1,096 research outputs found
Kainate receptors depress excitatory synaptic transmission at CA3-->CA1 synapses in the hippocampus via a direct presynaptic action
Kainate receptor activation depresses synaptic release of neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and metabotropic mechanisms have been suggested. We report here that the AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a presynaptic depression of glutamatergic transmission at CA3-->CA1 synapses in the hippocampus, which is not blocked by the AMPA receptor antagonist GYKI 53655 but is blocked by the AMPA/KA receptor antagonist CNQX. Neither a blockade of interneuronal discharge nor antagonists of several neuromodulators affect the depression, suggesting that it is not the result of indirect excitation and subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K(+), caused a depression of the presynaptic fiber volley and an increase in the frequency of miniature EPSCs. Neither effect was observed with DA, suggesting that DA does not depress transmission via a presynaptic depolarization. However, the effects of DA were abolished by the G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action
Basal forebrain volume reliably predicts the cortical spread of Alzheimer\u27s degeneration
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. Alzheimer\u27s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer\u27s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer\u27s disease using two independent samples of the Alzheimer\u27s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-b and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM!entorhinal over the entorhinal!NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-b moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM!entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer\u27s disease pathogenesis
Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects
Excess cortisol has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P < 0.05), hypercortisolemia resulted in higher glucose (P < 0.05) and free fatty acid concentrations (P < 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P < 0.01), indicating the presence of steroid-induced insulin resistance. Postabsorptive glucose production (P = 0.64) and the fractional contribution of gluconeogenesis to EGR (P = 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P < 0.05), implying a decrease in net glucose effectiveness (4.42 +/- 0.52 vs. 6.65 +/- 0.83 ml.kg-1.min-1; P < 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 +/- 0.24 vs. 3.82 +/- 0.51 ml.kg-1.min-1; P < 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P < 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-3H]glucose during hydrocortisone than during saline infusion (P < 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal beta-cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess impairs glucose tolerance by decreasing both insulin action and glucose effectiveness
Absence of COVID-19-associated changes in plasma coagulation proteins and pulmonary thrombosis in the ferret model
BACKGROUND: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection. OBJECTIVES: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis. MATERIAL AND METHODS: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed. RESULTS: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation. CONCLUSIONS: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited
Results on correlations and fluctuations from NA49
The large acceptance and high momentum resolution as well as the significant
particle identification capabilities of the NA49 experiment at the CERN SPS
allow for a broad study of fluctuations and correlations in hadronic
interactions. In the first part recent results on event-by-event charge and p_t
fluctuations are presented. Charge fluctuations in central Pb+Pb reactions are
investigated at three different beam energies (40, 80, and 158 AGeV), while for
the p_t fluctuations the focus is put on the system size dependence at 158
AGeV. In the second part recent results on Bose Einstein correlations of h-h-
pairs in minimum bias Pb+Pb reactions at 40 and 158 AGeV, as well as of K+K+
and K-K- pairs in central Pb+Pb collisions at 158 AGeV are shown. Additionally,
other types of two particle correlations, namely pi p, Lambda p, and Lambda
Lambda correlations, have been measured by the NA49 experiment. Finally,
results on the energy and system size dependence of deuteron coalescence are
discussed.Comment: 10 pages, 12 figures, Presented at Quark Matter 2002, Nantes, France,
Corrected error in Eq.
First Observation of Coherent Production in Neutrino Nucleus Interactions with 2 GeV
The MiniBooNE experiment at Fermilab has amassed the largest sample to date
of s produced in neutral current (NC) neutrino-nucleus interactions at
low energy. This paper reports a measurement of the momentum distribution of
s produced in mineral oil (CH) and the first observation of coherent
production below 2 GeV. In the forward direction, the yield of events
observed above the expectation for resonant production is attributed primarily
to coherent production off carbon, but may also include a small contribution
from diffractive production on hydrogen. Integrated over the MiniBooNE neutrino
flux, the sum of the NC coherent and diffractive modes is found to be (19.5
1.1 (stat) 2.5 (sys))% of all exclusive NC production at
MiniBooNE. These measurements are of immediate utility because they quantify an
important background to MiniBooNE's search for
oscillations.Comment: Submitted to Phys. Lett.
Experimental Study of the Shortest Reset Word of Random Automata
In this paper we describe an approach to finding the shortest reset word of a
finite synchronizing automaton by using a SAT solver. We use this approach to
perform an experimental study of the length of the shortest reset word of a
finite synchronizing automaton. The largest automata we considered had 100
states. The results of the experiments allow us to formulate a hypothesis that
the length of the shortest reset word of a random finite automaton with
states and 2 input letters with high probability is sublinear with respect to
and can be estimated as $1.95 n^{0.55}.
Bose-Einstein Correlations of Charged Kaons in Central Pb+Pb Collisions at
Bose-Einstein correlations of charged kaons were measured near mid-rapidity
in central Pb+Pb collisions at 158 AGeV by the NA49 experiment at the
CERN SPS. Source radii were extracted using the Yano-Koonin-Podgoretsky and
Bertsch-Pratt parameterizations. The results are compared to published pion
data. The measured dependence for kaons and pions is consistent with
collective transverse expansion of the source and a freeze-out time of about
9.5 .Comment: 14 pages with 7 figures, submitted to Phys. Lett.
Two-proton correlations from 158 AGeV Pb+Pb central collisions
The two-proton correlation function at midrapidity from Pb+Pb central
collisions at 158 AGeV has been measured by the NA49 experiment. The results
are compared to model predictions from static thermal Gaussian proton source
distributions and transport models RQMD and VENUS. An effective proton source
size is determined by minimizing CHI-square/ndf between the correlation
functions of the data and those calculated for the Gaussian sources, yielding
3.85 +-0.15(stat.) +0.60-0.25(syst.) fm. Both the RQMD and the VENUS model are
consistent with the data within the error in the correlation peak region.Comment: RevTeX style, 6 pages, 4 figures, 1 table. More discussion are added
about the structure on the tail of the correlation function. The systematic
error is revised. To appear in Phys. Lett.
Event-by-event fluctuations of average transverse momentum in central Pb+Pb collisions at 158 GeV per nucleon
We present first data on event-by-event fluctuations in the average
transverse momentum of charged particles produced in Pb+Pb collisions at the
CERN SPS. This measurement provides previously unavailable information allowing
sensitive tests of microscopic and thermodynamic collision models and to search
for fluctuations expected to occur in the vicinity of the predicted QCD phase
transition. We find that the observed variance of the event-by-event average
transverse momentum is consistent with independent particle production modified
by the known two-particle correlations due to quantum statistics and final
state interactions and folded with the resolution of the NA49 apparatus. For
two specific models of non-statistical fluctuations in transverse momentum
limits are derived in terms of fluctuation amplitude. We show that a
significant part of the parameter space for a model of isospin fluctuations
predicted as a consequence of chiral symmetry restoration in a non-equilibrium
scenario is excluded by our measurement.Comment: 6 pages, 2 figures, submitted to Phys. Lett.
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