819 research outputs found
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SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons
yesMultiple pathways participate in the AMPA receptor trafficking that underlies long-term potentiation (LTP) of synaptic transmission. Here we demonstrate that protein SUMOylation is required for insertion of the GluA1 AMPAR subunit following transient glycine-evoked increase in AMPA receptor surface expression (ChemLTP) in dispersed neuronal cultures. ChemLTP increases co-localisation of SUMO-1 and the SUMO conjugating enzyme Ubc9 and with PSD95 consistent with the recruitment of SUMOylated proteins to dendritic spines. In addition, we show that ChemLTP increases dendritic levels of SUMO-1 and Ubc9 mRNA. Consistent with activity dependent translocation of these mRNAs to sites near synapses, levels of the mRNA binding and dendritic transport protein CPEB are also increased by ChemLTP. Importantly, reducing the extent of substrate protein SUMOylation by overexpressing the deSUMOylating enzyme SENP-1 or inhibiting SUMOylation by expressing dominant negative Ubc9 prevent the ChemLTP-induced increase in both AMPAR surface expression and dendritic SUMO-1 mRNA. Taken together these data demonstrate that SUMOylation of synaptic protein(s) involved in AMPA receptor trafficking is necessary for activity-dependent increases in AMPAR surface expression.Medical Research Council, the European Research Council and the Wellcome Trus
The effect of relative hypotension on 30-day mortality in older people receiving emergency care
Research has observed increased mortality among older people attending the emergency department (ED) who had systolic pressureâ>â7 mmHg lower than baseline primary care values. This study aimed to (1) assess feasibility of identifying this ârelative hypotensionâ using readily available ED data, (2) externally validate the 7 mmHg threshold, and (3) refine a threshold for clinically important relative hypotension. A single-centre retrospective cohort study linked year 2019 data for ED attendances by people aged over 64 to hospital discharge vital signs within the previous 18 months. Frailty and comorbidity scores were calculated. Previous discharge (âbaselineâ) vital signs were subtracted from initial ED values to give individualsâ relative change. Cox regression analysis compared relative hypotensionâ>â7 mmHg with mean time to mortality censored at 30 days. The relative hypotension threshold was refined using a fully adjusted risk tool formed of logistic regression models. Receiver operating characteristics were compared to NEWS2 models with and without incorporation of relative systolic. 5136 (16%) of 32,548 ED attendances were linkable with recent discharge vital signs. Relative hypotensionâ>â7 mmHg was associated with increased 30-day mortality (HR 1.98; 95% CI 1.66â2.35). The adjusted risk tool (AUC: 0.69; sensitivity: 0.61; specificity: 0.68) estimated each 1 mmHg relative hypotension to increase 30-day mortality by 2% (OR 1.02; 95% CI 1.02â1.02). 30-day mortality prediction was marginally better with NEWS2 (AUC: 0.73; sensitivity: 0.59; specificity: 0.78) and NEWS2â+ârelative systolic (AUC: 0.74; sensitivity: 0.63; specificity: 0.75). Comparison of ED vital signs with recent discharge observations was feasible for 16% individuals. The association of relative hypotensionâ>â7 mmHg with 30-day mortality was externally validated. Indeed, any relative hypotension appeared to increase risk, but model characteristics were poor. These findings are limited to the context of older people with recent hospital admissions
Measurements of Scintillation Efficiency and Pulse-Shape for Low Energy Recoils in Liquid Xenon
Results of observations of low energy nuclear and electron recoil events in
liquid xenon scintillator detectors are given. The relative scintillation
efficiency for nuclear recoils is 0.22 +/- 0.01 in the recoil energy range 40
keV - 70 keV. Under the assumption of a single dominant decay component to the
scintillation pulse-shape the log-normal mean parameter T0 of the maximum
likelihood estimator of the decay time constant for 6 keV < Eee < 30 keV
nuclear recoil events is equal to 21.0 ns +/- 0.5 ns. It is observed that for
electron recoils T0 rises slowly with energy, having a value ~ 30 ns at Eee ~
15 keV. Electron and nuclear recoil pulse-shapes are found to be well fitted by
single exponential functions although some evidence is found for a double
exponential form for the nuclear recoil pulse-shape.Comment: 11 pages, including 5 encapsulated postscript figure
Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2.
Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged â„65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], â„75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade â„3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346
Governing infrastructure networks for a low carbon economy:co-evolution of technologies and institutions in UK electricity distribution networks
Multimessenger astronomy with the Einstein Telescope
Gravitational waves (GWs) are expected to play a crucial role in the
development of multimessenger astrophysics. The combination of GW observations
with other astrophysical triggers, such as from gamma-ray and X-ray satellites,
optical/radio telescopes, and neutrino detectors allows us to decipher science
that would otherwise be inaccessible. In this paper, we provide a broad review
from the multimessenger perspective of the science reach offered by the third
generation interferometric GW detectors and by the Einstein Telescope (ET) in
particular. We focus on cosmic transients, and base our estimates on the
results obtained by ET's predecessors GEO, LIGO, and Virgo.Comment: 26 pages. 3 figures. Special issue of GRG on the Einstein Telescope.
Minor corrections include
Active Galactic Nuclei at the Crossroads of Astrophysics
Over the last five decades, AGN studies have produced a number of spectacular
examples of synergies and multifaceted approaches in astrophysics. The field of
AGN research now spans the entire spectral range and covers more than twelve
orders of magnitude in the spatial and temporal domains. The next generation of
astrophysical facilities will open up new possibilities for AGN studies,
especially in the areas of high-resolution and high-fidelity imaging and
spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These
studies will address in detail a number of critical issues in AGN research such
as processes in the immediate vicinity of supermassive black holes, physical
conditions of broad-line and narrow-line regions, formation and evolution of
accretion disks and relativistic outflows, and the connection between nuclear
activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic
Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical
Symposia Serie
The composition of the protosolar disk and the formation conditions for comets
Conditions in the protosolar nebula have left their mark in the composition
of cometary volatiles, thought to be some of the most pristine material in the
solar system. Cometary compositions represent the end point of processing that
began in the parent molecular cloud core and continued through the collapse of
that core to form the protosun and the solar nebula, and finally during the
evolution of the solar nebula itself as the cometary bodies were accreting.
Disentangling the effects of the various epochs on the final composition of a
comet is complicated. But comets are not the only source of information about
the solar nebula. Protostellar disks around young stars similar to the protosun
provide a way of investigating the evolution of disks similar to the solar
nebula while they are in the process of evolving to form their own solar
systems. In this way we can learn about the physical and chemical conditions
under which comets formed, and about the types of dynamical processing that
shaped the solar system we see today.
This paper summarizes some recent contributions to our understanding of both
cometary volatiles and the composition, structure and evolution of protostellar
disks.Comment: To appear in Space Science Reviews. The final publication is
available at Springer via http://dx.doi.org/10.1007/s11214-015-0167-
Search for the standard model Higgs boson in tau final states
We present a search for the standard model Higgs boson using hadronically
decaying tau leptons, in 1 inverse femtobarn of data collected with the D0
detector at the Fermilab Tevatron ppbar collider. We select two final states:
tau plus missing transverse energy and b jets, and tau+ tau- plus jets. These
final states are sensitive to a combination of associated W/Z boson plus Higgs
boson, vector boson fusion and gluon-gluon fusion production processes. The
observed ratio of the combined limit on the Higgs production cross section at
the 95% C.L. to the standard model expectation is 29 for a Higgs boson mass of
115 GeV.Comment: publication versio
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