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

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

Low preoperative skeletal muscle density is predictive for negative postoperative outcomes in older women with ovarian cancer

Objective. To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer.Methods. A multicenter, retrospective cohort study was performed in women >= 70 years old receiving surgery for primary, advanced stage ovarian cancer. Skeletal muscle mass and density were assessed in axial CT slices on level L3. Low skeletal muscle mass was defined as skeletal muscle index = 2).Conclusion. Low skeletal muscle density, as a proxy of muscle quality, is associated with poor postoperative outcomes in older patients with advanced stage ovarian cancer. These findings can contribute to postoperative risk assessment and clinical decision making. (C) 2021 The Author(s). Published by Elsevier Inc.Cervix cance

IGAPS: the merged IPHAS and UVEX optical surveys of the Northern Galactic Plane

The INT Galactic Plane Survey (IGAPS) is the merger of the optical photometric surveys, IPHAS and UVEX, based on data from the Isaac Newton Telescope (INT) obtained between 2003 and 2018. Here, we present the IGAPS point source catalogue. It contains 295.4 million rows providing photometry in the filters, i, r, narrow-band Hα, g, and U_(RGO). The IGAPS footprint fills the Galactic coordinate range, |b| 5σ confidence)

IGAPS: the merged IPHAS and UVEX optical surveys of theNorthern Galactic Plane

The INT Galactic Plane Survey (IGAPS) is the merger of the optical photometric surveys, IPHAS and UVEX, based on data from the Isaac Newton Telescope (INT) obtained between 2003 and 2018. Here, we present the IGAPS point source catalogue. It contains 295.4 million rows providing photometry in the filters, i, r, narrow-band Halpha, g and U_RGO. The IGAPS footprint fills the Galactic coordinate range, |b| < 5deg and 30deg < l < 215deg. A uniform calibration, referred to the Pan-STARRS system, is applied to g, r and i, while the Halpha calibration is linked to r and then is reconciled via field overlaps. The astrometry in all 5 bands has been recalculated on the Gaia DR2 frame. Down to i ~ 20 mag (Vega system), most stars are also detected in g, r and Halpha. As exposures in the r band were obtained within the IPHAS and UVEX surveys a few years apart, typically, the catalogue includes two distinct r measures, r_I and r_U. The r 10sigma limiting magnitude is ~21, with median seeing 1.1 arcsec. Between ~13th and ~19th magnitudes in all bands, the photometry is internally reproducible to within 0.02 magnitudes. Stars brighter than r=19.5 have been tested for narrow-band Halpha excess signalling line emission, and for variation exceeding |r_I-r_U| = 0.2 mag. We find and flag 8292 candidate emission line stars and over 53000 variables (both at >5sigma confidence). The 174-column catalogue will be available via CDS Strasbourg.Comment: 28 pages, 22 figure

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies

"Those are your words, not mine!" Defence strategies for denying speaker commitment

Language Use in Past and Presen

Integrated Epigenome Profiling of Repressive Histone Modifications, DNA Methylation and Gene Expression in Normal and Malignant Urothelial Cells

Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction between histone and DNA modifications, and differences between normal and malignant urothelial cells represent carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20–30% of genes and both marks in 5% of genes. H3K9m3 was detected in 5–10% of genes but was not associated with overall expression. DNA methylation was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3 were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples according to the presence and phenotype of bladder cancer