3,704 research outputs found
Average Estimates in Line Graphs Are Biased Toward Areas of Higher Variability
We investigate variability overweighting, a previously undocumented bias in
line graphs, where estimates of average value are biased toward areas of higher
variability in that line. We found this effect across two preregistered
experiments with 140 and 420 participants. These experiments also show that the
bias is reduced when using a dot encoding of the same series. We can model the
bias with the average of the data series and the average of the points drawn
along the line. This bias might arise because higher variability leads to
stronger weighting in the average calculation, either due to the longer line
segments (even though those segments contain the same number of data values) or
line segments with higher variability being otherwise more visually salient.
Understanding and predicting this bias is important for visualization design
guidelines, recommendation systems, and tool builders, as the bias can
adversely affect estimates of averages and trends
Dust-Gas Scaling Relations and OH Abundance in the Galactic ISM
Observations of interstellar dust are often used as a proxy for total gas
column density . By comparing thermal dust data
(Release 1.2) and new dust reddening maps from Pan-STARRS 1 and 2MASS (Green et
al. 2018), with accurate (opacity-corrected) HI column densities and
newly-published OH data from the Arecibo Millennium survey and 21-SPONGE, we
confirm linear correlations between dust optical depth , reddening
and the total proton column density in the range
(130)10cm, along sightlines with no molecular gas
detections in emission. We derive an / ratio of
(9.41.6)10cmmag for purely atomic sightlines
at 5, which is 60 higher than the canonical value of
Bohlin et al. (1978). We report a 40 increase in opacity
=/, when moving from the low column
density (510cm) to moderate column
density (510cm) regime, and suggest that
this rise is due to the evolution of dust grains in the atomic ISM. Failure to
account for HI opacity can cause an additional apparent rise in ,
of the order of a further 20. We estimate molecular hydrogen column
densities from our derived linear relations, and hence
derive the OH/H abundance ratio of 110
for all molecular sightlines. Our results show no evidence of systematic trends
in OH abundance with in the range
(0.110)10cm. This suggests
that OH may be used as a reliable proxy for H in this range, which includes
sightlines with both CO-dark and CO-bright gas.Comment: The revised manuscript is accepted for publication in The
Astrophysical Journa
A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.
Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative
An outbreak of severe respiratory tract infection caused by human metapneumovirus in a residential care facility for elderly in Utrecht, the Netherlands, January to March 2010
Recognition of infections with human metapneumovirus (HMPV) among institutionalised elderly is rising. When HMPV was found to be the causative agent of an outbreak of pneumonia in a residential care facility for elderly in the Netherlands, an elaborate outbreak investigation was set up, including active surveillance for new cases. From clinical cases, defined by fever (> 38°C) and symptoms of respiratory tract infections, respiratory samples for analyses of viral pathogens by real-time Reverse Transcriptase Polymerase Chain Reaction (rRT-PCR) and blood samples for determination of HMPV-specific IgM and IgG antibody titres were taken. Five staff members and 18 residents fulfilled the clinical case definition. Of those, five residents tested positive for HMPV by rRT-PCR. The combination of rRT-PCR and serology identified nine confirmed cases, six probable cases, six possible cases and ruled out two persons as cases. Among residents, the outbreak of HMPV had an attack rate, ranging from 5% for laboratory-confirmed cases, to 13% for clinical cases. This outbreak investigation shows that HMPV is a potential serious pathogen for institutionalised elderly
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Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.
Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials
A novel AhR ligand, 2AI, protects the retina from environmental stress.
Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2'-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice
Agouti Expression in Human Adipose Tissue: Functional Consequences and Increased Expression in Type 2 Diabetes
It is well recognized that the agouti/melanocortin system is an important regulator of body weight homeostasis. Given that agouti is expressed in human adipose tissue and that the ectopic expression of agouti in adipose tissue results in moderately obese mice, the link between agouti expression in human adipose tissue and obesity/type 2 diabetes was investigated. Although there was no apparent relationship between agouti mRNA levels and BMI, agouti mRNA levels were significantly elevated in subjects with type 2 diabetes. The regulation of agouti in cultured human adipocytes revealed that insulin did not regulate agouti mRNA, whereas dexamethasone treatment potently increased the levels of agouti mRNA. Experiments with cultured human preadipocytes and with cells obtained from transgenic mice that overexpress agouti demonstrated that melanocortin receptor (MCR) signaling in adipose tissue can regulate both preadipocyte proliferation and differentiation. Taken together, these results reveal that agouti can regulate adipogenesis at several levels and suggest that there are functional consequences of elevated agouti levels in human adipose tissue. The influence of MCR signaling on adipogenesis combined with the well-established role of MCR signaling in the hypothalamus suggest that adipogenesis is coordinately regulated with food intake and energy expenditure
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