The influence of albedo on the size of hard X-ray flare sources

Context: Hard X-rays from solar flares are an important diagnostic of particle acceleration and transport in the solar atmosphere. Any observed X-ray flux from on-disc sources is composed of direct emission plus Compton backscattered photons (albedo). This affects both the observed spectra and images as well as the physical quantities derived from them such as the spatial and spectral distributions of accelerated electrons or characteristics of the solar atmosphere. Aims: We propose a new indirect method to measure albedo and to infer the directivity of X-rays in imaging using RHESSI data. Methods: Visibility forward fitting is used to determine the size of a disc event observed by RHESSI as a function of energy. This is compared to the sizes of simulated sources from a Monte Carlo simulation code of photon transport in the chromosphere for different degrees of downward directivity and true source sizes to find limits on the true source size and the directivity. Results: The observed full width half maximum of the source varies in size between 7.4 arcsec and 9.1 arcsec with the maximum between 30 and 40 keV. Such behaviour is expected in the presence of albedo and is found in the simulations. A source size smaller than 6 arcsec is improbable for modest directivities and the true source size is likely to be around 7 arcsec for small directivities. Conclusions: While it is difficult to image the albedo patch directly, the effect of backscattered photons on the observed source size can be estimated. The increase in source size caused by albedo has to be accounted for when computing physical quantities that include the size as a parameter such as flare energetics. At the same time, the study of the albedo signature provides vital information about the directivity of X-rays and related electrons.Comment: 8 pages, 6 figures, A&A (accepted

A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse

BACKGROUND: Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%). RESULTS: We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects. CONCLUSIONS: These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components

Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied a next-generation sequencing approach to identify the gene responsible for this phenotype in two consanguineous families

Exploring 4D Quantum Hall Physics with a 2D Topological Charge Pump

The discovery of topological states of matter has profoundly augmented our understanding of phase transitions in physical systems. Instead of local order parameters, topological phases are described by global topological invariants and are therefore robust against perturbations. A prominent example thereof is the two-dimensional integer quantum Hall effect. It is characterized by the first Chern number which manifests in the quantized Hall response induced by an external electric field. Generalizing the quantum Hall effect to four-dimensional systems leads to the appearance of a novel non-linear Hall response that is quantized as well, but described by a 4D topological invariant - the second Chern number. Here, we report on the first observation of a bulk response with intrinsic 4D topology and the measurement of the associated second Chern number. By implementing a 2D topological charge pump with ultracold bosonic atoms in an angled optical superlattice, we realize a dynamical version of the 4D integer quantum Hall effect. Using a small atom cloud as a local probe, we fully characterize the non-linear response of the system by in-situ imaging and site-resolved band mapping. Our findings pave the way to experimentally probe higher-dimensional quantum Hall systems, where new topological phases with exotic excitations are predicted

Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.</p

Cloning and characterization of Lxr and Srebp1, and their potential roles in regulation of LC-PUFA biosynthesis in rabbitfish Siganus canaliculatus

Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability to biosynthesize C20-22 long-chain polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors, which is generally absent or low in marine teleosts. Thus, understanding the molecular basis of LC-PUFA biosynthesis in rabbitfish will contribute to efforts aimed at optimizing LC-PUFA biosynthesis in teleosts, especially marine species. In the present study, the importance of the transcription factors liver X receptor (Lxr) and sterol regulatory element-binding protein 1 (Srebp1) in regulation of LC-PUFA biosynthesis in rabbitfish was investigated. First, full-length cDNAs of Lxr and Srebp1 were cloned and characterized. The Lxr mRNA displayed a ubiquitous tissue expression pattern while Srebp1 was highly expressed in eyes, brain and intestine. In rabbitfish primary hepatocytes treated with Lxr agonist T0901317, the expression of Lxr and Srebp1 was activated, accompanied by elevated mRNA levels of &Delta;4 and &Delta;6/&Delta;5 fatty acyl desaturases (Fad), key enzymes of LC-PUFA biosynthesis, as well as peroxisome proliferator-activated receptor &gamma; (Ppar&gamma;). In addition, Srebp1 displayed higher expression levels in liver of rabbitfish fed a vegetable oil diet or reared at 10 ppt salinity, which were conditions reported to increase the liver expression of &Delta;4 and &Delta;6/&Delta;5 Fad and LC-PUFA biosynthetic ability, than fish fed a fish oil diet or reared at 32 ppt, respectively. These results suggested that Lxr and Srebp1 are involved in regulation of LC-PUFA biosynthesis probably by promoting the expression of two Fads in rabbitfish liver, which, to our knowledge, is the first report in marine teleosts

Comparison of heavy-ion transport simulations: Collision integral with pions and Δ resonances in a box

We compare ten transport codes for a system confined in a box, aiming at improved handling of the production of $\Delta$ resonances and pions, which is indispensable for constraining high-density symmetry energy from observables such as the $\pi^-/\pi^+$ yield ratio in heavy-ion collisions. The system in a box is initialized with nucleons at saturation density and at 60 MeV temperature. The reactions $NN\leftrightarrow N\Delta$ and $\Delta\leftrightarrow N\pi$ are implemented, but the Pauli blocking and the mean-field potential are deactivated in the present comparison. Results are compared to those from the two reference cases of a chemically equilibrated ideal gas mixture and of the rate equation. In the results of the numbers of $\Delta$ and $\pi$, deviations from the reference values are observed in many codes, and they depend significantly on the size of the time step. These deviations are tied to different ways in ordering the sequence of collisions and decays, that take place in the same time step. Better agreements are seen in the reaction rates and the number ratios among the isospin species of $\Delta$ and $\pi$. These are, however, affected by the correlations, which are absent in the Boltzmann equation, but are induced by the way particle scatterings are treated in transport calculations. The uncertainty in the transport-code predictions of the $\pi^-/\pi^+$ ratio for the system initialized at n/p = 1.5, after letting the existing $\Delta$ resonances decay, is found to be within a few percent, which is sufficiently small so that it does not strongly impact constraining the high-density symmetry energy from heavy-ion collisions. Most of the sources of uncertainties have been understood, and individual codes may be further improved. This investigation will be extended in the future to heavy-ion collisions to ensure the problems identified here remain under control.Comment: 36 pages, 27 figures; a new Fig. 21 and revised results from some codes, achieving improved and consistent understandin

Exploring the physiological, neurophysiological and cognitive performance effects of elevated carbon dioxide concentrations indoors

Rationale: An accumulation of CO2 in occupied indoor spaces is correlated to negative impacts on concentration, sleepiness and aspects of cognitive performance. However factors such as: (a) the relative effect of CO2 itself compared to other pollutants; (b) the minimum necessary exposure time for cognitive performance to be affected; and (c) the physiological drivers of cognitive performance reductions due to increased indoor CO2 concentrations are not yet clear. Method: A within-subjects counterbalanced study design was used to test cognitive performance, subjective and physiological parameters of 31 volunteers during short (< 40 minutes) exposures to normal CO2 (830 ppm) and high CO2 (2,700 ppm, raised by introducing pure CO2 alongside the occupant generated CO2). The study was conducted in a small naturally ventilated office and EEG was used as an objective indicator of sleepiness. Results: The addition of pure CO2 to the room resulted in the absence of an expected learning effect in two cognitive performance test battery components without measurably affecting any of the physiological, psychological, or reported comfort, sick building syndrome and health variables measured. However participants who had slept less the previous night appeared more susceptible to becoming sleepier as a result of the increased CO2. Contributions: The results suggest (1) the addition of pure CO2 may influence aspects of cognitive performance after only short exposures (2) these changes occur in the absence of clear physiological drivers, (3) lack of sleep may mediate people’s response to higher CO2 concentration

Genomic heterogeneity of multiple synchronous lung cancer

Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events