Quality Over Quantity: Advantages of Using Alpha-Synuclein Preformed Fibril Triggered Synucleinopathy to Model Idiopathic Parkinson’s Disease

Animal models have significantly advanced our understanding of Parkinson’s disease (PD). Alpha-synuclein (α-syn) has taken center stage due to its genetic connection to familial PD and localization to Lewy bodies, one pathological hallmark of PD. Animal models developed on the premise of elevated alpha-synuclein via germline manipulation or viral vector-mediated overexpression are used to investigate PD pathophysiology and vet novel therapeutics. While these models represented a step forward compared to their neurotoxicant model predecessors, they rely on overexpression of supraphysiological levels of α-syn to trigger toxicity. However, whereas SNCA-linked familial PD is associated with elevated α-syn, elevated α-syn is not associated with idiopathic PD. Therefore, the defining feature of the α-syn overexpression models may fail to appropriately model idiopathic PD. In the last several years a new model has been developed in which α-syn preformed fibrils are injected intrastriatally and trigger normal endogenous levels of α-syn to misfold and accumulate into Lewy body-like inclusions. Following a defined period of inclusion accumulation, distinct phases of neuroinflammation and progressive degeneration can be detected in the nigrostriatal system. In this perspective, we highlight the fact that levels of α-syn achieved in overexpression models generally exceed those observed in idiopathic and even SNCA multiplication-linked PD. This raises the possibility that supraphysiological α-syn expression may drive pathophysiological mechanisms not relevant to idiopathic PD. We argue in this perspective that synucleinopathy triggered to form within the context of normal α-syn expression represents a more faithful animal model of idiopathic PD when examining the role of neuroinflammation or the relationship between a-syn aggregation and toxicity

Discovery of Two Distant Type Ia Supernovae in the Hubble Deep Field North with the Advanced Camera for Surveys

We present observations of the first two supernovae discovered with the recently installed Advanced Camera for Surveys (ACS) on the Hubble Space Telescope. The supernovae were found in Wide Field Camera images of the Hubble Deep Field North taken with the F775W, F850LP, and G800L optical elements as part of the ACS guaranteed time observation program. Spectra extracted from the ACS G800L grism exposures confirm that the objects are Type Ia supernovae (SNe Ia) at redshifts z=0.47 and z=0.95. Follow-up HST observations have been conducted with ACS in F775W and F850LP and with NICMOS in the near-infrared F110W bandpass, yielding a total of 9 flux measurements in the 3 bandpasses over a period of 50 days in the observed frame. We discuss many of the important issues in doing accurate photometry with the ACS. We analyze the multi-band light curves using two different fitting methods to calibrate the supernovae luminosities and place them on the SNe Ia Hubble diagram. The resulting distances are consistent with the redshift-distance relation of the accelerating universe model, although evolving intergalactic grey dust remains as a less likely possibility. The relative ease with which these SNe Ia were found, confirmed, and monitored demonstrates the potential ACS holds for revolutionizing the field of high-redshift SNe Ia, and therefore of testing the accelerating universe cosmology and constraining the "epoch of deceleration".Comment: 11 pages, 8 embedded figures. Accepted for publication in Ap

UVUDF: Ultraviolet Imaging of the Hubble Ultradeep Field with Wide-field Camera 3

We present an overview of a 90-orbit Hubble Space Telescope treasury program to obtain near ultraviolet imaging of the Hubble Ultra Deep Field using the Wide Field Camera 3 UVIS detector with the F225W, F275W, and F336W filters. This survey is designed to: (i) Investigate the episode of peak star formation activity in galaxies at 1<z<2.5; (ii) Probe the evolution of massive galaxies by resolving sub-galactic units (clumps); (iii) Examine the escape fraction of ionizing radiation from galaxies at z~2-3; (iv) Greatly improve the reliability of photometric redshift estimates; and (v) Measure the star formation rate efficiency of neutral atomic-dominated hydrogen gas at z~1-3. In this overview paper, we describe the survey details and data reduction challenges, including both the necessity of specialized calibrations and the effects of charge transfer inefficiency. We provide a stark demonstration of the effects of charge transfer inefficiency on resultant data products, which when uncorrected, result in uncertain photometry, elongation of morphology in the readout direction, and loss of faint sources far from the readout. We agree with the STScI recommendation that future UVIS observations that require very sensitive measurements use the instrument's capability to add background light through a "post-flash". Preliminary results on number counts of UV-selected galaxies and morphology of galaxies at z~1 are presented. We find that the number density of UV dropouts at redshifts 1.7, 2.1, and 2.7 is largely consistent with the number predicted by published luminosity functions. We also confirm that the image mosaics have sufficient sensitivity and resolution to support the analysis of the evolution of star-forming clumps, reaching 28-29th magnitude depth at 5 sigma in a 0.2 arcsecond radius aperture depending on filter and observing epoch.Comment: Accepted A

Day-to-day intrapersonal variability in mobility patterns and association with perceived stress: A cross-sectional study using GPS from 122 individuals in three European cities

Many aspects of our life are related to our mobility patterns and individuals can exhibit strong tendencies towards routine in their daily lives. Intrapersonal day-to-day variability in mobility patterns has been associated with mental health outcomes. The study aims were: (a) calculate intrapersonal day-to-day variability in mobility metrics for three cities; (b) explore interpersonal variability in mobility metrics by sex, season and city, and (c) describe intrapersonal variability in mobility and their association with perceived stress. Data came from the Physical Activity through Sustainable Transport Approaches (PASTA) project, 122 eligible adults wore location measurement devices over 7-consecutive days, on three occasions during 2015 (Antwerp: 41, Barcelona: 41, London: 40). Participants completed the Short Form Perceived Stress Scale (PSS-4). Day-to-day variability in mobility was explored via six mobility metrics using distance of GPS point from home (meters:m), distance travelled between consecutive GPS points (m) and energy expenditure (metabolic equivalents:METs) of each GPS point collected (n = 3,372,919). A Kruskal-Wallis H test determined whether the median daily mobility metrics differed by city, sex and season. Variance in correlation quantified day-to-day intrapersonal variability in mobility. Levene's tests or Kruskal-Wallis tests were applied to assess intrapersonal variability in mobility and perceived stress. There were differences in daily distance travelled, maximum distance from home and METS between individuals by sex, season and, for proportion of time at home also, by city. Intrapersonal variability across all mobility metrics were highly correlated; individuals had daily routines and largely stuck to them. We did not observe any association between stress and mobility. Individuals are habitual in their daily mobility patterns. This is useful for estimating environmental exposures and in fuelling simulation studies

Cultural value orientations, internalized homophobia, and accommodation in romantic relationships

In the present study, we examined the impact of cultural value orientations (i.e., the personally oriented value of individualism, and the socially oriented values of collectivism, familism, romanticism, and spiritualism) on accommodation (i.e., voice and loyalty, rather than exit and neglect, responses to partners' anger or criticism) in heterosexual and gay relationships; and we examined the impact of internalized homophobia (i.e., attitudes toward self, other, and disclosure) on accommodation specifically in gay relationships. A total of 262 heterosexuals (102 men and 162 women) and 857 gays (474 men and 383 women) participated in the present study. Consistent with hypotheses, among heterosexuals and gays, socially oriented values were significantly and positively related to accommodation (whereas the personally oriented value of individualism was unrelated to accommodation); and among gays in particular, internalized homophobia was significantly and negatively related to accommodation. Implications for the study of heterosexual and gay relationships are discussed. © 2005 by The Haworth Press, Inc. All rights reserved

A High Throughput Genetic Screen Identifies New Early Meiotic Recombination Functions in Arabidopsis thaliana

Meiotic recombination is initiated by the formation of numerous DNA double-strand breaks (DSBs) catalysed by the widely conserved Spo11 protein. In Saccharomyces cerevisiae, Spo11 requires nine other proteins for meiotic DSB formation; however, unlike Spo11, few of these are conserved across kingdoms. In order to investigate this recombination step in higher eukaryotes, we took advantage of a high-throughput meiotic mutant screen carried out in the model plant Arabidopsis thaliana. A collection of 55,000 mutant lines was screened, and spo11-like mutations, characterised by a drastic decrease in chiasma formation at metaphase I associated with an absence of synapsis at prophase, were selected. This screen led to the identification of two populations of mutants classified according to their recombination defects: mutants that repair meiotic DSBs using the sister chromatid such as Atdmc1 or mutants that are unable to make DSBs like Atspo11-1. We found that in Arabidopsis thaliana at least four proteins are necessary for driving meiotic DSB repair via the homologous chromosomes. These include the previously characterised DMC1 and the Hop1-related ASY1 proteins, but also the meiotic specific cyclin SDS as well as the Hop2 Arabidopsis homologue AHP2. Analysing the mutants defective in DSB formation, we identified the previously characterised AtSPO11-1, AtSPO11-2, and AtPRD1 as well as two new genes, AtPRD2 and AtPRD3. Our data thus increase the number of proteins necessary for DSB formation in Arabidopsis thaliana to five. Unlike SPO11 and (to a minor extent) PRD1, these two new proteins are poorly conserved among species, suggesting that the DSB formation mechanism, but not its regulation, is conserved among eukaryotes