Ultra-compact binaries: relevance and role of Utrecht

We present a short overview of the formation and evolution of ultra-compact binaries. They are relevant to a surprisingly large number of astrophysical phenomena (binary interactions, mass transfer stability, explosive phenomena such as type Ia supernovae and gravitational waves).Comment: To appear in proceedings of "370 years of astronomy in Utrecht", Noordwijkerhout, The Netherlands, April 2-5, 2012 (ASP Conference Series

Population synthesis of classical low-mass X-ray binaries in the Galactic Bulge

Aims. We model the present-day population of 'classical' low-mass X-ray binaries (LMXBs) with neutron star accretors, which have hydrogen-rich donor stars. Their population is compared with that of hydrogen-deficient LMXBs, known as ultracompact X-ray binaries (UCXBs). We model the observable LMXB population and compare it to observations. Methods. We combine the binary population synthesis code SeBa with detailed LMXB evolutionary tracks to model the size and properties of the present-day LMXB population in the Galactic Bulge. Whether sources are persistent or transient, and what their instantaneous X-ray luminosities are, is predicted using the thermal-viscous disk instability model. Results. We find a population of ~2.1 x 10^3 LMXBs with neutron star accretors. Of these about 15 - 40 are expected to be persistent (depending on model assumptions), with luminosities higher than 10^35 erg s^-1. About 7 - 20 transient sources are expected to be in outburst at any given time. Within a factor of two these numbers are consistent with the observed population of bright LMXBs in the Bulge. This gives credence to our prediction of the existence of a population of ~1.6 x 10^3 LMXBs with low donor masses that have gone through the period minimum, and have present-day mass transfer rates below 10^-11 Msun yr^-1. Conclusions. Even though the observed population of hydrogen-rich LMXBs in the Bulge is larger than the observed population of (hydrogen-deficient) UCXBs, the latter have a higher formation rate. While UCXBs may dominate the total LMXB population at the present, the majority would be very faint, or may have become detached and produced millisecond radio pulsars. In that case UCXBs would contribute significantly more to the formation of millisecond radio pulsars than hydrogen-rich LMXBs. [abridged]Comment: 8 pages, 10 figures. Accepted for publication in Astronomy and Astrophysics. v2: minor language correction

Formation of the planet around the millisecond pulsar J1719-1438

Context. Recently the discovery of PSR J1719-1438, a 5.8 ms pulsar with a companion in a 2.2 hr orbit, was reported. The combination of this orbital period and the very low mass function is unique. The discoverers, Bailes et al., proposed an ultracompact X-ray binary (UCXB) as the progenitor system. However, the standard UCXB scenario would not produce this system as the time required to reach this orbital period exceeds the current estimate of the age of the Universe. The detached state of the system aggravates the problem. Aims. We want to understand the evolutionary history of PSR J1719-1438, and determine under which circumstances it could have evolved from an UCXB. Methods. We model UCXB evolution varying the donor size and investigate the effect of a wind mass loss from the donor, and compare the results with the observed characteristics of PSR J1719-1438. Results. An UCXB can reach a 2.2 hr orbit within the age of the Universe, provided that 1) the millisecond pulsar can significantly heat and expand the donor by pulsar irradiation, or 2) the system loses extra orbital angular momentum, e.g. via a fast wind from the donor. Conclusions. The most likely scenario for the formation of PSR J1719-1438 is UCXB evolution driven by angular momentum loss via the usual gravitational wave emission, which is enhanced by angular momentum loss via a donor wind of ~3x10^-13 Msun/yr. Depending on the size of the donor during the evolution, the companion presently probably has a mass of ~1-3 Jupiter masses, making it a very low mass white dwarf as proposed by Bailes et al. Its composition can be either helium or carbon-oxygen. A helium white dwarf companion makes the long (for an UCXB) orbital period easier to explain, but the required inclination makes it a priori less likely than a carbon-oxygen white dwarf.Comment: 5 pages, 4 figures. Accepted for publication in Astronomy and Astrophysics. v2: Updated a referenc

Time-resolved X-Shooter spectra and RXTE light curves of the ultra-compact X-ray binary candidate 4U 0614+091

In this paper we present X-Shooter time resolved spectroscopy and RXTE PCA light curves of the ultra-compact X-ray binary candidate 4U 0614+091. The X-Shooter data are compared to the GMOS data analyzed previously by Nelemans et al. (2004). We confirm the presence of C III and O II emission features at ~ 4650 {\AA} and ~ 5000 {\AA}. The emission lines do not show evident Doppler shifts that could be attributed to the motion of the donor star/hot spot around the center of mass of the binary. We note a weak periodic signal in the red-wing/blue-wing flux ratio of the emission feature at ~ 4650 {\AA}. The signal occurs at P = 30.23 +/- 0.03 min in the X-Shooter and at P = 30.468 +/- 0.006 min in the GMOS spectra when the source was in the low/hard state. Due to aliasing effects the period in the GMOS and X-Shooter data could well be the same. We deem it likely that the orbital period is thus close to 30 min, however, as several photometric periods have been reported for this source in the literature already, further confirmation of the 30 min period is warranted. We compare the surface area of the donor star and the disc of 4U 0614+091 with the surface area of the donor star and the disc in typical hydrogen-rich low-mass X-ray binaries and the class of AM Canum Venaticorum stars and argue that the optical emission in 4U 0614+091 is likely dominated by the disc emission. Additionally, we search for periodic signals in all the publicly available RXTE PCA light curves of 4U 0614+091 which could be associated with the orbital period of this source. A modulation at the orbital period with an amplitude of ~ 10% such as those that have been found in other ultra-compact X-ray binaries (4U 0513-40, 4U 1820-30) is not present in 4U 0614+091.Comment: Accepted for publication in MNRAS, 11 pages, 7 figure

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

The complex disorder Cantu syndrome (CS) arises from gainof-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb-) efflux assays and patchclamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-Associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS

Potent cytotoxic effects of Calomeria amaranthoides on ovarian cancers

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer remains the leading cause of death from gynaecological malignancy. More than 60% of the patients are presenting the disease in stage III or IV. In spite of combination of chemotherapy and surgery the prognosis stays poor for therapy regimen.</p> <p>Methods</p> <p>The leaves of a plant endemic to Australia, <it>Calomeria amaranthoides</it>, were extracted and then fractionated by column chromatography. <it>In vitro </it>cytotoxicity tests were performed with fractions of the plant extract and later with an isolated compound on ovarian cancer cell lines, as well as normal fibroblasts at concentrations of 1-100 μg/mL (crude extract) and 1-10 μg/mL (compound). Cytotoxicity was measured after 24, 48 and 72 hours by using a non-fluorescent substrate, Alamar blue.</p> <p><it>In vivo </it>cytotoxicity was tested on ascites, developed in the abdomen of nude mice after inoculation with human OVCAR₃cells intraperitoneally. The rate of change in abdomen size for the mice was determined by linear regression and statistically evaluated for significance by the unpaired t test.</p> <p>Results</p> <p>Two compounds were isolated by chromatographic fractionation and identified by ¹H-NMR, ¹³C-NMR and mass spectrometry analyses, EPD, an α-methylene sesquiterpene lactone of the eremophilanolide subtype, and EPA, an α-methylene carboxylic acid.</p> <p>Cytotoxicity of EPD for normal fibroblasts at all time points IC₅₀was greater than 10 μg/mL, whereas, for OVCAR₃cells at 48 hours IC₅₀was 5.3 μg/mL (95% confidence interval 4.3 to 6.5 μg/mL).</p> <p>Both, the crude plant extract as well as EPD killed the cancer cells at a final concentration of 10 μg/mL and 5 μg/mL respectively, while in normal cells only 20% cell killing effect was observed. EPA had no cytotoxic effects.</p> <p>Changes in abdomen size for control versus Cisplatin treated mice were significantly different, P = 0.023, as were control versus EPD treated mice, P = 0.025, whereas, EPD versus Cisplatin treated mice were not significantly different, P = 0.13.</p> <p>Conclusions</p> <p>For the first time both crude plant extract from <it>Calomeria amaranthoides </it>and EPD have been shown to have potent anti-cancer effects against ovarian cancer.</p

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with >20 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel–Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding

Partner-independent fusion gene detection by multiplexed CRISPR/Cas9 enrichment and long-read Nanopore sequencing

Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment possibilities. The promiscuity of fusion genes with respect to partner choice and exact breakpoint-positions restricts their detection in the diagnostic setting, even for known and recurrent fusion gene configurations. To accurately identify these gene fusions in an unbiased manner, we developed FUDGE: a FUsion gene Detection assay from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for enrichment and detection of fusion gene drivers (e.g. BRAF, EWSR1, KMT2A/MLL) - without prior knowledge of fusion partner or breakpoint-location - to long-read Nanopore sequencing. FUDGE encompasses a dedicated bioinformatics approach (NanoFG) to detect fusion genes from Nanopore sequencing data. Our strategy is flexible with respect to target choice and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in a single sequencing run. We observe on average a 508 fold on-target enrichment and identify fusion breakpoints at nucleotide resolution - all within two days. We demonstrate that FUDGE effectively identifies fusion genes in cancer cell lines, tumor samples and on whole genome amplified DNA irrespective of partner gene or breakpoint-position in 100% of cases. Furthermore, we show that FUDGE is superior to routine diagnostic methods for fusion gene detection. In summary, we have developed a rapid and versatile fusion gene detection assay, providing an unparalleled opportunity for pan-cancer detection of fusion genes in routine diagnostics

PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression

Background: The inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC50 = 14 nM with inside-out patch clamp methodology) and specific IK1 inhibitor that interacts with the cytoplasmic pore region of the KIR2.1 ion channel, encoded by KCNJ2. At 10 μM, PA-6 increases wild-type (WT) KIR2. 1 expression in HEK293T cells upon chronic treatment. We hypothesized that PA-6 will interact with and inhibit V93I and D172N KIR2.1 channels, whereas impact on channel expression at the plasma membrane requires higher concentrations. Methods: Molecular modelling was performed with the human KIR2.1 closed state homology model using FlexX. WT and mutant KIR2.1 channels were expressed in HEK293 cells. Patch clamp single cell electrophysiology measurements were performed in the whole cell and inside-out mode of the patch clamp method. KIR2.1 expression level and localization were determined by western blot analysis and immunofluorescence microscopy, respectively. Results: PA-6 docking in the V93I/D172N double mutant homology model of KIR2.1 demonstrated that mutations and drug-binding site are >30 Å apart. PA-6 inhibited WT and V93I outward currents with similar potency (IC50 = 35.5 and 43.6 nM at +50 mV for WT and V93I), whereas D172N currents were less sensitive (IC50 = 128.9 nM at +50 mV) using inside-out patch-clamp electrophysiology. In whole cell mode, 1 μM of PA-6 inhibited outward IK1 at −50 mV by 28 ± 36%, 18 ± 20% and 10 ± 6%, for WT, V93I and D172N channels respectively. Western blot analysis demonstrated that PA-6 (5 μM, 24 h) increased KIR2.1 expression levels of WT (6.3 ± 1.5 fold), and V93I (3.9 ± 0.9) and D172N (4.8 ± 2.0) mutants. Immunofluorescent microscopy demonstrated dose-dependent intracellular KIR2.1 accumulation following chronic PA-6 application (24 h, 1 and 5 μM). Conclusions: 1) KCNJ2 gain-of-function mutations V93I and D172N in the KIR2.1 ion channel do not impair PA-6 mediated inhibition of IK1, 2) PA-6 elevates KIR2.1 protein expression and induces intracellular KIR2.1 accumulation, 3) PA-6 is a strong candidate for further preclinical evaluation in treatment of congenital SQT3 and AF