Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow—and hopefully one day stop—the progression of AD, which is a devastating dementing disorder

The genome of Aeromonas salmonicida subsp. salmonicida A449: insights into the evolution of a fish pathogen

Background Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that is the causative agent of furunculosis, a bacterial septicaemia of salmonid fish. While other species of Aeromonas are opportunistic pathogens or are found in commensal or symbiotic relationships with animal hosts, A. salmonicida subsp. salmonicida causes disease in healthy fish. The genome sequence of A. salmonicida was determined to provide a better understanding of the virulence factors used by this pathogen to infect fish. Results The nucleotide sequences of the A. salmonicida subsp. salmonicida A449 chromosome and two large plasmids are characterized. The chromosome is 4,702,402 bp and encodes 4388 genes, while the two large plasmids are 166,749 and 155,098 bp with 178 and 164 genes, respectively. Notable features are a large inversion in the chromosome and, in one of the large plasmids, the presence of a Tn21 composite transposon containing mercury resistance genes and an In2 integron encoding genes for resistance to streptomycin/spectinomycin, quaternary ammonia compounds, sulphonamides and chloramphenicol. A large number of genes encoding potential virulence factors were identified; however, many appear to be pseudogenes since they contain insertion sequences, frameshifts or in-frame stop codons. A total of 170 pseudogenes and 88 insertion sequences (of ten different types) are found in the A. salmonicida genome. Comparison with the A. hydrophila ATCC 7966T genome reveals multiple large inversions in the chromosome as well as an approximately 9% difference in gene content indicating instances of single gene or operon loss or gain. A limited number of the pseudogenes found in A. salmonicida A449 were investigated in other Aeromonas strains and species. While nearly all the pseudogenes tested are present in A. salmonicida subsp. salmonicida strains, only about 25% were found in other A. salmonicida subspecies and none were detected in other Aeromonas species. Conclusion Relative to the A. hydrophila ATCC 7966T genome, the A. salmonicida subsp. salmonicida genome has acquired multiple mobile genetic elements, undergone substantial rearrangement and developed a significant number of pseudogenes. These changes appear to be a consequence of adaptation to a specific host, salmonid fish, and provide insights into the mechanisms used by the bacterium for infection and avoidance of host defence systems.Peer reviewed: YesNRC publication: Ye

2014 Military Family Lifestyle Survey: Comprehensive Report

This report summarizes the results and analysis of the fifth annual Blue Star Families Military Family Lifestyle Survey. It covers military lifestyle, civilian intersections, transitioning and veteran employment, financial readiness, and military family members\u27 about and benefits

Aβ-40 Y10F Increases βfibrils Formation but Attenuates the Neurotoxicity of Amyloid-β Peptide

Alzheimer’s disease (AD) is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation

Many body physics from a quantum information perspective

The quantum information approach to many body physics has been very successful in giving new insight and novel numerical methods. In these lecture notes we take a vertical view of the subject, starting from general concepts and at each step delving into applications or consequences of a particular topic. We first review some general quantum information concepts like entanglement and entanglement measures, which leads us to entanglement area laws. We then continue with one of the most famous examples of area-law abiding states: matrix product states, and tensor product states in general. Of these, we choose one example (classical superposition states) to introduce recent developments on a novel quantum many body approach: quantum kinetic Ising models. We conclude with a brief outlook of the field.Comment: Lectures from the Les Houches School on "Modern theories of correlated electron systems". Improved version new references adde

Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD

Resource distributions affect social learning on multiple timescales

We study how learning is shaped by foraging opportunities and self-organizing processes and how this impacts on the effects of “copying what neighbors eat” on multiple timescales. We use an individual-based model with a rich environment, where group foragers learn what to eat. We vary foraging opportunities by changing local variation in resources, studying copying in environments with pure patches, varied patches, and uniform distributed resources. We find that copying can help individuals explore the environment by sharing information, but this depends on how foraging opportunities shape the learning process. Copying has the greatest impact in varied patches, where local resource variation makes learning difficult, but local resource abundance makes copying easy. In contrast, copying is redundant or excessive in pure patches where learning is easy, and mostly ineffective in uniform environments where learning is difficult. Our results reveal that the mediation of copying behavior by individual experience is crucial for the impact of copying. Moreover, we find that the dynamics of social learning at short timescales shapes cultural phenomena. In fact, the integration of learning on short and long timescales generates cumulative cultural improvement in diet. Our results therefore provide insight into how and when such processes can arise. These insights need to be taken into account when considering behavioral patterns in nature

Dual Effect of Beta-Amyloid on α7 and α4β2 Nicotinic Receptors Controlling the Release of Glutamate, Aspartate and GABA in Rat Hippocampus

BACKGROUND: We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. METHODOLOGY/FINDINGS: WE USED A DUAL APPROACH: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. CONCLUSIONS/SIGNIFICANCE: The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used