Establishing the presence and severity of fluctuations is important in managing Parkinson's Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a ...Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system.
The Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm.
This Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations.
The Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Swift intensive accretion disk reverberation mapping of four AGN yielded light curves sampled ∼200-350 times in 0.3-10 keV X-ray and six UV/optical bands. Uniform reduction and cross-correlation ...analysis of these data sets yields three main results: (1) The X-ray/UV correlations are much weaker than those within the UV/optical, posing severe problems for the lamp-post reprocessing model in which variations in a central X-ray corona drive and power those in the surrounding accretion disk. (2) The UV/optical interband lags are generally consistent with as predicted by the centrally illuminated thin accretion disk model. While the average interband lags are somewhat larger than predicted, these results alone are not inconsistent with the thin disk model given the large systematic uncertainties involved. (3) The one exception is the U band lags, which are on average a factor of ∼2.2 larger than predicted from the surrounding band data and fits. This excess appears to be due to diffuse continuum emission from the broad-line region (BLR). The precise mixing of disk and BLR components cannot be determined from these data alone. The lags in different AGN appear to scale with mass or luminosity. We also find that there are systematic differences between the uncertainties derived by JAVELIN versus more standard lag measurement techniques, with JAVELIN reporting smaller uncertainties by a factor of 2.5 on average. In order to be conservative only standard techniques were used in the analyses reported herein.
Swift monitoring of NGC 4151 with an ∼6 hr sampling over a total of 69 days in early 2016 is used to construct light curves covering five bands in the X-rays (0.3-50 keV) and six in the ultraviolet ...(UV)/optical (1900-5500 Å). The three hardest X-ray bands (>2.5 keV) are all strongly correlated with no measurable interband lag, while the two softer bands show lower variability and weaker correlations. The UV/optical bands are significantly correlated with the X-rays, lagging ∼3-4 days behind the hard X-rays. The variability within the UV/optical bands is also strongly correlated, with the UV appearing to lead the optical by ∼0.5-1 days. This combination of 3 day lags between the X-rays and UV and 1 day lags within the UV/optical appears to rule out the "lamp-post" reprocessing model in which a hot, X-ray emitting corona directly illuminates the accretion disk, which then reprocesses the energy in the UV/optical. Instead, these results appear consistent with the Gardner & Done picture in which two separate reprocessings occur: first, emission from the corona illuminates an extreme-UV-emitting toroidal component that shields the disk from the corona; this then heats the extreme-UV component, which illuminates the disk and drives its variability.
In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with ...stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dynamical histories of planetary systems, as well as the atmospheric evolution of highly irradiated planets, can be studied by characterizing the ultra-short-period planet population, which the TESS ...mission is particularly well suited to discover. Here, we report on the follow-up of a transit signal detected in the TESS sector 19 photometric time series of the M3.0 V star TOI-1685 (2MASS J04342248+4302148). We confirm the planetary nature of the transit signal, which has a period of
P
b
= 0.6691403
−0.0000021
+0.0000023
d, using precise radial velocity measurements taken with the CARMENES spectrograph. From the joint photometry and radial velocity analysis, we estimate the following parameters for TOI-1685 b: a mass of
M
b
= 3.78
−0.63
+0.63
M
⊕
, a radius of
R
b
= 1.70
−0.07
+0.07
R
⊕
, which together result in a bulk density of
ρ
b
= 4.21
−0.82
+0.95
g cm
−3
, and an equilibrium temperature of
T
eq
= 1069
−16
+16
K. TOI-1685 b is the least dense ultra-short-period planet around an M dwarf known to date. TOI-1685 b is also one of the hottest transiting super-Earth planets with accurate dynamical mass measurements, which makes it a particularly attractive target for thermal emission spectroscopy. Additionally, we report with moderate evidence an additional non-transiting planet candidate in the system, TOI-1685 c, which has an orbital period of
P
c
= 9.02
−0.12
+0.10
d.
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FMFMET, NUK, UL, UM, UPUK
Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and ...studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. ...Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1
G93A
mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1
G93A
mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1
G93A
mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by ...immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα-, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
We present the first intensive continuum reverberation mapping study of the high accretion-rate Seyfert galaxy Mrk 110. The source was monitored almost daily for more than 200 d with the ...Swift X-ray and ultraviolet (UV)/optical telescopes, supported by ground-based observations from Las Cumbres Observatory, the Liverpool Telescope, and the Zowada Observatory, thus extending the wavelength coverage to 9100 Å. Mrk 110 was found to be significantly variable at all wavebands. Analysis of the intraband lags reveals two different behaviours, depending on the time-scale. On time-scales shorter than 10 d the lags, relative to the shortest UV waveband (∼1928 Å), increase with increasing wavelength up to a maximum of ∼2 d lag for the longest waveband (∼9100 Å), consistent with the expectation from disc reverberation. On longer time-scales, however, the g-band lags the Swift BAT hard X-rays by ∼10 d, with the z-band lagging the g-band by a similar amount, which cannot be explained in terms of simple reprocessing from the accretion disc. We interpret this result as an interplay between the emission from the accretion disc and diffuse continuum radiation from the broad-line region.
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