Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na+/K+-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2’s putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events

Sex Differences in Left Ventricular Electrical Dyssynchrony and Outcomes with Cardiac Resynchronization Therapy

BACKGROUND: Women seem to derive more benefit from cardiac resynchronization therapy (CRT) than men, even after accounting for the higher burden of risk factors for nonresponse often observed in men. OBJECTIVE: To assess for sex-specific differences in left ventricular (LV) electrical dyssynchrony as a contributing electrophysiological explanation for the greater degree of CRT benefit among women. METHODS: We compared the extent of baseline LV electrical dyssynchrony, as measured by the QRS area (QRSA), among men and women with left bundle branch block (LBBB) undergoing CRT at Duke University (n = 492, 35% women) overall and in relation to baseline QRS characteristics using independent sample t tests and Pearson correlation coefficients. Cox regression analyses were used to relate sex, QRSA, and QRS characteristics to the risk of cardiac transplantation, LV assist device implant, or death. RESULTS: Although the mean QRS duration (QRSd) did not differ by sex, QRSA was greater for women vs men (113.8 μVs vs 98.2 μVs, P < .001), owing to differences in the QRSd <150 ms subgroup (92.3 ± 28.7 μVs vs 67.6 ± 26.2 μVs, P < .001). Among those with nonstrict LBBB, mean QRSd was similar but QRSA was significantly greater among women than men (96.0 ± 25.0 μVs vs 63.6 ± 26.2 μVs, P < .001). QRSA was similar among men and women with strict LBBB (P = .533). Female sex was associated with better long-term outcomes in an unadjusted model (hazard ratio 0.623, confidence interval 0.454–0.857, P = .004) but sex no longer predicted outcomes after accounting for differences in QRSA. CONCLUSIONS: Our study suggests that sex-specific differences in LV dyssynchrony contribute to greater CRT benefit among women. Standard QRSd and morphology assessments seem to underestimate the extent of LV electrical dyssynchrony among women with LBBB

Diluting education? An ethnographic study of change in an Australian Ministry of Education

This ethnographic study captures the processes that led to change in an Australian public education system. The changes were driven by strong neo-liberal discourses which resulted in a shift from a shared understanding about leading educational change in schools by knowledge transfer to managing educational change as a process, in other words, allowing the schools to decide how to change. Inside an Australian state education bureaucracy at a time when the organisation was restructured and services decentralised, this study helps show some of the disturbing trends resulting from the further entrenchment of neo-liberal strategies. Although control was re-centralised by legitimising performance mechanisms, in the form of national testing, there are indications that the focus on national tests may have alarming consequences for the content and context of education. I argue that the complexities of learning and fundamental pedagogies are being lost in preference for an over reliance on data systems that are based on a shallow and narrow set of standardised measures

The WiggleZ Dark Energy Survey: Cosmological neutrino mass constraint from blue high-redshift galaxies

The absolute neutrino mass scale is currently unknown, but can be constrained from cosmology. The WiggleZ high redshift star-forming blue galaxy sample is less sensitive to systematics from non-linear structure formation, redshift-space distortions and galaxy bias than previous surveys. We obtain a upper limit on the sum of neutrino masses of 0.60eV (95% confidence) for WiggleZ+Wilkinson Microwave Anisotropy Probe. Combining with priors on the Hubble Parameter and the baryon acoustic oscillation scale gives an upper limit of 0.29eV, which is the strongest neutrino mass constraint derived from spectroscopic galaxy redshift surveys.Comment: Matches version accepted by PR

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Exposure to aircraft and road traffic noise and associations with heart disease and stroke in six European countries: a cross-sectional study

This work was supported by the Economic and Social Research Council (grant ES/F038763/1) with additional funding from the European Network for Noise and Health (ENNAH, EU FP7 grant number 226442)

A Tri-Oceanic Perspective: DNA Barcoding Reveals Geographic Structure and Cryptic Diversity in Canadian Polychaetes

Although polychaetes are one of the dominant taxa in marine communities, their distributions and taxonomic diversity are poorly understood. Recent studies have shown that many species thought to have broad distributions are actually a complex of allied species. In Canada, 12% of polychaete species are thought to occur in Atlantic, Arctic, and Pacific Oceans, but the extent of gene flow among their populations has not been tested.Sequence variation in a segment of the mitochondrial cytochrome c oxidase I (COI) gene was employed to compare morphological versus molecular diversity estimates, to examine gene flow among populations of widespread species, and to explore connectivity patterns among Canada's three oceans. Analysis of 1876 specimens, representing 333 provisional species, revealed 40 times more sequence divergence between than within species (16.5% versus 0.38%). Genetic data suggest that one quarter of previously recognized species actually include two or more divergent lineages, indicating that richness in this region is currently underestimated. Few species with a tri-oceanic distribution showed genetic cohesion. Instead, large genetic breaks occur between Pacific and Atlantic-Arctic lineages, suggesting their long-term separation. High connectivity among Arctic and Atlantic regions and low connectivity with the Pacific further supports the conclusion that Canadian polychaetes are partitioned into two distinct faunas.Results of this study confirm that COI sequences are an effective tool for species identification in polychaetes, and suggest that DNA barcoding will aid the recognition of species overlooked by the current taxonomic system. The consistent geographic structuring within presumed widespread species suggests that historical range fragmentation during the Pleistocene ultimately increased Canadian polychaete diversity and that the coastal British Columbia fauna played a minor role in Arctic recolonization following deglaciation. This study highlights the value of DNA barcoding for providing rapid insights into species distributions and biogeographic patterns in understudied groups

Changing genetic architecture of body mass index from infancy to early adulthood : an individual based pooled analysis of 25 twin cohorts

Publisher Copyright: © 2022, The Author(s).Background: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. Methods: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. Results: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. Conclusions: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.Peer reviewe