89 research outputs found
Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush.
Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21days in wild-type mice to greater than 38days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4weeks and tibial mixed sensory and motor nerve at 3weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush
Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure
Bounds from Primordial Black Holes with a Near Critical Collapse Initial Mass Function
Recent numerical evidence suggests that a mass spectrum of primordial black
holes (PBHs) is produced as a consequence of near critical gravitational
collapse. Assuming that these holes formed from the initial density
perturbations seeded by inflation, we calculate model independent upper bounds
on the mass variance at the reheating temperature by requiring the mass density
not exceed the critical density and the photon emission not exceed current
diffuse gamma-ray measurements. We then translate these results into bounds on
the spectral index n by utilizing the COBE data to normalize the mass variance
at large scales, assuming a constant power law, then scaling this result to the
reheating temperature. We find that our bounds on n differ substantially
(\delta n > 0.05) from those calculated using initial mass functions derived
under the assumption that the black hole mass is proportional to the horizon
mass at the collapse epoch. We also find a change in the shape of the diffuse
gamma-ray spectrum which results from the Hawking radiation. Finally, we study
the impact of a nonzero cosmological constant and find that the bounds on n are
strengthened considerably if the universe is indeed vacuum-energy dominated
today.Comment: 24 pages, REVTeX, 5 figures; minor typos fixed, two refs added,
version to be published in PR
Annihilation vs. Decay: Constraining dark matter properties from a gamma-ray detection
Most proposed dark matter candidates are stable and are produced thermally in
the early Universe. However, there is also the possibility of unstable (but
long-lived) dark matter, produced thermally or otherwise. We propose a strategy
to distinguish between dark matter annihilation and/or decay in the case that a
clear signal is detected in gamma-ray observations of Milky Way dwarf
spheroidal galaxies with gamma-ray experiments. The sole measurement of the
energy spectrum of an indirect signal would render the discrimination between
these cases impossible. We show that by examining the dependence of the
intensity and energy spectrum on the angular distribution of the emission, the
origin could be identified as decay, annihilation, or both. In addition, once
the type of signal is established, we show how these measurements could help to
extract information about the dark matter properties, including mass,
annihilation cross section, lifetime, dominant annihilation and decay channels,
and the presence of substructure. Although an application of the approach
presented here would likely be feasible with current experiments only for very
optimistic dark matter scenarios, the improved sensitivity of upcoming
experiments could enable this technique to be used to study a wider range of
dark matter models.Comment: 29 pp, 8 figs; replaced to match published version (minor changes and
some new references
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.Genetics of disease, diagnosis and treatmen
Global and national burden of diseases and injuries among children and adolescents between 1990 and 2013 findings from the global burden of disease 2013 study
IMPORTANCE: The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. OBJECTIVE: To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged < 5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study. EVIDENCE REVIEW: Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14 244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35 620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIVinfection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. FINDINGS: Of the 7.7 (95 uncertainty interval UI, 7.4-8.1) million deaths among children and adolescents globally in 2013,6.28 million occurred amongyounger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections amongyounger children (905 059 deaths; 95% UI, 810 304-998125), diarrheal diseases among older children (38 325 deaths; 95% UI, 30 365-47 678), and road injuries among adolescents (115186 deaths; 95% UI, 105185-124 870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world's deaths from neonatal encephalopathy. Half of the world's diarrheal deaths among children and adolescents occurred injust 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. CONCLUSIONS AND RELEVANCE: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed. Copyright 2016 American Medical Association. All rights reserved
Non-synaptic localization of the glutamate transporter EAAC1 in cultured hippocampal neurons
It has been postulated for several years that the high affinity neuronal glutamate uptake system plays a role in clearing glutamate from the synaptic cleft. Four different glutamate transporter subtypes are now identified, the major neuronal one being EAAC1. To be a good candidate for the reuptake of glutamate at the synaptic cleft, EAAC1 should be properly located at synapses, either at pre- or postsynaptic sites. We have investigated the distribution of EAAC1 in primary cultures of hippocampal neurons, which represent an advantageous model for the study of synaptogenesis and synaptic specializations. We have demonstrated that EAAC1 immunoreactivity is segregated in the somatodendritic compartment of fully differentiated hippocampal neurons, where it is localized in the dendritic shaft and in the spine neck, outside the area facing the active zone. No co-localization of EAAC1 immunoreactivity with the stainings produced by typical presynaptic and postsynaptic markers was ever observed, indicating that EAAC1 is not to be considered a synaptic protein. Accordingly, the developmental pattern of expression of EAAC1 was found to be different from that of typical synaptic markers. Moreover, EAAC1 was expressed in the somatodendritic compartment of hippocampal neurons already at Stages preceding the formation of synaptic contacts, and was also expressed in GABAergic interneurons with identical subcellular distribution. Taken together, these data rule against a possible role for EAAC1 in the clearance of glutamate from within the cleft and in the regulation of its time in the synapse. They suggest an unconventional non-synaptic function of this high-affinity glutamate carrier, not restricted to glutamatergic fibres
Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.
Item does not contain fulltextLesch-Nyhan disease, a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase, is associated with a prominent loss of striatal dopamine. The current studies address the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model of the disease, by assessing several markers of oxidative damage and free radical scavenging systems. Some of these measures provided evidence for an increase in oxidative stress in the mutant mice (aconitase activity, oxidized glutathione, and lipid peroxides), but others did not (superoxide dismutase, protein thiol content, carbonyl protein content, total glutathione, glutathione peroxidase, catalase, and thiobarbituric reducing substances). Immunolocalization of heme-oxygenase 1 provided no evidence for oxidative stress restricted to specific elements of the striatum or midbrain in the mutants. Striatal dopamine systems of the mutant mice were more vulnerable to a challenge with the neurotoxin 6-hydroxydopamine, but they were not protected by cross-breeding the mutants with transgenic mice over-expressing superoxide dismutase. Overall, these data provide evidence for increased oxidative stress, but the failure to protect the knockout mice by over-expressing SOD1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine
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