Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Iron oxidation at low temperature (260–500 C) in air and the effect of water vapor

The oxidation of iron has been studied at low temperatures (between 260 and 500 C) in dry air or air with 2 vol% H2O, in the framework of research on dry corrosion of nuclear waste containers during long-term interim storage. Pure iron is regarded as a model material for low-alloyed steel. Oxidation tests were performed in a thermobalance (up to 250 h) or in a laboratory furnace (up to 1000 h). The oxide scales formed were characterized using SEM-EDX, TEM, XRD, SIMS and EBSD techniques. The parabolic rate constants deduced from microbalance experiments were found to be in good agreement with the few existing values of the literature. The presence of water vapor in air was found to strongly influence the transitory stages of the kinetics. The entire structure of the oxide scale was composed of an internal duplex magnetite scale made of columnar grains and an external hematite scale made of equiaxed grains. 18O tracer experiments performed at 400 C allowed to propose a growth mechanism of the scale

The Cosmic Infrared Background: Measurements and Implications

The cosmic infrared background records much of the radiant energy released by processes of structure formation that have occurred since the decoupling of matter and radiation following the Big Bang. In the past few years, data from the Cosmic Background Explorer mission provided the first measurements of this background, with additional constraints coming from studies of the attenuation of TeV gamma-rays. At the same time there has been rapid progress in resolving a significant fraction of this background with the deep galaxy counts at infrared wavelengths from the Infrared Space Observatory instruments and at submillimeter wavelengths from the Submillimeter Common User Bolometer Array instrument. This article reviews the measurements of the infrared background and sources contributing to it, and discusses the implications for past and present cosmic processes.Comment: 61 pages, incl. 9 figures, to be published in Annual Reviews of Astronomy and Astrophysics, 2001, Vol. 3

Secular evolution versus hierarchical merging: galaxy evolution along the Hubble sequence, in the field and rich environments

In the current galaxy formation scenarios, two physical phenomena are invoked to build disk galaxies: hierarchical mergers and more quiescent external gas accretion, coming from intergalactic filaments. Although both are thought to play a role, their relative importance is not known precisely. Here we consider the constraints on these scenarios brought by the observation-deduced star formation history on the one hand, and observed dynamics of galaxies on the other hand: the high frequency of bars and spirals, the high frequency of perturbations such as lopsidedness, warps, or polar rings. All these observations are not easily reproduced in simulations without important gas accretion. N-body simulations taking into account the mass exchange between stars and gas through star formation and feedback, can reproduce the data, only if galaxies double their mass in about 10 Gyr through gas accretion. Warped and polar ring systems are good tracers of this accretion, which occurs from cold gas which has not been virialised in the system's potential. The relative importance of these phenomena are compared between the field and rich clusters. The respective role of mergers and gas accretion vary considerably with environment.Comment: 18 pages, 8 figures, review paper to "Penetrating Bars through Masks of Cosmic Dust: the Hubble Tuning Fork Strikes a New Note", Pilanesberg, ed. D. Block et al., Kluwe

QTL/microarray approach using pathway information

<p>Abstract</p> <p>Background</p> <p>A combined quantitative trait loci (QTL) and microarray-based approach is commonly used to find differentially expressed genes which are then identified based on the known function of a gene in the biological process governing the trait of interest. However, a low cutoff value in individual gene analyses may result in many genes with moderate but meaningful changes in expression being missed.</p> <p>Results</p> <p>We modified a gene set analysis to identify intersection sets with significantly affected expression for which the changes in the individual gene sets are less significant. The gene expression profiles in liver tissues of four strains of mice from publicly available microarray sources were analyzed to detect trait-associated pathways using information on the QTL regions of blood concentrations of high density lipoproteins (HDL) cholesterol and insulin-like growth factor 1 (IGF-1). Several metabolic pathways related to HDL levels, including lipid metabolism, ABC transporters and cytochrome P450 pathways were detected for HDL QTL regions. Most of the pathways identified for the IGF-1 phenotype were signal transduction pathways associated with biological processes for IGF-1's regulation.</p> <p>Conclusion</p> <p>We have developed a method of identifying pathways associated with a quantitative trait using information on QTL. Our approach provides insights into genotype-phenotype relations at the level of biological pathways which may help to elucidate the genetic architecture underlying variation in phenotypic traits.</p

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Regulation of Anthrax Toxin-Specific Antibody Titers by Natural Killer T Cell-Derived IL-4 and IFNγ

Activation of Natural Killer-like T cells (NKT) with the CD1d ligand α-GC leads to enhanced production of anthrax toxin protective Ag (PA)-neutralizing Abs, yet the underlying mechanism for this adjuvant effect is not known. In the current study we examined the role of Th1 and Th2 type responses in NKT-mediated enhancement of antibody responses to PA. First, the contribution of IL-4 and IFNγ to the production of PA-specific toxin-neutralizing Abs was examined. By immunizing C57Bl/6 controls IL-4−/− mice and IFNγ−/− mice and performing passive serum transfer experiments, it was observed that sera containing PA-specific IgG1, IgG2b and IgG2c neutralized toxin in vitro and conferred protection in vivo. Sera containing IgG2b and IgG2c neutralized toxin in vitro but were not sufficient for protection in vivo. Sera containing IgG1 and IgG2b neutralized toxin in vitro and conferred protection in vivo. IgG1 therefore emerged as a good correlate of protection. Next, C57Bl/6 mice were immunized with PA alone or PA plus a Th2-skewing α-GC derivative known as OCH. Neutralizing PA-specific IgG1 responses were modestly enhanced by OCH in C57Bl/6 mice. Conversely, IgG2b and IgG2c were considerably enhanced in PA/OCH-immunized IL-4−/− mice but did not confer protection. Finally, bone marrow chimeras were generated such that NKT cells were unable to express IL-4 or IFNγ. NKT-derived IL-4 was required for OCH-enhanced primary IgG1 responses but not recall responses. NKT-derived IL-4 and IFNγ also influenced primary and recall IgG2b and IgG2c titers. These data suggest targeted skewing of the Th2 response by α-GC derivatives can be exploited to optimize anthrax vaccination

Single-molecule sensing electrode embedded in-plane nanopore

Electrode-embedded nanopore is considered as a promising device structure for label-free single-molecule sequencing, the principle of which is based on nucleotide identification via transverse electron tunnelling current flowing through a DNA translocating through the pore. Yet, fabrication of a molecular-scale electrode-nanopore detector has been a formidable task that requires atomic-level alignment of a few nanometer sized pore and an electrode gap. Here, we report single-molecule detection using a nucleotide-sized sensing electrode embedded in-plane nanopore. We developed a self-alignment technique to form a nanopore-nanoelectrode solid-state device consisting of a sub-nanometer scale electrode gap in a 15 nm-sized SiO2 pore. We demonstrate single-molecule counting of nucleotide-sized metal-encapsulated fullerenes in a liquid using the electrode-integrated nanopore sensor. We also performed electrical identification of nucleobases in a DNA oligomer, thereby suggesting the potential use of this synthetic electrode-in-nanopore as a platform for electrical DNA sequencing