Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways

The risk of developing neurodegenerative diseases increases with age. Although many of the molecular pathways regulating proteotoxic stress and longevity are well characterized, their contribution to disease susceptibility remains unclear. In this study, we describe a new Caenorhabditis elegans model of Machado–Joseph disease pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron susceptibility to mutant ataxin-3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This reveals that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated athogenesis. Aging influences the ATXN3 phenotypes which can be suppressed by the nregulation of the insulin/insulin growth factor-1-like signaling pathway and activation of heat shock factor-1.This work was supported by grants from Fundacão Ciência eTecnologia (FCT) to P.M. (PTDC/SAU-GMG/64076/2006, PTDC/SAU-GMG/112617/2009, SFRH/BD/27258/2006 to A.T.C., UMINHO/BI/052/2010 to A.J. and SFRH/BD/51059/2010 to A.N.C.), from the National Ataxia Foundation to PM and from the National Institutes of Health (NIGMS, NIA and NINDS) to R.M. This work was also granted by the Hospital San Rafael (Coruna) with the Rafael Hervada prize on Biomedical Research (2010)

Decreased brain venous vasculature visibility on susceptibility-weighted imaging venography in patients with multiple sclerosis is related to chronic cerebrospinal venous insufficiency.

BACKGROUND: The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC). METHODS: 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: .9 mm. RESULTS: CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p < .0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter < .3 mm, and increased DFV compared to HC (all p < .0001). Subjects diagnosed with CCSVI had significantly increased DFV (p < .0001), decreased overall ATVV and ATVV of veins with a diameter < .3 mm (p < .003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p < .0001) on pre- and post-contrast SWI, but not in HC. CONCLUSIONS: MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS

Jugular venous reflux and brain parenchyma volumes in elderly patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUND: To determine whether or not jugular venous reflux (JVR) is associated with structural brain parenchyma changes in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: 16 AD patients (mean (SD): 81.9 (5.8) years), 33 MCI patients (mean (SD): 81.4 (6.1) years) and 18 healthy elderly controls (mean (SD): 81.5 (3.4) years) underwent duplex ultrasonography and magnetic resonance imaging scans to quantify structural brain parenchyma changes. Normalized whole brain (WB), gray matter (GM) and white matter (WM) volumes were collected, together with CSF volume. RESULTS: JVR was strongly associated with increased normalized WB (p = 0.014) and GM (p = 0.002) volumes across all three subject groups. There was a trend towards increased WB and GM volumes, which was accompanied by decreased CSF volume, in the JVR-positive subjects in both the MCI and AD groups. When the MCI and AD subjects were aggregated together significant increases were observed in both normalized WB (p = 0.009) and GM (p = 0.003) volumes for the JVR-positive group. No corresponding increases were observed for the JVR-positive subjects in the control group. Through receiver operating characteristic analysis of the brain volumetric data it was possible to discriminate between the JVR-positive and negative AD subjects with reasonable accuracy (sensitivity = 71.4%; specificity = 88.9%; p = 0.007). CONCLUSIONS: JVR is associated with intracranial structural changes in MCI and AD patients, which result in increased WB and GM volumes. The neuropathology of this unexpected and counterintuitive finding requires further investigation, but may suggest that JVR retrogradely transmits venous hypertension into the brain and leads to brain tissues swelling due to vasogenic edema

Chronic cerebrospinal venous insufficiency in multiple sclerosis: a historical perspective

Chronic cerebrospinal venous insufficiency (CCSVI) is a term used to describe impaired venous drainage from the central nervous system (CNS) caused by abnormalities in anatomy and flow affecting the extracranial veins. Recently, it has been proposed that CCSVI may contribute to the pathogenesis of multiple sclerosis (MS). It is hypothesized that venous obstruction results in abnormal flow that promotes inflammation at the blood-brain barrier and that this triggers a process marked by a disturbance of homeostasis within the CNS that leads to demyelination and neurodegeneration. The venous abnormalities of CCSVI are often diagnosed by ultrasound or magnetic resonance venography, however the prevalence of CCSVI detailed in groups of MS patients and patients without MS varies widely in published reports. Increased standardization of diagnostic studies to evaluate both anatomical and physiological findings associated with CCSVI is needed. The purpose of this article is to provide a background to understand the development of the theory of CCSVI and to frame the relevant issues regarding its diagnosis and relationship to the pathogenesis of MS

A new class of dark matter-free dwarf galaxies?: I. Clues from FCC 224, NGC 1052-DF2, and NGC 1052-DF4

Context. The discovery of quiescent, dark matter (DM)-deficient ultra-diffuse galaxies (UDGs) with overluminous globular clusters (GCs) has challenged galaxy formation models within the Lambda cold dark matter (Λ CDM) cosmological paradigm. Previously, such galaxies were only identified in the NGC 1052 group, raising the possibility that they are the result of unique, group-specific processes, and limiting their broader significance. The recent identification of FCC 224, a putative DM-deficient UDG on the outskirts of the Fornax Cluster, suggests that such galaxies are not confined to the NGC 1052 group but rather represent a broader phenomenon. Aims. We aim to investigate the DM content of FCC 224 and to explore its similarities to the DM-free dwarfs in the NGC 1052 group, DF2 and DF4, to determine whether or not it belongs to the same class of DM-deficient UDGs. Methods. We use high-resolution Keck Cosmic Web Imager (KCWI) spectroscopy to study the kinematics, stellar populations, and GC system of FCC 224, enabling direct comparisons with DF2 and DF4. Results. We find that FCC 224 is also DM-deficient and exhibits a distinct set of traits shared with DF2 and DF4, including slow and prolate rotation, quiescence in low-density environments, coeval formation of stars and GCs, flat stellar population gradients, a top-heavy GC luminosity function, and monochromatic GCs. Conclusions. These shared characteristics signal the existence of a previously unrecognised class of DM-deficient dwarf galaxies. This diagnostic framework provides a means of identifying additional examples and raises new questions for galaxy formation models within Λ CDM cosmology

The multiple classes of ultra-diffuse galaxies: can we tell them apart?

This study compiles stellar populations and internal properties of ultra-diffuse galaxies (UDGs) to highlight correlations with their local environment, globular cluster (GC) richness, and star formation histories. Complementing our sample of 88 UDGs, we include 36 low surface brightness dwarf galaxies with UDG-like properties, referred to as NUDGes (nearly UDGs). All galaxies were studied using the same spectral energy distribution fitting methodology to explore what sets UDGs apart from other galaxies. We show that NUDGes are similar to UDGs in all properties except for being, by definition, smaller and having higher surface brightness. We find that UDGs and NUDGes show similar behaviours in their GC populations, with the most metal-poor galaxies hosting consistently more GCs on average. This suggests that GC content may provide an effective way to distinguish extreme galaxies within the low surface brightness regime alongside traditional parameters like size and surface brightness. We confirm previous results using clustering algorithms that UDGs split into two main classes, which might be associated with the formation pathways of a puffy dwarf and a failed galaxy. The clustering applied to the UDGs + NUDGes data set yields an equivalent result. The difference in mass contained in the GC system suggests that galaxies in different environments have not simply evolved from one another but may have formed through distinct processes

Democratization and foreign policy in Southeast Asia: the case of the ASEAN Inter-Parliamentary Myanmar Caucus

This is an Author's Accepted Manuscript of an article published in Cambridge Review of International Affairs Vol. 22, Iss. 3, 2009 as published in the CAMBRIDGE REVIEW OF INTERNATIONAL AFFAIRS, 2009, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/09557570903104008

The Artist in the Library

Through the course of this paper I seek to intertwine a story of my own creative relationship with libraries with accounts of artists’ work, including the work of my students. My goal is to articulate the ways in which artists work with, in, and on libraries and in doing this to define features of a library aesthetic. It is impossible, writing in London in 2016, to ignore the dire context for UK public libraries. Reductions in local government funding have resulted in widespread disregard by local authorities to their responsibilities under the 1964 Public Libraries and Museums Act – their statutory duty to provide a ‘comprehensive and efficient library service for all persons to make use thereof’. (Culture, Media and Sport Committee 2012, online) Cuts to library services continue apace [{note}]1. Writers, poets, artists and authors add their pleas to the protests against closures [{note}]2, but go largely unheeded. The idea of defining a library aesthetic might seem futile in the face of this austerity drive, but through my analysis of such an aesthetic, I hope to explore the potential of artworks to highlight and extend our understanding of its possibilities