There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has ...the potential to be not only prognostic but also to predict benefit from particular interventions.
An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks.
A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers.
Combined knowledge of multiple genes' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application.
We report on deep, coordinated radio and X-ray observations of the black hole X-ray binary XTE J1118+480 in quiescence. The source was observed with the Karl G. Jansky Very Large Array for a total of ...17.5 h at 5.3 GHz, yielding a 4.8 ± 1.4 μJy radio source at a position consistent with the binary system. At a distance of 1.7 kpc, this corresponds to an integrated radio luminosity between 4 and 8 × 1025 erg s−1, depending on the spectral index. This is the lowest radio luminosity measured for any accreting black hole to date. Simultaneous observations with the Chandra X-ray Telescope detected XTE J1118+480 at 1.2 × 10−14 erg s−1 cm−2 (1–10 keV), corresponding to an Eddington ratio of ∼4 × 10−9 for a 7.5 M⊙ black hole. Combining these new measurements with data from the 2005 and 2000 outbursts available in the literature, we find evidence for a relationship of the form ℓr = α+βℓX (where ℓ denotes logarithmic luminosities), with β = 0.72 ± 0.09. XTE J1118+480 is thus the third system – together with GX339-4 and V404 Cyg – for which a tight, non-linear radio/X-ray correlation has been reported over more than 5 dex in ℓX. Confirming previous results, we find no evidence for a dependence of the correlation normalization of an individual system on orbital parameters, relativistic boosting, reported black hole spin and/or black hole mass. We then perform a clustering and linear regression analysis on what is arguably the most up-to-date collection of coordinated radio and X-ray luminosity measurements from quiescent and hard-state black hole X-ray binaries, including 24 systems. At variance with previous results, a two-cluster description is statistically preferred only for random errors ≲0.3 dex in both ℓr and ℓX, a level which we argue can be easily reached when the known spectral shape/distance uncertainties and intrinsic variability are accounted for. A linear regression analysis performed on the whole data set returns a best-fitting slope β = 0.61 ± 0.03 and intrinsic scatter σ0 = 0.31 ± 0.03 dex.
A proline-to-serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor ...neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels (Ca(2+)c); elevated Ca(2+)c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored Ca(2+)c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting Ca(2+)c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca(2+) insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca(2+) homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin.
The emergence of Zika and Ebola demonstrates the importance of understanding the role of sexual transmission in the spread of diseases with a primarily non-sexual transmission route. In this paper, ...we develop low-dimensional models for how an SIR disease will spread if it transmits through a sexual contact network and some other transmission mechanism, such as direct contact or vectors. We show that the models derived accurately predict the dynamics of simulations in the large population limit, and investigate ℛ0 and final size relations.
ABSTRACT
It is currently not known if repeating fast radio bursts (FRBs) are fundamentally different from those that have not been seen to repeat. One striking difference between repeaters and ...apparent non-repeaters in the Canadian Hydrogen Intensity Mapping Experiment sample is that the once-off events are typically shorter in duration than sources that have been detected two or more times. We offer a simple explanation for this discrepancy based on a selection effect due to beamed emission, in which highly beamed FRBs are less easily observed to repeat, but are abundant enough to detect often as once-off events. The explanation predicts that there is a continuous distribution of burst duration – not a static bimodal one – with a correlation between repetition rate and width. Pulse width and opening angle may be related by relativistic effects in shocks, where short-duration bursts have small solid angles due to a large common Lorentz factor. Alternatively, the relationship could be a geometric effect where narrow beams sweep past the observer more quickly, as with pulsars. Our model has implications for the FRB emission mechanism and energy scale, volumetric event rates, and the application of FRBs to cosmology.
The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally ...restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.
In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.
A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.
In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic ...dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts.
We report the detection of steady radio emission from the known X-ray source X9 in the globular cluster 47 Tuc. With a double-peaked C iv emission line in its ultraviolet spectrum providing a clear ...signature of accretion, this source had been previously classified as a cataclysmic variable. In deep ATCA (Australia Telescope Compact Array) imaging from 2010 and 2013, we identified a steady radio source at both 5.5 and 9.0 GHz, with a radio spectral index (defined as S
ν ∝ να) of α = −0.4 ± 0.4. Our measured flux density of 42 ± 4 μJy beam−1 at 5.5 GHz implies a radio luminosity (νL
ν) of 5.8 × 1027 erg s−1, significantly higher than any previous radio detection of an accreting white dwarf. Transitional millisecond pulsars, which have the highest radio-to-X-ray flux ratios among accreting neutron stars (still a factor of a few below accreting black holes at the same L
X), show distinctly different patterns of X-ray and radio variability than X9. When combined with archival X-ray measurements, our radio detection places 47 Tuc X9 very close to the radio/X-ray correlation for accreting black holes, and we explore the possibility that this source is instead a quiescent stellar-mass black hole X-ray binary. The nature of the donor star is uncertain; although the luminosity of the optical counterpart is consistent with a low-mass main-sequence donor star, the mass transfer rate required to produce the high quiescent X-ray luminosity of 1033 erg s−1 suggests the system may instead be ultracompact, with an orbital period of order 25 min. This is the fourth quiescent black hole candidate discovered to date in a Galactic globular cluster, and the only one with a confirmed accretion signature from its optical/ultraviolet spectrum.
Observations of thermonuclear X-ray bursts from accreting neutron stars (NSs) in low-mass X-ray binary systems can be used to constrain NS masses and radii. Most previous work of this type has set ...these constraints using Planck function fits as a proxy: the models and the data are both fit with diluted blackbody functions to yield normalizations and temperatures that are then compared with each other. For the first time, we here fit atmosphere models of X-ray bursting NSs directly to the observed spectra. We present a hierarchical Bayesian fitting framework that uses current X-ray bursting NS atmosphere models with realistic opacities and relativistic exact Compton scattering kernels as a model for the surface emission. We test our approach against synthetic data and find that for data that are well described by our model, we can obtain robust radius, mass, distance, and composition measurements. We then apply our technique to Rossi X-ray Timing Explorer observations of five hard-state X-ray bursts from 4U 1702−429. Our joint fit to all five bursts shows that the theoretical atmosphere models describe the data well, but there are still some unmodeled features in the spectrum corresponding to a relative error of 1–5% of the energy flux. After marginalizing over this intrinsic scatter, we find that at 68% credibility, the circumferential radius of the NS in 4U 1702−429 is R = 12.4±0.4 km, the gravitational mass is M = 1.9±0.3 M⊙, the distance is 5.1 < D/ kpc < 6.2, and the hydrogen mass fraction is X < 0.09.
Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted ...proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish a reactive amidyl radical that readily adds to pendant alkenes. A series of H-atom, electron, and proton transfer events with a thiophenol cocatalyst furnish the product and regenerate the active forms of the photocatalyst and base. Mechanistic studies indicate that the amide substrate can be selectively homolyzed via PCET in the presence of the thiophenol, despite a large difference in bond dissociation free energies between these functional groups.
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