151 research outputs found
C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors
NMDA receptors interact via the extended intracellular C-terminal domain of the NR2 subunits with constituents of the postsynaptic density for purposes of retention, clustering, and functional regulation at central excitatory synapses. To examine the role of the C-terminal domain of NR2A in the synaptic localization and function of NR2A-containing NMDA receptors in hippocampal Schaffer collateral–CA1 pyramidal cell synapses, we analyzed mice which express NR2A only in its C-terminally truncated form. In CA1 cell somata, the levels, activation, and deactivation kinetics of extrasynaptic NMDA receptor channels were comparable in wild-type and mutant NR2A^(ΔC/ΔC) mice. At CA1 cell synapses, however, the truncated receptors were less concentrated than their full-length counterparts, as indicated by immunodetection in cultured neurons, synaptosomes, and postsynaptic densities. In the mutant, the NMDA component of evoked EPSCs was reduced in a developmentally progressing manner and was even more reduced in miniature EPSCs (mEPSCs) elicited by spontaneous glutamate release. Moreover, pharmacologically isolated NMDA currents evoked by synaptic stimulation had longer latencies and displayed slower rise and decay times, even in the presence of an NR2B-specific antagonist. These data strongly suggest that the C-terminal domain of NR2A subunits is important for the precise synaptic arrangement of NMDA receptors
FACT: Learning Governing Abstractions Behind Integer Sequences
Integer sequences are of central importance to the modeling of concepts
admitting complete finitary descriptions. We introduce a novel view on the
learning of such concepts and lay down a set of benchmarking tasks aimed at
conceptual understanding by machine learning models. These tasks indirectly
assess model ability to abstract, and challenge them to reason both
interpolatively and extrapolatively from the knowledge gained by observing
representative examples. To further aid research in knowledge representation
and reasoning, we present FACT, the Finitary Abstraction Comprehension Toolkit.
The toolkit surrounds a large dataset of integer sequences comprising both
organic and synthetic entries, a library for data pre-processing and
generation, a set of model performance evaluation tools, and a collection of
baseline model implementations, enabling the making of the future advancements
with ease.Comment: Accepted to the 36th Conference on Neural Information Processing
Systems (NeurIPS 2022) Track on Datasets and Benchmarks. 37 page
Discontinuities of the integrated density of states for random operators on Delone sets
Despite all the analogies with "usual random" models, tight binding operators
for quasicrystals exhibit a feature which clearly distinguishes them from the
former: the integrated density of states may be discontinuous. This phenomenon
is identified as a local effect, due to occurrence of eigenfunctions with
bounded support.Comment: 9 pages, 2 figure
study protocol for a randomised controlled trial
Background Immunosuppression with calcineurin inhibitors remains the mainstay
of treatment after kidney transplantation; however, long-term use of these
drugs may be associated with nephrotoxicity. In this regard, the current
approach is to optimise available immunosuppressive regimens to reduce the
calcineurin inhibitor dose while protecting renal function without affecting
the efficacy. The ATHENA study is designed to evaluate renal function in two
regimens: an everolimus and reduced calcineurin inhibitor-based regimen versus
a standard treatment protocol with mycophenolic acid and tacrolimus in de novo
kidney transplant recipients. Method/Design ATHENA is a 12-month, multicentre,
open-label, prospective, randomised, parallel-group study in de novo kidney
transplant recipients (aged 18 years or older) receiving renal allografts from
deceased or living donors. Eligible patients are randomised (1:1:1) prior to
transplantation to one of the following three treatment arms: everolimus
(starting dose 1.5 mg/day; C0 3–8 ng/mL) with cyclosporine or everolimus
(starting dose 3 mg/day; C0 3–8 ng/mL) with tacrolimus or mycophenolic acid
(enteric-coated mycophenolate sodium at 1.44 g/day or mycophenolate mofetil at
2 g/day) with tacrolimus; in combination with corticosteroids. All patients
receive induction therapy with basiliximab. The primary objective is to
demonstrate non-inferiority of renal function (eGFR by the Nankivell formula)
in one of the everolimus arms compared with the standard group at month 12
post transplantation. The key secondary objective is to assess the incidence
of treatment failure, defined as biopsy-proven acute rejection, graft loss, or
death, among the treatment groups. Other objectives include assessment of the
individual components of treatment failure, incidence and severity of viral
infections, incidence and duration of delayed graft function, incidence of
indication biopsies, slow graft function and wound healing complications, and
overall safety and tolerability. Exploratory objectives include evaluation of
left ventricular hypertrophy assessed by the left ventricular mass index,
evolution of human leukocyte antigen and non-human leukocyte antigen
antibodies, and a cytomegalovirus substudy. Discussion As one of the largest
European multicentre kidney transplant studies, ATHENA will determine whether
a de novo everolimus-based regimen can preserve renal function versus the
standard of care. This study further assesses a number of clinical issues
which impact long-term outcomes post transplantation; hence, its results will
have a major clinical impact
Design and rationale of the ATHENA study – A 12-month, multicentre, prospective study evaluating the outcomes of a de novo everolimus-based regimen in combination with reduced cyclosporine or tacrolimus versus a standard regimen in kidney transplant patients: study protocol for a randomised controlled trial
Background: Immunosuppression with calcineurin inhibitors remains the mainstay of treatment after kidney transplantation; however, long-term use of these drugs may be associated with nephrotoxicity. In this regard, the current approach is to optimise available immunosuppressive regimens to reduce the calcineurin inhibitor dose while protecting renal function without affecting the efficacy. The ATHENA study is designed to evaluate renal function in two regimens: an everolimus and reduced calcineurin inhibitor-based regimen versus a standard treatment protocol with mycophenolic acid and tacrolimus in de novo kidney transplant recipients. Method/Design: ATHENA is a 12-month, multicentre, open-label, prospective, randomised, parallel-group study in de novo kidney transplant recipients (aged 18 years or older) receiving renal allografts from deceased or living donors. Eligible patients are randomised (1:1:1) prior to transplantation to one of the following three treatment arms: everolimus (starting dose 1.5 mg/day; C0 3–8 ng/mL) with cyclosporine or everolimus (starting dose 3 mg/day; C0 3–8 ng/mL) with tacrolimus or mycophenolic acid (enteric-coated mycophenolate sodium at 1.44 g/day or mycophenolate mofetil at 2 g/day) with tacrolimus; in combination with corticosteroids. All patients receive induction therapy with basiliximab. The primary objective is to demonstrate non-inferiority of renal function (eGFR by the Nankivell formula) in one of the everolimus arms compared with the standard group at month 12 post transplantation. The key secondary objective is to assess the incidence of treatment failure, defined as biopsy-proven acute rejection, graft loss, or death, among the treatment groups. Other objectives include assessment of the individual components of treatment failure, incidence and severity of viral infections, incidence and duration of delayed graft function, incidence of indication biopsies, slow graft function and wound healing complications, and overall safety and tolerability. Exploratory objectives include evaluation of left ventricular hypertrophy assessed by the left ventricular mass index, evolution of human leukocyte antigen and non-human leukocyte antigen antibodies, and a cytomegalovirus substudy. Discussion: As one of the largest European multicentre kidney transplant studies, ATHENA will determine whether a de novo everolimus-based regimen can preserve renal function versus the standard of care. This study further assesses a number of clinical issues which impact long-term outcomes post transplantation; hence, its results will have a major clinical impact. Trial registration: Clinicaltrials.gov: NCT01843348 , date of registration – 18 April 2013; EUDRACT number: 2011-005238-21, date of registration – 20 March 201
On the Use of Ly-alpha Emitters as Probes of Reionization
We use numerical simulations to study the effects of the patchiness of a
partly reionized intergalactic medium (IGM) on the observability of Ly-alpha
emitters (LAEs) at high redshifts (z ~ 6). We present a new model that divides
the Ly-alpha radiative transfer into a (circum-)galactic and an extragalactic
(IGM) part, and investigate how the choice of intrinsic line model affects the
IGM transmission results. We use our model to study the impact of neutral
hydrogen on statistical observables such as the Ly-alpha restframe equivalent
width (REW) distribution, the LAE luminosity function and the two-point
correlation function. We find that if the observed changes in LAE luminosity
functions and equivalent width distributions between z ~ 6 and z ~ 7 are to be
explained by an increased IGM neutral fraction alone, we require an extremely
late and rapid reionization scenario, where the Universe was ~ 40 % ionized at
z = 7, ~ 50 % ionized at z = 6.5 and ~ 100 % ionized at z = 6. This is in
conflict with other observations, suggesting that intrinsic LAE evolution at z
> 6 cannot be completely neglected. We show how the two-point correlation
function can provide more robust constraints once future observations obtain
larger LAE samples, and provide predictions for the sample sizes needed to tell
different reionization scenarios apart.Comment: Accepted for publication in MNRA
Detection of pre-existing SARS-CoV-2-reactive T cells in unexposed renal transplant patients
Background: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known.
Methods: Fifty-seven patients were included in this case-control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane-SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay.
Results: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4(+) T cells reactive against at least one SARS-CoV-2 protein. CD8(+) T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals.
Conclusions: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection
Modeling and characterization of the SPIDER half-wave plate
Spider is a balloon-borne array of six telescopes that will observe the
Cosmic Microwave Background. The 2624 antenna-coupled bolometers in the
instrument will make a polarization map of the CMB with approximately one-half
degree resolution at 145 GHz. Polarization modulation is achieved via a
cryogenic sapphire half-wave plate (HWP) skyward of the primary optic. We have
measured millimeter-wave transmission spectra of the sapphire at room and
cryogenic temperatures. The spectra are consistent with our physical optics
model, and the data gives excellent measurements of the indices of A-cut
sapphire. We have also taken preliminary spectra of the integrated HWP, optical
system, and detectors in the prototype Spider receiver. We calculate the
variation in response of the HWP between observing the CMB and foreground
spectra, and estimate that it should not limit the Spider constraints on
inflation
Cancer hospital advertising and outcomes: trust the messenger?
Hospitals have made substantial investments in advertising for cancer services in the past two decades, totalling over US$200 million in 2016 alone. Advertisements promoting cancer centres are unavoidable in the USA. They hang on highway billboards and on air during prime-time programming. Some advertisements claim superior outcomes, others highlight access to clinical trials, and many present heart-warming patient stories that might be non-representative of actual outcomes. Data suggest that patients are highly aware of advertisements and are likewise influenced by them
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