Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies

Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

LRRK2 is one of the most important genetic contributors to Parkinson's disease (PD). Point mutations in this gene cause an autosomal dominant form of PD, but to date no cellular phenotype has been consistently linked with mutations in each of the functional domains (ROC, COR and Kinase) of the protein product of this gene. In this study, primary fibroblasts from individuals carrying pathogenic mutations in the three central domains of LRRK2 were assessed for alterations in the autophagy/lysosomal pathway using a combination of biochemical and cellular approaches. Mutations in all three domains resulted in alterations in markers for autophagy/lysosomal function compared to wild type cells. These data highlight the autophagy and lysosomal pathways as read outs for pathogenic LRRK2 function and as a marker for disease, and provide insight into the mechanisms linking LRRK2 function and mutations

First Measurement of Coherent Elastic Neutrino-Nucleus Scattering on Argon

We report the first measurement of coherent elastic neutrino-nucleus scattering (\cevns) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two independent analyses prefer \cevns over the background-only null hypothesis with greater than $3\sigma$ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2 $\pm$ 0.7) $\times$10$^{-39}$ cm$^2$ -- consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the \cevns process and provides improved constraints on non-standard neutrino interactions.Comment: 8 pages, 5 figures with 2 pages, 6 figures supplementary material V3: fixes to figs 3,4 V4: fix typo in table 1, V5: replaced missing appendix, V6: fix Eq 1, new fig 3, V7 final version, updated with final revision

Enjoyment of the shopping experience:impact on customers’ repatronage intentions and gender influence

In this paper the authors investigate enjoyment of the shopping experience, its influence on consumers’ intention to repatronise a regional shopping centre and the effect of gender differences on shopping enjoyment. Four dimensions of shopping enjoyment are proposed and a 16-item measure is developed to assess 536 consumer perceptions of the shopping experience across five counties in the United Kingdom. Findings indicate that shopping experience enjoyment has a significant positive influence upon customers’ repatronage intentions. Furthermore, men are found to have a stronger relationship of enjoyment with repatronage than women. The implications of these results are discussed, together with managerial implications, study limitations, and future research directions

Hydrogel-forming microneedle arrays made from light-responsive materials for on-demand transdermal drug delivery

We describe, for the first time, stimuli-responsive hydrogel-forming microneedle (MN) arrays that enable delivery of a clinically-relevant model drug (ibuprofen) upon application of light. MN arrays were prepared using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) by micromolding. The obtained MN arrays showed good mechanical properties. The system was loaded with up to 5% (w/w) ibuprofen included in a light-responsive 3,5-dimethoxybenzoin conjugate. Raman spectroscopy confirmed the presence of the conjugate inside the polymeric MN matrix. In vitro, this system was able to deliver up to three doses of 50 mg of ibuprofen upon application of an optical trigger over a prolonged period of time (up to 160 hours). This makes the system appealing as a controlled release device for prolonged periods of time. We believe that this technology has potential for use in “on-demand” delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care

Five characteristics of youth unemployment in Europe

Current levels of youth unemployment need to be understood in the context of increased labor market flexibility, an expansion of higher education, youth migration, and family legacies of long-term unemployment. Compared with previous recessions, European-wide policies and investments have significantly increased with attempts to support national policies. By mapping these developments and debates, we illustrate the different factors shaping the future of European labor markets. We argue that understanding youth unemployment requires a holistic approach that combines an analysis of changes in the economic sphere around labor market flexibility, skills attainment, and employer demand, as well as understanding the impact of family legacies affecting increasingly polarized trajectories for young people today. The success of EU policy initiatives and investments will be shaped by the ability of national actors to implement these effectively

Redrawing Boundaries: WITNESS and the Politics of Citizen Videos

This article engages with several pressing issues revolving around ‘citizen witnessing’, with specific reference to the human rights advocacy group, WITNESS. In the course of tracing WITNESS’ development over the past two decades, it offers an evaluative assessment of the challenges its members have faced in promoting a grassroots, citizen-centred approach to video reportage. More specifically, this advocacy is informed by an ethical commitment to advancing human rights causes by equipping citizens in crisis situations with cameras, and the training to use them, so that they might bear witness to the plight of others. In so doing, this article argues, WITNESS offers a tactical reformulation of the guiding tenets of peace journalism, one with considerable potential for recasting anew its strategic priorities

Bookselling online: an examination of consumer behaviour patterns.

Based upon empirical research, and using a range of methods, this paper examines the behaviour and experiences of consumers in online bookselling settings and offers comparison between online and offline (traditional) bookselling. The research finds that while the convenience of online bookshops is important, the key factors enticing consumers online are a combination of breadth of range, ease of access to obscure titles, as well as personalised recommendations and customer reviews. The research is of value to the book trade, highlighting consumer responses to widely adopted online marketing approaches. The research also contributes to scholarly knowledge in the fields of consumer behaviour, e-marketing and e-commerce in online bookselling, as well as providing findings which can be tested in other online settings, informing future theoretical research