Quantification of ferritin-bound iron in murine samples for Alzheimer's disease studies using species-specific isotope dilution mass spectrometry

Acknowledgments The project ReMiND 15HLT02 has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme. The authors gratefully thank Christoph Baumgartinger for his support with sample preparation as well as one independent referee for highly constructive comments.Peer reviewedPublisher PD

Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia

Investigation of the activity of a family of fusion proteins that cause aggressive leukemia suggests transcriptional elongation as a new mechanism for oncogenic transformation

Periapsis and gravitomagnetic precessions of stellar orbits in Kerr and Kerr-de Sitter black hole spacetimes

The exact solution for the motion of a test particle in a non-spherical polar orbit around a Kerr black hole is derived. Exact novel expressions for frame dragging (Lense-Thirring effect), periapsis advance and the orbital period are produced. The resulting formulae, are expressed in terms of Appell's first hypergeometric function $F_1$, Jacobi's amplitude function, and Appell's $F_1$ and Gau\ss hypergeometric function respectively. The exact expression for frame dragging is applied for the calculation of the Lense-Thirring effect for the orbits of S-stars in the central arcsecond of our Galaxy assuming that the galactic centre is a Kerr black hole, for various values of the Kerr parameter including those supported by recent observations. In addition, we apply our solutions for the calculation of frame dragging and periapsis advance for stellar non-spherical polar orbits in regions of strong gravitational field close to the event horizon of the galactic black hole, e.g. for orbits in the central milliarcsecond of our galaxy. Such orbits are the target of the GRAVITY experiment. We provide examples with orbital periods in the range of 100min - 54 days. Detection of such stellar orbits will allow the possibility of measuring the relativistic effect of periapsis advance with high precision at the strong field realm of general relativity. Further, an exact expression for the orbital period of a test particle in a non-circular equatorial motion around a Kerr black hole is produced. We also derive exact expressions for the periapsis advance and the orbital period for a test particle in a non-circular equatorial motion in the Kerr field in the presence of the cosmological constant in terms of Lauricella's fourth hypergeometric function $F_D$.Comment: LaTeX file, 46 pages, typos fixed, substantial changes, version published in Classical and Quantum Gravity, Vol 24 (2007) 1775-180

Intrinsic Structural Disorder Confers Cellular Viability on Oncogenic Fusion Proteins

Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations

New Insights into the Control of HIV-1 Transcription: When Tat Meets the 7SK snRNP and Super Elongation Complex (SEC)

Recent studies aimed at elucidating the mechanism controlling HIV-1 transcription have led to the identification and characterization of two multi-subunit complexes that both contain P-TEFb, a human transcription elongation factor and co-factor for activation of HIV-1 gene expression by the viral Tat protein. The first complex, termed the 7SK snRNP, acts as a reservoir where active P-TEFb can be withdrawn by Tat to stimulate HIV-1 transcription. The second complex, termed the super elongation complex (SEC), represents the form of P-TEFb delivered by Tat to the paused RNA polymerase II at the viral long terminal repeat during Tat transactivation. Besides P-TEFb, SEC also contains other elongation factors/co-activators, and they cooperatively stimulate HIV-1 transcription. Recent data also indicate SEC as a target for the mixed lineage leukemia (MLL) protein to promote the expression of MLL target genes and leukemogenesis. Given their roles in HIV-1/AIDS and cancer, further characterization of 7SK snRNP and SEC will help develop strategies to suppress aberrant transcriptional elongation caused by uncontrolled P-TEFb activation. As both complexes are also important for normal cellular gene expression, studying their structures and functions will elucidate the mechanisms that control metazoan transcriptional elongation in general

Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML

Polish children in Norway : between national discourses of belonging and everyday experiences of life abroad

This chapter examines dimensions of self-identification among Polish migrant children in Norway. The arguments are situated within childhood studies and take into account the novel framings of children in mobility/migration scholarship, as well as articularities of Polish context Stemming from the TRANSFAM research project (2013-2016), this work “gives children a voice” through a qualitative research methodology. The study illuminates those national, transnational and global elements that are paramount for daily life family practices and featured in children’s narratives. The paper focuses on the importance of socializing agents (family, peer groups, culture) for the constructions of belonging. It concludes with arguments for acknowledging the contemporary hybrid and relational identities of children who grow up transnationally between Norway and Poland