Adeno-Associated Virus Technologies and Methods for Targeted Neuronal Manipulation

Cell-type-specific expression of molecular tools and sensors is critical to construct circuit diagrams and to investigate the activity and function of neurons within the nervous system. Strategies for targeted manipulation include combinations of classical genetic tools such as Cre/loxP and Flp/FRT, use of cis-regulatory elements, targeted knock-in transgenic mice, and gene delivery by AAV and other viral vectors. The combination of these complex technologies with the goal of precise neuronal targeting is a challenge in the lab. This report will discuss the theoretical and practical aspects of combining current technologies and establish best practices for achieving targeted manipulation of specific cell types. Novel applications and tools, as well as areas for development, will be envisioned and discussed

Performance over professional learning and the complexity puzzle: lesson observation in England’s further education sector

Attempts to measure the quality of teaching and learning have resulted in an overreliance on quantitative performance data and the normalisation of a set of reductionist practices in England’s further education sector in recent years. Focusing on lesson observation as an illustrative example and drawing on data from a national study, this article examines the application of observation and its impact on further education teachers’ practice. In viewing lesson observation through a complexity theory lens and contextualising it against the wider neoliberal backdrop of the marketisation of education, we seek to critique the inadequacies of current reductionist approaches to teacher evaluation, whilst simultaneously opening up a debate regarding the consequences of seeing classrooms as complex adaptive systems. In focusing on performative models of lesson observation in particular, the article exposes what we perceive as some of the epistemological and methodological shortcomings of neoliberalism in practice, but also offers an alternative way forward in dealing with the contested practice of evaluating the quality of teaching and learning

Kinase inhibitors for the treatment of inflammatory and autoimmune disorders

Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases

The state of professional practice and policy in the English further education system: a view from below

This paper addresses a recurring theme regarding the UK’s Vocational Education and Training (VET) policy in which Further Education (FE) and training are primarily driven by employer demand. It explores the tensions associated with this process on the everyday working practices of FE practitioners and institutions and its impact on FE’s contribution to the wider processes of social and economic inclusion. At a time when Ofsted and employer-led organisations have cast doubt on the contribution of FE, we explore pedagogies of practice that are often unacknowledged by the current audit demands of officialdom. We argue that such practice provides a more enlightened view of the sector and the challenges it faces in addressing wider issues of social justice, employability and civic regeneration. At the same time, the irony of introducing laissez-faire initiatives designed to remove statutory qualifications for FE teachers ignores the progress made over the past decade in raising the professional profile and status of teachers and trainers in the sector. In addressing such issues, the paper explores the limits and possibilities of constructing professional and vocational knowledge from networks and communities of practice, schools, universities, business, employers and local authorities, in which FE already operates

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p

CART Peptide Is a Potential Endogenous Antioxidant and Preferentially Localized in Mitochondria

The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2′-Azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease