Differential associations of APOE-epsilon 2 and APOE-epsilon 4 alleles with PET-measured amyloid-beta and tau deposition in older individuals without dementia

Purpose: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. Results: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: − 0.31 [− 0.45, − 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [− 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ. Conclusion: Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology

Synapse-Associated Expression of an Acetylcholine Receptor-Inducing Protein, ARIA/Heregulin, and Its Putative Receptors, ErbB2 and ErbB3, in Developing Mammalian Muscle

AbstractDeveloping motor axons induce synaptic specializations in muscle fibers, including preferential transcription of acetylcholine receptor (AChR) subunit genes by subsynaptic nuclei. One candidate nerve-derived signaling molecule is AChR-inducing activity (ARIA)/heregulin, a ligand of the erbB family of receptor tyrosine kinases. Here, we asked whether ARIA and erbB kinases are expressed in patterns compatible with their proposed signaling roles. In developing muscle, ARIA was present not only at synaptic sites, but also in extrasynaptic regions of the muscle fiber. ARIA was synthesized, rather than merely taken up, by muscle cells, as indicated by the presence of ARIA mRNA in muscle and of ARIA protein in a clonal muscle cell line. ARIA-responsive myotubes expressed both erbB2 and erbB3, but little EGFR/erbB1 or erbB4. In adults, erbB2 and erbB3 were localized to the postsynaptic membrane. ErbB3 was restricted to the postsynaptic membrane perinatally, at a time when ARIA was still broadly distributed. Thus, our data are consistent with a model in which ARIA interacts with erbB kinases on the muscle cell surface to provide a local signal that induces synaptic expression of AChR genes. However, much of the ARIA is produced by muscle, not nerve, and the spatially restricted response may result from the localization of erbB kinases as well as of ARIA. Finally, we show that erbB3 is not concentrated at synaptic sites in mutant mice that lack rapsyn, a cytoskeletal protein required for AChR clustering, suggesting that pathways for synaptic AChR expression and clustering interact

EROS Variable Stars : Discovery of Beat Cepheids in the Small Magellanic Cloud and the effect of metallicity on pulsation

We report the discovery of eleven beat Cepheids in the Small Magellanic Cloud, using data obtained by the EROS microlensing survey. Four stars are beating in the fundamental and first overtone mode (F/1OT), seven are beating in the first and second overtone (1OT/2OT). The SMC F/1OT ratio is systematically higher than the LMC F/1OT, while the 1OT/2OT period ratio in the SMC Cepheids is the same as the LMC one.Comment: 4 pages, Latex file with 4 .ps figures. accepted for publication in A A Letter

The effect of metallicity on the Cepheid distance scale and its implications for the Hubble constant (H0H_0) determination

Recent HST determinations of the expansion's rate of the Universe (the Hubble constant, H_0) assumed that the Cepheid Period-Luminosity relation at V and I are independent of metallicity (Freedman, et al., 1996, Saha et al., 1996, Tanvir et al., 1995). The three groups obtain different vales for H_0. We note that most of this discrepancy stems from the asumption (by both groups) that the Period-Luminosity relation is independent of metallicity. We come to this conclusion as a result of our study of the Period-Luminosity relation of 481 Cepheids with 3 millions two colour measurements in the Large Magellanic Cloud and the Small Magellanic Cloud obtained as a by-product of the EROS microlensing survey. We find that the derived interstellar absorption corrections are particularly sensitive to the metallicity and when our result is applied to recent estimates based on HST Cepheids observations it makes the low-H_0 values higher and the high-H_0 value lower, bringing those discrepant estimates into agrement around $H_0 \approx 70 km/s Mpc^{-1}$.Comment: 4 pages, Latex, with 2 .ps accepted for publication astronomy and astrophysics Letter

Observational Limits on Machos in the Galactic Halo

We present final results from the first phase of the EROS search for gravitational microlensing of stars in the Magellanic Clouds by unseen deflectors (machos: MAssive Compact Halo Objects). The search is sensitive to events with time scales between 15 minutes and 200 days corresponding to deflector masses in the range 1.e-7 to a few solar masses. Two events were observed that are compatible with microlensing by objects of mass of about 0.1 Mo. By comparing the results with the expected number of events for various models of the Galaxy, we conclude that machos in the mass range [1.e-7, 0.02] Mo make up less than 20% (95% C.L.) of the Halo dark matter.Comment: 4 pages, 3 Postscript figures, to be published in Astronomy & Astrophysic

Electrically tunable GHz oscillations in doped GaAs-AlAs superlattices

Tunable oscillatory modes of electric-field domains in doped semiconductor superlattices are reported. The experimental investigations demonstrate the realization of tunable, GHz frequencies in GaAs-AlAs superlattices covering the temperature region from 5 to 300 K. The orgin of the tunable oscillatory modes is determined using an analytical and a numerical modeling of the dynamics of domain formation. Three different oscillatory modes are found. Their presence depends on the actual shape of the drift velocity curve, the doping density, the boundary condition, and the length of the superlattice. For most bias regions, the self-sustained oscillations are due to the formation, motion, and recycling of the domain boundary inside the superlattice. For some biases, the strengths of the low and high field domain change periodically in time with the domain boundary being pinned within a few quantum wells. The dependency of the frequency on the coupling leads to the prediction of a new type of tunable GHz oscillator based on semiconductor superlattices.Comment: Tex file (20 pages) and 16 postscript figure

Temperature dependence of current self-oscillations and electric field domains in sequential tunneling doped superlattices

We examine how the current--voltage characteristics of a doped weakly coupled superlattice depends on temperature. The drift velocity of a discrete drift model of sequential tunneling in a doped GaAs/AlAs superlattice is calculated as a function of temperature. Numerical simulations and theoretical arguments show that increasing temperature favors the appearance of current self-oscillations at the expense of static electric field domain formation. Our findings agree with available experimental evidence.Comment: 7 pages, 5 figure

Nasopharyngeal Colonization and Invasive Disease Are Enhanced by the Cell Wall Hydrolases LytB and LytC of Streptococcus pneumoniae

Background: Streptococcus pneumoniae is a common colonizer of the human nasopharynx and one of the major pathogens causing invasive disease worldwide. Dissection of the molecular pathways responsible for colonization, invasion, and evasion of the immune system will provide new targets for antimicrobial or vaccine therapies for this common pathogen. Methodology/Principal Findings: We have constructed mutants lacking the pneumococcal cell wall hydrolases (CWHs) LytB and LytC to investigate the role of these proteins in different phases of the pneumococcal pathogenesis. Our results show that LytB and LytC are involved in the attachment of S. pneumoniae to human nasopharyngeal cells both in vitro and in vivo. The interaction of both proteins with phagocytic cells demonstrated that LytB and LytC act in concert avoiding pneumococcal phagocytosis mediated by neutrophils and alveolar macrophages. Furthermore, C3b deposition was increased on the lytC mutant confirming that LytC is involved in complement evasion. As a result, the lytC mutant showed a reduced ability to successfully cause pneumococcal pneumonia and sepsis. Bacterial mutants lacking both LytB and LytC showed a dramatically impaired attachment to nasopharyngeal cells as well as a marked degree of attenuation in a mouse model of colonization. In addition, C3b deposition and phagocytosis was more efficient for the double lytB lytC mutant and its virulence was greatly impaired in both systemic and pulmonary models of infection. Conclusions/Significance: This study confirms that the CWHs LytB and LytC of S. pneumoniae are essential virulence factor

Brugada syndrome is associated with scar and endocardial involvement: Insights from high-density mapping with the Rhythmia™ mapping system

The authors report the first catheter ablation of Brugada syndrome in the literature using the Rhythmia™ mapping system. Learning points include: (1) low voltage areas can be documented while mapping in some individuals, suggesting that Brugada syndrome may not be a pure ion channel disorder; (2) typical long fractionated potentials can also be identified in the endocardium, supporting the need to map the endocardium in all Brugada patients requiring ablation; (3) disappearance of the typical coved pattern following ablation does not necessarily predict cure, as the patient we present experienced ventricular fibrillation recurrence a few months later

Assessment of Arthrobacter viscosus as reactive medium for forming permeable reactive biobarrier applied to PAHs remediation

Polycyclic aromatic hydrocarbons (PAHs) are significant environmental contaminants as they are present naturally as well as anthropogenically in soil, air and water. In spite of their low solubility, PAHs are spread to the environment, and they are present in surface water, industrial effluent or groundwater. Amongst all remediation technologies for treating groundwater contaminated with PAHs, the use of a permeable reactive biobarrier (PRBB) appears to be the most cost-effective, energy efficient, and environmentally sound approach. In this technology, the microorganisms are used as reactive medium to degrade or stabilize the contaminants. The main limits of this approach are that the microorganisms or consortium used for forming the PRBB should show adequate characteristics. They must be retained in the barrier-forming biofilm, and they should also have degradative ability for the target pollutants. The aim of the present work is to evaluate the viability of Arthrobacter viscosus as bioreactive medium for forming PRBB. Initially, the ability of A. viscosus to remove PAHs, benzo[a]anthracene 100 μM and phenanthrene 100 μM was evaluated operating in a batch bench-scale bioreactor. In both cases, total benzo[a]anthracene and phenanthrene removals were obtained after 7 and 3 days, respectively. Furthermore, the viability of the microorganisms was evaluated in the presence of chromium in a continuous mode. As a final point, the adhesion of A. viscosus to sepiolite forming a bioreactive material to build PRBB was demonstrated. In view of the attained results, it can be concluded that A. viscosus could be a suitable microorganism to form a bioreactive medium for PAHs remediation.This work has been supported by the Spanish Ministry of Economy and Competitiveness and FEDER Funds (Project CTM 2011-25389). Marta Pazos received financial support under the Ramon y Cajal programme and Marta Cobas under the final project master grant "Campus do Mar Knowledge in depth"