178 research outputs found
Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A
Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity
Energetics of the Einstein-Rosen spacetime
A study covering some aspects of the Einstein--Rosen metric is presented. The
electric and magnetic parts of the Weyl tensor are calculated. It is shown that
there are no purely magnetic E--R spacetimes, and also that a purely electric
E--R spacetime is necessarily static. The geodesics equations are found and
circular ones are analyzed in detail. The super--Poynting and the
``Lagrangian'' Poynting vectors are calculated and their expressions are found
for two specific examples. It is shown that for a pulse--type solution, both
expressions describe an inward radially directed flow of energy, far behind the
wave front. The physical significance of such an effect is discussed.Comment: 19 pages Latex.References added and updated.To appear in
Int.J.Theor.Phy
A stochastic model for heart rate fluctuations
Normal human heart rate shows complex fluctuations in time, which is natural,
since heart rate is controlled by a large number of different feedback control
loops. These unpredictable fluctuations have been shown to display fractal
dynamics, long-term correlations, and 1/f noise. These characterizations are
statistical and they have been widely studied and used, but much less is known
about the detailed time evolution (dynamics) of the heart rate control
mechanism. Here we show that a simple one-dimensional Langevin-type stochastic
difference equation can accurately model the heart rate fluctuations in a time
scale from minutes to hours. The model consists of a deterministic nonlinear
part and a stochastic part typical to Gaussian noise, and both parts can be
directly determined from the measured heart rate data. Studies of 27 healthy
subjects reveal that in most cases the deterministic part has a form typically
seen in bistable systems: there are two stable fixed points and one unstable
one.Comment: 8 pages in PDF, Revtex style. Added more dat
Anisotropy studies around the galactic centre at EeV energies with the Auger Observatory
Data from the Pierre Auger Observatory are analyzed to search for
anisotropies near the direction of the Galactic Centre at EeV energies. The
exposure of the surface array in this part of the sky is already significantly
larger than that of the fore-runner experiments. Our results do not support
previous findings of localized excesses in the AGASA and SUGAR data. We set an
upper bound on a point-like flux of cosmic rays arriving from the Galactic
Centre which excludes several scenarios predicting sources of EeV neutrons from
Sagittarius . Also the events detected simultaneously by the surface and
fluorescence detectors (the `hybrid' data set), which have better pointing
accuracy but are less numerous than those of the surface array alone, do not
show any significant localized excess from this direction.Comment: Matches published versio
Evidence for a mixed mass composition at the `ankle' in the cosmic-ray spectrum
We report a first measurement for ultra-high energy cosmic rays of the
correlation between the depth of shower maximum and the signal in the water
Cherenkov stations of air-showers registered simultaneously by the fluorescence
and the surface detectors of the Pierre Auger Observatory. Such a correlation
measurement is a unique feature of a hybrid air-shower observatory with
sensitivity to both the electromagnetic and muonic components. It allows an
accurate determination of the spread of primary masses in the cosmic-ray flux.
Up till now, constraints on the spread of primary masses have been dominated by
systematic uncertainties. The present correlation measurement is not affected
by systematics in the measurement of the depth of shower maximum or the signal
in the water Cherenkov stations. The analysis relies on general characteristics
of air showers and is thus robust also with respect to uncertainties in
hadronic event generators. The observed correlation in the energy range around
the `ankle' at differs significantly from
expectations for pure primary cosmic-ray compositions. A light composition made
up of proton and helium only is equally inconsistent with observations. The
data are explained well by a mixed composition including nuclei with mass . Scenarios such as the proton dip model, with almost pure compositions, are
thus disfavoured as the sole explanation of the ultrahigh-energy cosmic-ray
flux at Earth.Comment: Published version. Added journal reference and DOI. Added Report
Numbe
Microwave determination of the quasiparticle scattering time in YBa2Cu3O6.95
We report microwave surface resistance (Rs) measurements on two very-high-quality YBa2Cu3O6.95 crystals which exhibit extremely low residual loss at 1.2 K (2-6 ΌΩ at 2 GHz), a broad, reproducible peak at around 38 K, and a rapid increase in loss, by 4 orders of magnitude, between 80 and 93 K. These data provide one ingredient in the determination of the temperature dependence of the real part of the microwave conductivity, Ï1(T), and of the quasiparticle scattering time. The other necessary ingredient is an accurate knowledge of the magnitude and temperature dependence of the London penetration depth, λ(T). This is derived from published data, from microwave data of Anlage, Langley, and co-workers and from, high-quality ÎŒSR data. We infer, from a careful analysis of all available data, that λ2(0)/λ2(T) is well approximated by the simple function 1-t2, where t=T/Tc, and that the low-temperature data are incompatible with the existence of an s-wave, BCS-like gap. Combining the Rs and λ(T) data, we find that Ï1(T), has a broad peak around 32 K with a value about 20 times that at Tc. Using a generalized two-fluid model, we extract the temperature dependence of the quasiparticle scattering rate which follows an exponential law, exp(T/T0), where T0â12 K, for T between 15 and 84 K. Such a temperature dependence has previously been observed in measurements of the nuclear spin-lattice relaxation rate. Both the uncertainties in our analysis and the implications for the mechanism of high-temperature superconductivity are discussed
Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study
Cellular mechanisms in basic and clinical gastroenterology and hepatolog
Phase 1â2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
BACKGROUND
Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.
METHODS
We conducted a phase 1â2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.
RESULTS
A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar punctureârelated adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], â18 to 27) for the 20-mg dose, â25 percentage points (95% CI, â40 to â5) for the 40-mg dose, â19 percentage points (95% CI, â35 to 2) for the 60-mg dose, and â33 percentage points (95% CI, â47 to â16) for the 100-mg dose.
CONCLUSIONS
In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar punctureârelated adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699. opens in new tab; EudraCT number, 2015-004098-33. opens in new tab.
Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study
A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study
In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4
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