Long-Term Protective Effects of Methamphetamine Preconditioning Against Single-Day Methamphetamine Toxic Challenges

Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH –induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems

Energetics, forces, and quantized conductance in jellium modeled metallic nanowires

Energetics and quantized conductance in jellium modeled nanowires are investigated using the local density functional based shell correction method, extending our previous study of uniform in shape wires [C. Yannouleas and U. Landman, J. Phys. Chem. B 101, 5780 (1997)] to wires containing a variable shaped constricted region. The energetics of the wire (sodium) as a function of the length of the volume conserving, adiabatically shaped constriction leads to formation of self selecting magic wire configurations. The variations in the energy result in oscillations in the force required to elongate the wire and are directly correlated with the stepwise variations of the conductance of the nanowire in units of 2e^2/h. The oscillatory patterns in the energetics and forces, and the correlated stepwise variation in the conductance are shown, numerically and through a semiclassical analysis, to be dominated by the quantized spectrum of the transverse states at the narrowmost part of the constriction in the wire.Comment: Latex/Revtex, 11 pages with 5 Postscript figure

The Mathematical Universe

I explore physics implications of the External Reality Hypothesis (ERH) that there exists an external physical reality completely independent of us humans. I argue that with a sufficiently broad definition of mathematics, it implies the Mathematical Universe Hypothesis (MUH) that our physical world is an abstract mathematical structure. I discuss various implications of the ERH and MUH, ranging from standard physics topics like symmetries, irreducible representations, units, free parameters, randomness and initial conditions to broader issues like consciousness, parallel universes and Godel incompleteness. I hypothesize that only computable and decidable (in Godel's sense) structures exist, which alleviates the cosmological measure problem and help explain why our physical laws appear so simple. I also comment on the intimate relation between mathematical structures, computations, simulations and physical systems.Comment: Replaced to match accepted Found. Phys. version, 31 pages, 5 figs; more details at http://space.mit.edu/home/tegmark/toe.htm

On the selection of AGN neutrino source candidates for a source stacking analysis with neutrino telescopes

The sensitivity of a search for sources of TeV neutrinos can be improved by grouping potential sources together into generic classes in a procedure that is known as source stacking. In this paper, we define catalogs of Active Galactic Nuclei (AGN) and use them to perform a source stacking analysis. The grouping of AGN into classes is done in two steps: first, AGN classes are defined, then, sources to be stacked are selected assuming that a potential neutrino flux is linearly correlated with the photon luminosity in a certain energy band (radio, IR, optical, keV, GeV, TeV). Lacking any secure detailed knowledge on neutrino production in AGN, this correlation is motivated by hadronic AGN models, as briefly reviewed in this paper. The source stacking search for neutrinos from generic AGN classes is illustrated using the data collected by the AMANDA-II high energy neutrino detector during the year 2000. No significant excess for any of the suggested groups was found.Comment: 43 pages, 12 figures, accepted by Astroparticle Physic

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele