Continuous oral chloroquine as a novel route for Plasmodium prophylaxis and cure in experimental murine models

<p>Abstract</p> <p>Background</p> <p>Chloroquine (CQ) is utilized as both cure and prophylaxis to <it>Plasmodium </it>infection. In animal studies, CQ administration to experimental animals is via intraperitoneal (i.p.) injection of a single dose that varies from daily to several times per week. Such daily administration can be distressing to the animals and provoke aggressive behaviors that may affect the immune responses of the animal and interfere with data read-outs.</p> <p>Findings</p> <p>We describe a novel, viable and efficacious prophylactic and curative administration route whereby chloroquine is continuously supplied in the drinking water to experimental animals. The prophylactic effect is robust and the curative effect against patent blood stage infection comparable to the traditional route of i.p. administration. Continuous drinking water administration may decrease animal stress responses and thus improve the reliability of experimental data.</p

the role of firms

Der Standortwechsel von Firmen in Länder mit niedrigen Sozialstandards wird in der Regel als treibende Kraft des abwärtsgerichteten regulativen Wettbewerbs zwischen Staaten angesehen. Es gibt allerdings eine Vielzahl von Fällen in denen genau das Gegenteil passiert: Firmen halten sich freiwillig an Sozialstandards (CSR) und üben sogar Druck auf Regierungen aus, um striktere Regulierung zu erwirken. In diesem Arbeitspapier zeigen wir, unter welchen Bedingungen Firmen zur Verwirklichung anspruchsvollerer Sozialstandards in Ländern mit geringer regulativer Kapazität beitragen. Zunächst stellen wir Hypothesen aus der bereits existierenden Literatur vor und arbeiten ihre Erklärungskraft für die hier diskutierte Problematik heraus. Das Arbeitspapier untersucht die Reaktion der südafrikanischen Textil- und Automobilindustrie auf die HIV Pandemie. Die südafrikanische Regierung hat nur begrenzte Kapazitäten aufgebracht, um sich gegen die Verbreitung des Virus zur Wehr zu setzen. Unter welchen Bedingungen versuchen Firmen den Staat im Kampf gegen HIV/AIDS zu unterstützen?Firms relocating production to countries with lower social standards are regarded as driving force behind the regulatory ‘race to the bottom’. However, there are numerous instances in which the behavior of firms reveals just the opposite: They adhere to self-regulatory standards (CSR) and even pressure governments to issue stricter public regulations. We intend to identify the conditions under which firms contribute to higher regulatory standards in states with weak regulatory capacities, thereby following a ‘race to the top’ rather than a ‘race to the bottom’- logic. Theoretically, we set out to test in how far the existing literature can be utilized to answer this question. Empirically, the assessment concentrates on the textile and automotive industries in South Africa and HIV/AIDS abatement. Only limited state capacities have been involved in fighting HIV/AIDS in South Africa. Under which conditions do firms try to foster state capacities for the fight against the disease

Private Equity Entities and Conglomerates: What are the Differences?

For passenger fuel cell vehicles (FCVs), customers will expect to start the vehicle and drive almost immediately, implying a very short system warmup to full power.While hybridization strategies may fulfill this expectation, the extent of hybridization will be dictated by the time required for the fuel cell system to reach normal operating temperatures. Quick-starting fuel cell systems are impeded by two problems: 1) the freezing of residual water or water generated by starting the stack at below freezing temperatures and 2) temperature-dependent fuel cell performance, improving as the temperature reaches the normal range. Cold start models exist in the literature; however, there does not appear to be a model that fully captures the thermal characteristics of the stack during sub-freezing startup conditions. Existing models do not include stack internal heating methods or endplate thermal mass effect on end cells.The focus of this research is the development and use of a sub-freezing thermal model for a polymer electrolyte fuel cell stack and system designed for integration within a direct hydrogen hybrid FCV. The stack is separated into individual cell layers to determine an accurate temperature distribution within the stack. Unlike a lumped model, which may use a single temperature as an indicator of the stack’s thermal condition, a layered model can reveal the effect of the endplate thermal mass on the end cells, and accommodate the evaluation of internal heating methods that may mitigate this effect.This research is designed to answer the following motivating questions:· What detailed thermal model design will accurately characterize the fuel cell stack and system during the sub-freezing startup operation?· What are the effects of different startup strategies on energy consumption and time to normal operation?These questions are addressed in this dissertation. Major research findings include the following recommendations for the best startup strategies based on model parameter values and assumptions: 1) use internal heating methods (other than stack reactions) below 0ºC, 2) circulate coolant for uniform heat distribution, 3) minimize coolant loop thermal mass, 4) heat the endplates, and 5) use metal such as stainless steel for the bipolar plates

Glutathione deficiency down-regulates hepatic lipogenesis in rats

<p>Abstract</p> <p>Background</p> <p>Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level. This study was performed to investigate the role of glutathione in the regulation of this process. For that purpose, male rats were treated with buthionine sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase, for 7 days and compared with untreated control rats.</p> <p>Results</p> <p>BSO treatment caused a significant reduction of total glutathione in liver (-70%), which was attributable to diminished levels of reduced glutathione (GSH, -71%). Glutathione-deficient rats had lower triglyceride concentrations in their livers than the control rats (-23%), whereas the circulating triglycerides and the cholesterol concentrations in plasma and liver were not different between the two groups of rats. Livers of glutathione-deficient rats had lower mRNA abundance of sterol regulatory element-binding protein (SREBP)-1c (-47%), Spot (S)14 (-29%) and diacylglycerol acyltransferase 2 (DGAT-2, -27%) and a lower enzyme activity of fatty acid synthase (FAS, -26%) than livers of the control rats. Glutathione-deficient rats had also a lower hepatic activity of the redox-sensitive protein-tyrosine phosphatase (PTP)1B, and a higher concentration of irreversible oxidized PTP1B than control rats. No differences were observed in protein expression of total PTP1B and the mature mRNA encoding active XBP1s, a key regulator of unfolded protein and ER stress response.</p> <p>Conclusion</p> <p>This study shows that glutathione deficiency lowers hepatic triglyceride concentrations via influencing lipogenesis. The reduced activity of PTP1B and the higher concentration of irreversible oxidized PTP1B could be, at least in part, responsible for this effect.</p

A crucial role for the C‐terminal domain of exported protein 1 during the mosquito and hepatic stages of the Plasmodium bergheilife cycle

© 2019 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Intracellular Plasmodium parasites develop inside a parasitophorous vacuole (PV), a specialised compartment enclosed by a membrane (PVM) that contains proteins of both host and parasite origin. Although exported protein 1 (EXP1) is one of the earliest described parasitic PVM proteins, its function throughout the Plasmodium life cycle remains insufficiently understood. Here, we show that whereas the N-terminus of Plasmodium berghei EXP1 (PbEXP1) is essential for parasite survival in the blood, parasites lacking PbEXP1's entire C-terminal (CT) domain replicate normally in the blood but cause less severe pathology than their wild-type counterparts. Moreover, truncation of PbEXP1's CT domain not only impairs parasite development in the mosquito but also abrogates PbEXP1 localization to the PVM of intrahepatic parasites, severely limiting their replication and preventing their egress into the blood. Our findings highlight the importance of EXP1 during the Plasmodium life cycle and identify this protein as a promising target for antiplasmodial intervention.This study was sup- ported by German Research Foundation (Deutsche Forschungsgemeinschaft ‐ DFG) Grants SPP 1580 (to A.‐K. M.) and SFB1129 (to A.‐K. M.); Fundação para a Ciência e Tecnologia, Portugal (FCT‐PT) Grants UID/BIM/50005/2019 (Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado) and 02/SAICT/2017 (to M. P.). M. S.‐V. was supported by an FCT‐PT Grant PD/BD/105838/2014. D. F. was supported by FEEI and FCT‐MEC. M. P. was supported by FCT‐PT Investigador FCT 2013 and CEEC 2018 fellowship. A.‐K. M. was a recipient of a Maternity Leave Stipend by the German Center for Infection Research (DZIF, Heidelberg Site)info:eu-repo/semantics/publishedVersio

The ecological origins of snakes as revealed by skull evolution

The ecological origin of snakes remains amongst the most controversial topics in evolution, with three competing hypotheses: fossorial; marine; or terrestrial. Here we use a geometric morphometric approach integrating ecological, phylogenetic, paleontological, and developmental data for building models of skull shape and size evolution and developmental rate changes in squamates. Our large-scale data reveal that whereas the most recent common ancestor of crown snakes had a small skull with a shape undeniably adapted for fossoriality, all snakes plus their sister group derive from a surface-terrestrial form with non-fossorial behavior, thus redirecting the debate toward an underexplored evolutionary scenario. Our comprehensive heterochrony analyses further indicate that snakes later evolved novel craniofacial specializations through global acceleration of skull development. These results highlight the importance of the interplay between natural selection and developmental processes in snake origin and diversification, leading first to invasion of a new habitat and then to subsequent ecological radiations.Peer reviewe

American eel resilience to simulated fluid shear associated with passage through hydroelectric turbines

American eel (Anguilla rostrata) populations have declined within their native range along the eastern coast of North America due to factors such as commercial fishing, habitat alteration, and dams. American eel are catadromous fish species, and high mortality rates (>40%) have been observed for freshwater life-stage adult eel passing downstream through hydropower turbines. Lacerations and sectioning of fish have been observed downstream of turbines and these injuries are commonly associated with direct contact with the turbine runner, whether through blade strike or pinching and grinding. Exposure to fluid shear may also be a source of injury, however, little is known about American eel susceptibility to this physical stressor. Eels are considerably flexible when compared to other fish species and lack other morphological characteristics that would make them susceptible to fluid shear, such as protruding eyes, large scales, and large operculum. European eel, which have previously been tested for susceptibility to fluid shear, were found to be resilient. To determine if American eel are also resilient to fluid shear, forty American eel were exposed to a water jet, simulating severe fluid shear (strain rate > 800 s−1) that fish may experience when passing downstream through turbines. No immediate or delayed (48 h) signs of injury were observed after exposure to severe fluid shear. Based on this study, and a previous study conducted on American eel susceptibility to barotrauma, the source of injury and mortality of American eel passing through turbines is likely attributed to blade strike or pinching and grinding

Chasing Lions: Co-Designing Human-Drone Interaction in Sub-Saharan Africa

Drones are an exciting technology that is quickly being adopted in the global consumer market. Africa has become a center of deployment with the first drone airport established in Rwanda and drones currently being used for applications such as medical deliveries, agriculture, and wildlife monitoring. Despite this increasing presence of drones, there is a lack of research on stakeholders' perspectives from this region. We ran a human-drone interaction user study (N=15) with experts from several sub-Saharan countries using a co-design methodology. Participants described novel applications and identified important design aspects for the integration of drones in this context. Our results highlight the potential of drones to address real world problems, the need for them to be culturally situated, and the importance of considering the social aspects of their interaction with humans. This research highlights the need for diverse perspectives in the human-drone interaction design process.Comment: To be published in the ACM conference on Designing Interactive Systems (DIS '20

Citalopram Improves Obsessive-Compulsive Crossword Puzzling in Frontotemporal Dementia

Behavioral variant frontotemporal dementia (bvFTD) is characterized by severe changes in personality/behavior. Recent studies have provided evidence that a decrease in serotonin receptors and neuronal loss in the raphe nuclei play a role in the bvFTD pathology. Serotonergic antidepressants have been reported to diminish behavioral disturbances in bvFTD, particularly repetitive behaviors, disinhibition, apathy, sexually inappropriate behaviors, and hyperorality. Here, we present the case of an 80-year-old Caucasian male patient with clinically and biomarker supported bvFTD (“probable” bvFTD; disease-specific alterations in 18F-fluorodesoxyglucose positron emission tomography and magnetic resonance imaging). The patient exhibited behavioral disinhibition, apathy, a loss of empathy, perseverative behavior during testing, hyperorality, changes in diet, and executive deficits in neuropsychological testing. Remarkably, he failed in solving crosswords by systematically filling in the blanks by letters in alphabetical order (A, B, C, D, etc.), indicating obsessive-compulsive behavior. One year later, the patient visited the clinic again for a follow-up investigation. He had taken 20 mg of citalopram per day for 1 consecutive year. Remarkably, he had regained the ability to fill in crossword puzzles correctly, although the neuropsychiatric inventory showed overall only small improvement in behavioral impairment. A regimen of 20 mg citalopram per day over the course of 1 year led to a specific improvement in one of the bvFTD core symptoms, obsessive-compulsive behavior, most pronounced in solving crossword puzzles. This case contributes to the understanding of the neuropharmacological correlates of bvFTD and supports the treatment of bvFTD’s behavioral symptoms with selective serotonin reuptake inhibitors

A highthroughput infrastructure for density functional theory calculations

a b s t r a c t The use of high-throughput density functional theory (DFT) calculations to screen for new materials and conduct fundamental research presents an exciting opportunity for materials science and materials innovation. High-throughput DFT typically involves computations on hundreds, thousands, or tens of thousands of compounds, and such a change of scale requires new calculation and data management methodologies. In this article, we describe aspects of the necessary data infrastructure for such projects to handle data generation and data analysis in a scalable way. We discuss the problem of accurately computing properties of compounds across diverse chemical spaces with a single exchange correlation functional, and demonstrate that errors in the generalized gradient approximation are highly dependent on chemical environment