivery, with secondary outcomes including need for transfusion, number and duration of antepartum admissions, type of delivery, and neonatal outcomes. A total of 140 patients were needed to show a 3-week prolongation of pregnancy in the pessary group; however, the trial was stopped early due to budgetary issues. Results  Of the 33 eligible women, 17 were enrolled. Although not statistically significant, the mean GA at delivery in the CP group was greater than women in the EM group (36.5 ± 1.23 vs. 36.0 ± 2.0; p  = 0.1673). The number and duration of antepartum admissions was greater in the EM group (2.7 ± 0.58 vs. 16.0 ± 22.76 days; p  = 0.1264) as well. Conclusion  Although the study was underpowered to determine the primary outcome, safety and feasibility of CP in pregnancies complicated with previa were demonstrated