Catching NGC4051 in the low state with XMM-Newton

The Narrow Line Seyfert 1 galaxy NGC4051 shows unusual low flux states, lasting several months, when the 2-10 keV X-ray spectrum becomes unusually hard (photon index<1) while the spectrum at lower X-ray energies is dominated by a large soft excess. A Chandra TOO of the low state has shown that the soft excess and hard components are variable and well-correlated. The variability of the hard component rules out an origin in a distant reflector. Here we present results from a recent XMM-Newton TOO of NGC4051 in the low state, which allows a much more detailed examination of the nature of the hard and soft spectral components in the low state. We demonstrate that the spectral shape in the low state is consistent with the extrapolation of the spectral pivoting observed at higher fluxes. The XMM-Newton data also reveals the warm absorbing gas in emission, as the drop in the primary continuum flux unmasks prominent emission lines from a range of ion species.Comment: 4 pages, 4 figures. Proc. of the meeting: "The Restless High-Energy Universe" (Amsterdam, The Netherlands), E.P.J. van den Heuvel, J.J.M. in 't Zand, and R.A.M.J. Wijers Ed

The Blazar Sequence: Validity and Predictions

The "blazar sequence" posits that the most powerful BL Lacertae objects and flat-spectrum radio quasars should have relatively small synchrotron peak frequencies, nu_peak, and that the least powerful such objects should have the highest nu_peak values. This would have strong implications for our understanding of jet formation and physics and the possible detection of powerful, moderately high-redshift TeV blazars. I review the validity of the blazar sequence by using the results of very recent surveys and compare its detailed predictions against observational data. I find that the blazar sequence in its simplest form is ruled out. However, powerful flat-spectrum radio quasars appear not to reach the nu_peak typical of BL Lacs. This could indeed be related to some sort of sequence, although it cannot be excluded that it is instead due to a selection effect.Comment: 9 pages, 4 figures, invited talk at the Workshop "The Multi-messenger approach to high energy gamma-ray sources", Barcelona, Spain, July 4-7, 2006, to appear in the proceeding

Active Galaxies in the UV

In this article we present different aspects of AGN studies demonstrating the importance of the UV spectral range. Most important diagnostic lines for studying the general physical conditions as well as the metalicities in the central broad line region in AGN are emitted in the UV. The UV/FUV continuum in AGN excites not only the emission lines in the immediate surrounding but it is responsible for the ionization of the intergalactic medium in the early stages of the universe. Variability studies of the emission line profiles of AGN in the UV give us information on the structure and kinematics of the immediate surrounding of the central supermassive black hole as well as on its mass itself.Comment: 29 pages, 13 figures, Ap&SS in pres

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

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Post-translational modification of barley 14-3-3A is isoform-specific and involves removal of the hypervariable C-terminus

The 14-3-3 protein family is a family of regulatory proteins involved in diverse cellular processes. In a previous study of regulation of individual 14-3-3 isoforms in the germinating barley embryo, we found that a post-translationally modified, 28 kDa form of 14-3-3A was present in specific cell fractions of the germinated embryo. In the present study, we identify the nature of the modification of 14-3-3A, and show that the 28 kDa doublet is the result of cleavage of the C-terminus. The 28 kDa forms of 14-3-3A lack ten or twelve amino acid residues at the non-conserved C-terminus of the protein, respectively. Barley 14-3-3B and 14-3-3C are not modified in a similar way. Like the 30 kDa form, in vitro produced 28 kDa 14-3-3A is still capable of binding AHA2 H+-ATPase in an overlay assay. Our results show a novel isoform-specific post-translational modification of 14-3-3 proteins that is regulated in a tissue-specific and developmental way