Amyloid Oligomers as Blood Biomarkers in the Diagnosis of Alzheimer’s Disease

Oligomeric forms of the peptide, β-amyloid, (Aβ) are known to be toxic to human and rodent neurones, and have been identified as possible causative agents in the loss of cognitive function in Alzheimer’s Disease (AD). An ELISA assay has been developed capable of detecting oligomeric forms of Aβ in biological fluids, but not detecting monomeric species. The ELISA has been validated with a number of synthetic variant sequences of Aβ and the effects of known inhibitors of Aβ oligomer formation. Significantly raised levels of oligomers were detected in sera samples from AD patients, compared to age-matched control sera

Surface acoustic wave attenuation by a two-dimensional electron gas in a strong magnetic field

The propagation of a surface acoustic wave (SAW) on GaAs/AlGaAs heterostructures is studied in the case where the two-dimensional electron gas (2DEG) is subject to a strong magnetic field and a smooth random potential with correlation length Lambda and amplitude Delta. The electron wave functions are described in a quasiclassical picture using results of percolation theory for two-dimensional systems. In accordance with the experimental situation, Lambda is assumed to be much smaller than the sound wavelength 2*pi/q. This restricts the absorption of surface phonons at a filling factor \bar{\nu} approx 1/2 to electrons occupying extended trajectories of fractal structure. Both piezoelectric and deformation potential interactions of surface acoustic phonons with electrons are considered and the corresponding interaction vertices are derived. These vertices are found to differ from those valid for three-dimensional bulk phonon systems with respect to the phonon wave vector dependence. We derive the appropriate dielectric function varepsilon(omega,q) to describe the effect of screening on the electron-phonon coupling. In the low temperature, high frequency regime T << Delta (omega_q*Lambda /v_D)^{alpha/2/nu}, where omega_q is the SAW frequency and v_D is the electron drift velocity, both the attenuation coefficient Gamma and varepsilon(omega,q) are independent of temperature. The classical percolation indices give alpha/2/nu=3/7. The width of the region where a strong absorption of the SAW occurs is found to be given by the scaling law |Delta \bar{\nu}| approx (omega_q*Lambda/v_D)^{alpha/2/nu}. The dependence of the electron-phonon coupling and the screening due to the 2DEG on the filling factor leads to a double-peak structure for Gamma(\bar{\nu}).Comment: 17 pages, 3 Postscript figures, minor changes mad

Quantum Hall Effect in Three Dimensional Layered Systems

Using a mapping of a layered three-dimensional system with significant inter-layer tunneling onto a spin-Hamiltonian, the phase diagram in the strong magnetic field limit is obtained in the semi-classical approximation. This phase diagram, which exhibit a metallic phase for a finite range of energies and magnetic fields, and the calculated associated critical exponent, $\nu=4/3$, agree excellently with existing numerical calculations. The implication of this work for the quantum Hall effect in three dimensions is discussed.Comment: 4 pages + 4 figure

Leptonic μ \mu - and τ \tau -decays: mass effects, polarization effects and O(α) O(\alpha) radiative corrections

We calculate the radiative corrections to the unpolarized and the four polarized spectrum and rate functions in the leptonic decay of a polarized $\mu$ into a polarized electron. The new feature of our calculation is that we keep the mass of the final state electron finite which is mandatory if one wants to investigate the threshold region of the decay. Analytical results are given for the energy spectrum and the polar angle distribution of the final state electron whose longitudinal and transverse polarization is calculated. We also provide analytical results on the integrated spectrum functions. We analyze the $m_e \to 0$ limit of our general results and investigate the quality of the $m_e \to 0$ approximation. In the $m_e \to 0$ case we discuss in some detail the role of the $O(\alpha)$ anomalous helicity flip contribution of the final electron which survives the $m_e \to 0$ limit. The results presented in this 0203048 also apply to the leptonic decays of polarized $\tau$-leptons for which we provide numerical results.Comment: 39 pages, 11 postscript figures added. Updated version. Four references added. A few text improvements. Final version to appear in Phys.Rev.

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a ‘bi-lineage’ differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony-formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition

FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer

FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.Oncogene advance online publication, 22 December 2014; doi:10.1038/onc.2014.421.published_or_final_versio