746 research outputs found
A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses
Many contemporary studies have shown that astrocytes play a significant role
in modulating both short and long form of synaptic plasticity. There are very
few experimental models which elucidate the role of astrocyte over Long-term
Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of
astrocytes in induction of LTP at single hippocampal synapses. They suggested a
purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA)
Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic
induction were not investigated. Here, in this article, we propose a
mathematical model for astrocyte modulated LTP which successfully emulates the
experimental findings of Perea & Araque (2007). Our study suggests the role of
retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically
modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to
appear
Phenomenology of event shapes at hadron colliders
We present results for matched distributions of a range of dijet event shapes
at hadron colliders, combining next-to-leading logarithmic (NLL) accuracy in
the resummation exponent, next-to-next-to leading logarithmic (NNLL) accuracy
in its expansion and next-to-leading order (NLO) accuracy in a pure alpha_s
expansion. This is the first time that such a matching has been carried out for
hadronic final-state observables at hadron colliders. We compare our results to
Monte Carlo predictions, with and without matching to multi-parton tree-level
fixed-order calculations. These studies suggest that hadron-collider event
shapes have significant scope for constraining both perturbative and
non-perturbative aspects of hadron-collider QCD. The differences between
various calculational methods also highlight the limits of relying on
simultaneous variations of renormalisation and factorisation scale in making
reliable estimates of uncertainties in QCD predictions. We also discuss the
sensitivity of event shapes to the topology of multi-jet events, which are
expected to appear in many New Physics scenarios.Comment: 70 pages, 25 figures, additional material available from
http://www.lpthe.jussieu.fr/~salam/pp-event-shapes
Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat
The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling
A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition
Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The
plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis
of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread
action on brain function through modulation of synap–tic transmission and plasticity. Recent experimental studies have
characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain
regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and
memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and
investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI), a prominent form of shortterm
synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key
characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical
description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to
test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked.
The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit
DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing
rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate
experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a
stepping stone for future deciphering of the role of endocannabinoids in synaptic transmission as a feedback mechanism
both at synaptic and network level
Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis
Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease
Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector
Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente
Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the Berlin Aging Study II
Background Aging and latent infection with Cytomegalovirus (CMV) are thought
to be major factors driving the immune system towards immunosenescence,
primarily characterized by reduced amounts of naïve T-cells and increased
memory T-cells, potentially associated with higher morbidity and mortality.
The composition of both major compartments, γδ as well as αβ T-cells, is
altered by age and CMV, but detailed knowledge of changes to the γδ subset is
currently limited. Results Here, we have surveyed a population of 73 younger
(23–35 years) and 144 older (62–85 years) individuals drawn from the Berlin
Aging Study II, investigating the distribution of detailed differentiation
phenotypes of both γδ and αβ T-cells. Correlation of frequencies and absolute
counts of the identified phenotypes with age and the presence of CMV revealed
a lower abundance of Vδ2-positive and a higher amount of Vδ1-positive cells.
We found higher frequencies of late-differentiated and lower frequencies of
early-differentiated cells in the Vδ1+ and Vδ1-Vδ2-, but not in the Vδ2+
populations in elderly CMV-seropositive individuals confirming the association
of these Vδ2-negative cells with CMV-immunosurveillance. We identified the
highest Vδ1:Vδ2 ratios in the CMV-seropositive elderly. The observed increased
CD4:CD8 ratios in the elderly were significantly lower in CMV-seropositive
individuals, who also possessed a lower naïve and a larger late-differentiated
compartment of CD8+ αβ T-cells, reflecting the consensus in the literature.
Conclusions Our findings illustrate in detail the strong influence of CMV on
the abundance and differentiation pattern of γδ T-cells as well as αβ T-cells
in older and younger people. Mechanisms responsible for the phenotypic
alterations in the γδ T-cell compartment, associated both with the presence of
CMV and with age require further clarification
Altered ureteric branching morphogenesis and nephron endowment in offspring of diabetic and insulin-treated pregnancy
<div><p>There is strong evidence from human and animal models that exposure to maternal hyperglycemia during <i>in utero</i> development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified <i>ex vivo</i> using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7±23.3 vs. STZ 153.2±24.6, mean±SEM, <i>p</i><0.01) and ureteric tree length (control 33.1±2.6 mm vs. STZ 17.6±2.7 mm, <i>p</i> = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2±64.9 vs. STZ 822.4±74.0, <i>p<</i>0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.</p> </div
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