Brief isoflurane anesthesia regulates striatal AKT-GSK3 beta signaling and ameliorates motor deficits in a rat model of early-stage Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3 beta (GSK313) and neurodegenerative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3 beta inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3 beta within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3 beta signaling in nave rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3 beta at the inhibitory Ser9 residue, and induced phosphorylation of AKT(Thr308) (protein kinase B; negative regulator of GSK3 beta) in the striatum of naive rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.Peer reviewe

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease

Parkinson's disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to striatal dopamine depletion. A partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion causes 40-60% dopamine depletion in the lesioned rat striatum, modeling the early stage of PD. In this study, we explored the connectivity between the brain regions in partially 6-OHDA lesioned male Wistar rats under urethane anesthesia using functional magnetic resonance imaging (fMRI) at 5 weeks after the 6-OHDA infusion. Under urethane anesthesia, the brain fluctuates between the two states, resembling rapid eye movement (REM) and non-REM sleep states. We observed clear urethane-induced sleep-like states in 8/19 lesioned animals and 8/18 control animals. 6-OHDA lesioned animals exhibited significantly lower functional connectivity between the brain regions. However, we observed these differences only during the REM-like sleep state, suggesting the involvement of the nigrostriatal dopaminergic pathway in REM sleep regulation. Corticocortical and corticostriatal connections were decreased in both hemispheres, reflecting the global effect of the lesion. Overall, this study describes a promising model to study PD-related sleep disorders in rats using fMRI.Peer reviewe

Sixty Years of Fractal Projections

Sixty years ago, John Marstrand published a paper which, among other things, relates the Hausdorff dimension of a plane set to the dimensions of its orthogonal projections onto lines. For many years, the paper attracted very little attention. However, over the past 30 years, Marstrand's projection theorems have become the prototype for many results in fractal geometry with numerous variants and applications and they continue to motivate leading research.Comment: Submitted to proceedings of Fractals and Stochastics

How AI Systems Challenge the Conditions of Moral Agency?

The article explores the effects increasing automation has on our conceptions of human agency. We conceptualize the central features of human agency as ableness, intentionality, and rationality and define responsibility as a central feature of moral agency. We discuss suggestions in favor of holding AI systems moral agents for their functions but join those who refute this view. We consider the possibility of assigning moral agency to automated AI systems in settings of machine-human cooperation but come to the conclusion that AI systems are not genuine participants in joint action and cannot be held morally responsible. Philosophical issues notwithstanding, the functions of AI systems change human agency as they affect our goal setting and pursuing by influencing our conceptions of the attainable. Recommendation algorithms on news sites, social media platforms, and in search engines modify our possibilities to receive accurate and comprehensive information, hence influencing our decision making. Sophisticated AI systems replace human workforce even in such demanding fields as medical surgery, language translation, visual arts, and composing music. Being second to a machine in an increasing number of fields of expertise will affect how human beings regard their own abilities. We need a deeper understanding of how technological progress takes place and how it is intertwined with economic and political realities. Moral responsibility remains a human characteristic. It is our duty to develop AI to serve morally good ends and purposes. Protecting and strengthening the conditions of human agency in any AI environment is part of this task.Peer reviewe

Human-Driven Design: A Human-Driven Approach to the Design of Technology

Part 1: Society, Social Responsibility, Ethics and ICTInternational audienceIn the midst of the many large-scale societal and technological transformations, there is a need for design approaches that respect human values and needs and are able to integrate multiple perspectives into technology design in order to work for outcomes that are interesting, feasible and sustainable in all senses of the term. For this purpose, we discuss a possible approach to the design of technology that is driven by human and social values, is collaborative in nature and reflective in terms of responsibility and ethics in the design. We call this approach ‘Human-Driven Design’ and argue that it is needed especially when designing for enabling and emerging information and communication technologies. A human-driven design approach should focus on the early phases of design, be strongly future-oriented and aim to contribute to innovation for a sustainable society and better quality of life in the future

Adenoviral Gene Therapy Vectors in Clinical Use—Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety

Adenoviral vectors are commonly used in clinical gene therapy. Apart from oncolytic adenoviruses, vector replication is highly undesired as it may pose a safety risk for the treated patient. Thus, careful monitoring for the formation of replication-competent adenoviruses (RCA) during vector manufacturing is required. To render adenoviruses replication deficient, their genomic E1 region is deleted. However, it has been known for a long time that during their propagation, some viruses will regain their replication capability by recombination in production cells, most commonly HEK293. Recently developed RCA assays have revealed that many clinical batches contain more RCA than previously assumed and allowed by regulatory authorities. The clinical significance of the higher RCA content has yet to be thoroughly evaluated. In this review, we summarize the biology of adenovirus vectors, their manufacturing methods, and the origins of RCA formed during HEK293-based vector production. Lastly, we share our experience using minimally RCA-positive serotype 5 adenoviral vectors based on observations from our clinical cardiovascular gene therapy studies

Life-based design of digital services supporting the sense of security for home-dwelling people living with memory disorder

Abstract Memory disorder impairs people’s independent functioning in daily life and thus threatens their safe living at home. Living at home safely requires the diversification of in-home services and forms of assistance for those living with memory disorder. The aim of this paper is to describe the life-based design process of the ongoing TuTunKo-project (2016–2017) and provide ideas for a practical operational model based on the experiences gained during the project. The goal of the project is to design a platform for digital services that support the sense of security and quality of everyday life of home-dwelling people living with memory disorder. In addition, instruments will be developed to evaluate the sense of security and life management of those with the condition and their family members