The Galactic black hole transient H1743-322 during outburst decay: connections between timing noise, state transitions and radio emission

Multi-wavelength observations of Galactic black hole transients during outburst decay are instrumental for our understanding of the accretion geometry and the formation of outflows around black hole systems. H1743-322, a black hole transient observed intensely in X-rays and also covered in the radio band during its 2003 decay, provides clues about the changes in accretion geometry during state transitions and also the general properties of X-ray emission during the intermediate and the low-hard states. In this work, we report on the evolution of spectral and temporal properties in X-rays and the flux in the radio band with the goal of understanding the nature of state transitions observed in this source. We concentrate on the transition from the thermal dominant state to the intermediate state that occurs on a timescale of one day. We show that the state transition is associated with a sudden increase in power-law flux. We determine that the ratio of the power-law flux to the overall flux in the 3--25 keV band must exceed 0.6 to observe strong timing noise. Even after the state transition, once this ratio was below 0.6, the system transited back to the thermal dominant state for a day. We show that the emission from the compact radio core does not turn on during the transition from the thermal dominant state to the intermediate state but does turn on when the source reaches the low-hard state, as seen in 4U 1543-47 and GX 339-4. We find that the photon index correlates strongly with the QPO frequency and anti-correlates with the rms amplitude of variability. We also show that the variability is more likely to be associated with the power-law emission than the disk emission.Comment: 23 pages, 5 Figures, 1 Table, accepted for publication in Ap

Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

Suzaku Observations of the Black Hole H1743-322 in Outburst

We observed the Galactic black hole candidate H1743-322 with Suzaku for approximately 32 ksec, while the source was in a low/hard state during its 2008 outburst. We collected and analyzed the data with the HXD/PIN, HXD/GSO and XIS cameras spanning the energy range from 0.7-200 keV. Fits to the spectra with simple models fail to detect narrow Fe XXV and Fe XXVI absorption lines, with 90% confidence upper limits of 3.5 eV and 2.5 eV on the equivalent width, respectively. These limits are commensurate with those in the very high state, but are well below the equivalent widths of lines detected in the high/soft state, suggesting that disk winds are partially state-dependent. We discuss these results in the context of previous detections of ionized Fe absorption lines in H1743-322 and connections to winds and jets in accreting systems. Additionally, we report the possible detection of disk reflection features, including an Fe K emission line.Comment: 16 pages, 4 figures, 4 tables. Accepted for publication in ApJ

High- and low-frequency quasi-periodic oscillations in the X-ray light curves of the black hole transient H1743-322

We present a variability study of the black hole candidate and X-ray transient H1743-322 during its 2003/2004 outburst. We analyzed five Rossi X-ray Timing Explorer observations that were performed as part of a multi-wavelength campaign, as well as six observations from the early rise of the outburst. The source was observed in several black hole states and showed various types of X-ray variability, including high frequency quasi-periodic oscillations (QPOs) at 240 Hz and 160 Hz (i.e. with a 3:2 frequency ratio), several types of low frequency QPOs, and strong variations on a time scale of a few hundred seconds. The discovery of high frequency QPOs in H1743-322 supports predictions that these QPOs should be more easily observed in high inclination systems. In one of our observations we observed a transition in count rate and color, during which we were able to follow the smooth evolution of the low-frequency QPOs from type-B to type-A. We classify the X-ray observations and QPOs, and briefly discuss the QPOs in terms of recently proposed models.Comment: Submitted to Ap

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification (=CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma

Phylogenetic Analysis of the Neks Reveals Early Diversification of Ciliary-Cell Cycle Kinases

NIMA-related kinases (Neks) have been studied in diverse eukaryotes, including the fungus Aspergillus and the ciliate Tetrahymena. In the former, a single Nek plays an essential role in cell cycle regulation; in the latter, which has more than 30 Neks in its genome, multiple Neks regulate ciliary length. Mammalian genomes encode an intermediate number of Neks, several of which are reported to play roles in cell cycle regulation and/or localize to centrosomes. Previously, we reported that organisms with cilia typically have more Neks than organisms without cilia, but were unable to establish the evolutionary history of the gene family

Angelman Syndrome Protein UBE3A Interacts with Primary Microcephaly Protein ASPM, Localizes to Centrosomes and Regulates Chromosome Segregation

Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome

Transcription Factor STOX1A Promotes Mitotic Entry by Binding to the CCNB1 Promotor

Background: In this study we investigated the involvement of the transcription factor STOX1A in the regulation of the cell cycle. Methodology/Principal Findings: We found that several major cell cycle regulatory genes were differentially expressed upon STOX1A stimulation and knockdown in the neuroblastoma cell line SH-SY5Y. This includes STOX1A dependent differential regulation of cyclin B1 expression, a cyclin which is known to regulate mitotic entry during the cell cycle. The differential regulation of cyclin B1 expression by STOX1A is direct as shown with chromatin immunoprecipitation. Results furthermore suggest that mitotic entry is enhanced through the direct upregulation of cyclin B1 expression effectuated b