1,063 research outputs found
A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141495/1/jlb0943.pd
Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B.
Noncanonical WNT pathways function independently of the β-catenin transcriptional co-activator to regulate diverse morphogenetic and pathogenic processes. Recent studies showed that noncanonical WNTs, such as WNT5A, can signal the degradation of several downstream effectors, thereby modulating these effectors' cellular activities. The protein domain(s) that mediates the WNT5A-dependent degradation response, however, has not been identified. By coupling protein mutagenesis experiments with a flow cytometry-based degradation reporter assay, we have defined a protein domain in the kinesin superfamily protein KIF26B that is essential for WNT5A-dependent degradation. We found that a human disease-causing KIF26B mutation located at a conserved amino acid within this domain compromises the ability of WNT5A to induce KIF26B degradation. Using pharmacological perturbation, we further uncovered a role of glycogen synthase kinase 3 (GSK3) in WNT5A regulation of KIF26B degradation. Lastly, based on the identification of the WNT5A-responsive domain, we developed a new reporter system that allows for efficient profiling of WNT5A-KIF26B signaling activity in both somatic and stem cells. In conclusion, our study identifies a new protein domain that mediates WNT5A-dependent degradation of KIF26B and provides a new tool for functional characterization of noncanonical WNT5A signaling in cells
Employing knowledge translation interventions to increase the use of therapeutic hypothermia post arrest: the SPARC Network Trial
On ion gyro-harmonic structuring in the stimulated electromagnetic emission spectrum during second electron gyro-harmonic heating
Struggling with Meaningfulness when Context Shifts:Volunteer Work in a German Refugee Shelter
Use of specific Green's functions for solving direct problems involving a heterogeneous rigid frame porous medium slab solicited by acoustic waves
A domain integral method employing a specific Green's function (i.e.,
incorporating some features of the global problem of wave propagation in an
inhomogeneous medium) is developed for solving direct and inverse scattering
problems relative to slab-like macroscopically inhomogeneous porous obstacles.
It is shown how to numerically solve such problems, involving both
spatially-varying density and compressibility, by means of an iterative scheme
initialized with a Born approximation. A numerical solution is obtained for a
canonical problem involving a two-layer slab.Comment: submitted to Math.Meth.Appl.Sc
Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: Involvement of src family protein kinases
The increased production of amyloid beta -peptide (A beta) in Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain cortical cultures to A beta administration and found a marked increase in the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c (MAP2c). We also found that paired helical filaments of aggregated and hyperphosphorylated tau are tyrosine phosphorylated, indicating that changes in the phosphotyrosine content of cytoplasmic proteins in response to A beta are potentially an important process. Increased tyrosine phosphorylation of cytoskeletal and other neuronal proteins was specific to fibrillar A beta (25-35) and A beta (1-42). The tyrosine phosphorylation was blocked by addition of the Src family tyrosine kinase inhibitor 4-amino-5-( 4-chlorophenyl)- 7(t-butyl) pyrazol(3,4-D) pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family, from A beta (25-35)-treated neurons showed an increased association of Fyn with FAK. A beta treatment of cells also stimulated the sustained activation of extracellular regulated kinase-2, which was blocked by addition of PP2 and LY 294002, suggesting that FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein (MAP) kinase signaling in A beta -treated neurons. This cascade of signaling events contains the earliest biochemical changes in neurons to be described in response to A beta exposure and may be critical for subsequent neurodegenerative changes
Adalimumab in Patients with Active Noninfectious Uveitis
BACKGROUND:
Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled
inflammation, as well as for the adverse effects of long-term glucocorticoid
therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a
glucocorticoid-sparing agent for the treatment of noninfectious uveitis.
METHODS:
This multinational phase 3 trial involved adults who had active noninfectious intermediate
uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment
for 2 or more weeks. Investigators and patients were unaware of the study-group
assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab
(a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched
placebo. All patients received a mandatory prednisone burst followed by tapering of
prednisone over the course of 15 weeks. The primary efficacy end point was the time
to treatment failure occurring at or after week 6. Treatment failure was a multicomponent
outcome that was based on assessment of new inflammatory lesions, best
corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine
ranked secondary efficacy end points were assessed, and adverse events were reported.
RESULTS:
The median time to treatment failure was 24 weeks in the adalimumab group and 13
weeks in the placebo group. Among the 217 patients in the intention-to-treat population,
those receiving adalimumab were less likely than those in the placebo group to
have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70;
P<0.001). Outcomes with regard to three secondary end points (change in anterior
chamber cell grade, change in vitreous haze grade, and change in best corrected visual
acuity) were significantly better in the adalimumab group than in the placebo
group. Adverse events and serious adverse events were reported more frequently
among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8
vs. 13.6 serious adverse events per 100 person-years).
CONCLUSIONS:
In our trial, adalimumab was found to be associated with a lower risk of uveitic flare
or visual impairment and with more adverse events and serious adverse events than
was placebo
Stimulated Brillouin scattering during electron gyro-harmonic heating at EISCAT
Observations of secondary radiation, stimulated electromagnetic emission (SEE), produced during ionospheric modification experiments using ground-based, highpower, high-frequency (HF) radio waves are considered. The High Frequency Active Auroral Research Program (HAARP) facility is capable of generating narrowband SEE in the form of stimulated Brillouin scatter (SBS) and stimulated ion Bernstein scatter (SIBS) in the SEE spectrum. Such narrowband SEE spectral lines have not been reported using the European Incoherent Scatter (EISCAT) heater facility before. This work reports the first EISCAT results of narrowband SEE spectra and compares them to SEE previously observed at HAARP during electron gyro-harmonic heating. An analysis of experimental SEE data shows observations of emission lines within 100 Hz of the pump frequency, interpreted as SBS, during the 2012 July EISCAT campaign. Experimental results indicate that SBS strengthens as the pump frequency approaches the third electron gyro-harmonic. Also, for different heater antenna beam angles, the CUTLASS radar backscatter induced by HF radio pumping is suppressed near electron gyro-harmonics, whereas electron temperature enhancement weakens as measured by EISCAT/UHF radar. The main features of these new narrowband EISCAT observations are generally consistent with previous SBS measurements at HAARP
Bifurcations in annular electroconvection with an imposed shear
We report an experimental study of the primary bifurcation in
electrically-driven convection in a freely suspended film. A weakly conducting,
submicron thick smectic liquid crystal film was supported by concentric
circular electrodes. It electroconvected when a sufficiently large voltage
was applied between its inner and outer edges. The film could sustain rapid
flows and yet remain strictly two-dimensional. By rotation of the inner
electrode, a circular Couette shear could be independently imposed. The control
parameters were a dimensionless number , analogous to the Rayleigh
number, which is and the Reynolds number of the
azimuthal shear flow. The geometrical and material properties of the film were
characterized by the radius ratio , and a Prandtl-like number . Using measurements of current-voltage characteristics of a large number of
films, we examined the onset of electroconvection over a broad range of
, and . We compared this data quantitatively to
the results of linear stability theory. This could be done with essentially no
adjustable parameters. The current-voltage data above onset were then used to
infer the amplitude of electroconvection in the weakly nonlinear regime by
fitting them to a steady-state amplitude equation of the Landau form. We show
how the primary bifurcation can be tuned between supercritical and subcritical
by changing and .Comment: 17 pages, 12 figures. Submitted to Phys. Rev. E. Minor changes after
refereeing. See also http://mobydick.physics.utoronto.c
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