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Fluorescence of iron ions induced by an X-ray laser allows the relative oscillator strength for Fe xvii emission to be determined; it is found to differ by 3.6 σ from the best quantum mechanical calculations, suggesting that the poor agreement between prediction and observations of the brightest Fe  xvii line is rooted in the quality of the underlying atomic wavefunctions used in the models. New look at highly charged astrophysical iron The interpretation of some of the spectral data from the Chandra and XMM-Newton orbiting X-ray missions has been complicated by discrepancies between theory and observation involving the emission lines from the highly charged Fe 16+ ion, also known as Fe XVII. Specifically, the intensity of the strongest Fe XVII line, one of the brightest X-ray emissions from galaxies and stars, is generally weaker than predicted. Sven Bernitt et al . report the results of laboratory experiments in which a target of iron ions was fluoresced with femtosecond X-ray pulses from a free-electron laser. They find a relative oscillator strength that differs by 3.6 σ from the best quantum mechanical calculations, suggesting that the poor agreement is rooted in the calculations of the underlying atomic dynamics and that the current astrophysical models are not at fault. Highly charged iron (Fe 16+ , here referred to as Fe  xvii ) produces some of the brightest X-ray emission lines from hot astrophysical objects 1 , including galaxy clusters and stellar coronae, and it dominates the emission of the Sun at wavelengths near 15 ångströms. The Fe  xvii spectrum is, however, poorly fitted by even the best astrophysical models. A particular problem has been that the intensity of the strongest Fe  xvii line is generally weaker than predicted 2 , 3 . This has affected the interpretation of observations by the Chandra and XMM-Newton orbiting X-ray missions 1 , fuelling a continuing controversy over whether this discrepancy is caused by incomplete modelling of the plasma environment in these objects or by shortcomings in the treatment of the underlying atomic physics. Here we report the results of an experiment in which a target of iron ions was induced to fluoresce by subjecting it to femtosecond X-ray pulses from a free-electron laser 4 ; our aim was to isolate a key aspect of the quantum mechanical description of the line emission. Surprisingly, we find a relative oscillator strength that is unexpectedly low, differing by 3.6 σ from the best quantum mechanical calculations. Our measurements suggest that the poor agreement is rooted in the quality of the underlying atomic wavefunctions rather than in insufficient modelling of collisional processes.

Birt–Hogg–Dubé (BHD) syndrome is a tumor-suppressor gene disorder characterized by skin tumors, cystic lung disease and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1), and in Schizosaccharomyces pombe , Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino-acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the BHD gene, regulates mammalian target of rapamycin activity in vivo , we generated a mouse with targeted inactivation of the Bhd gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.

Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O 2 )-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O 2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. As miR-124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O 2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O 2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1 , MAPK14 /p38α and SERP1 , factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.

Birt–Hogg–Dubé (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd −/− cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFβ-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFβ-dependent transcription and apoptosis, which has implications for the development of targeted therapies.

The von Hippel–Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix–loop–helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2α suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.

Methods for reducing the radius, temperature and space charge of a non-neutral plasma are usually reported for conditions which approximate an ideal Penning Malmberg trap. Here, we show that (i) similar methods are still effective under surprisingly adverse circumstances: we perform strong drive regime (SDR) compression and SDREVC in a strong magnetic mirror field using only 3 out of 4 rotating wall petals. In addition, we demonstrate (ii) an alternative to SDREVC, using e-kick instead of evaporative cooling (EVC) and (iii) an upper limit for how much plasma can be cooled to $T<20\\ \\mathrm {K}$ using EVC. This limit depends on the space charge, not on the number of particles or the plasma density.

The ASACUSA (atomic spectroscopy and collisions using slow antiprotons) Cusp experiment requires the production of dense positron plasmas with a high repetition rate to produce a beam of antihydrogen. In this work, details of the positron production apparatus used for the first observation of the antihydrogen beam, and subsequent measurements, are described in detail. This apparatus replaced the previous compact trap design resulting in an improvement in the positron accumulation rate by a factor of $52\\pm 3$.

The ASACUSA collaboration produces a beam of antihydrogen atoms by mixing pure positron and antiproton plasmas in a strong magnetic field with a double cusp geometry. The positrons cool via cyclotron radiation inside the cryogenic trap. Low positron temperature is essential for increasing the fraction of antihydrogen atoms which reach the ground state prior to exiting the trap. Many experimental groups observe that such plasmas reach equilibrium at a temperature well above the temperature of the surrounding electrodes. This problem is typically attributed to electronic noise and plasma expansion, which heat the plasma. The present work reports anomalous heating far beyond what can be attributed to those two sources. The heating seems to be a result of the axially open trap geometry, which couples the plasma to the external (300 K) environment via microwave radiation.

The ASACUSA Collaboration at CERNs Antiproton Decelerator aims to measure the ground state hyperfine splitting of antihydrogen with high precision to test the fundamental symmetry of CPT (combination of charge conjugation, parity transformation, and time reversal). For this purpose an antihydrogen detector has been developed. Its task is to count the arriving antihydrogen atoms and therefore distinguish backgroundevents (mainly cosmics) from antiproton annihilations originating from antihydrogen atoms which are produced only in small amounts. A central BGO crystal disk with position sensitive read-out detects the annihilation and a surrounding two-layered hodoscope is used for tracking charged secondaries. The hodoscope has been recently upgraded to allow precise vertex reconstruction. A machine learning analysis based on measured antiproton annihilations and cosmic rays has been developed to identify antihydrogen events.

Von Hippel–Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q ( Vhl 2B/2B ) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2α. Differentiated Vhl 2B/2B -derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1 . Vhl 2B/2B teratomas additionally displayed a growth advantage over Vhl −/− -derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl 2B/2B mice displayed mid-gestational embryonic lethality, whereas adult Vhl 2B/+ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.