VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC

Multi-Wavelength Observations of a Flux Rope Failed in the Eruption and Associated M-Class Flare from NOAA AR 11045

We present the multi-wavelength observations of a flux rope that was trying to erupt from NOAA AR 11045 and the associated M-class solar flare on 12 February 2010 using space and ground based observations from TRACE, STEREO, SOHO/MDI, Hinode/XRT and BBSO. While the flux rope was rising from the active region, an M1.1/2F class flare was triggered nearby one of its footpoints. We suggest that the flare triggering was due to the reconnection of a rising flux rope with the surrounding low-lying magnetic loops. The flux rope reached a projected height of ~0.15 Rs with a speed of ~90 km/s while the soft X-ray flux enhanced gradually during its rise. The flux rope was suppressed by an overlying field and the filled plasma moved towards the negative polarity field to the west of its activation site. We find the first observational evidence of the initial suppression of a flux rope due to a remnant filament visible both at chromospheric and coronal temperatures that evolved couple of days before at the same location in the active region. SOHO/MDI magnetograms show the emergence of a bipole ~12 h prior to the flare initiation. The emerged negative polarity moved towards the flux rope activation site, and flare triggering near the photospheric polarity inversion line (PIL) took place. The motion of the negative polarity region towards PIL helped in the build-up of magnetic energy at the flare and flux rope activation site. This study provides a unique observational evidence of a rising flux rope that failed to erupt due to a remnant filament and overlying magnetic field, as well as associated triggering of an M-class flare.Comment: 20 pages, 11 figures, Sol. Phy

Physics of Solar Prominences: II - Magnetic Structure and Dynamics

Observations and models of solar prominences are reviewed. We focus on non-eruptive prominences, and describe recent progress in four areas of prominence research: (1) magnetic structure deduced from observations and models, (2) the dynamics of prominence plasmas (formation and flows), (3) Magneto-hydrodynamic (MHD) waves in prominences and (4) the formation and large-scale patterns of the filament channels in which prominences are located. Finally, several outstanding issues in prominence research are discussed, along with observations and models required to resolve them.Comment: 75 pages, 31 pictures, review pape

Measurement of the Charged Multiplicities in b, c and Light Quark Events from Z0 Decays

Average charged multiplicities have been measured separately in $b$, $c$ and light quark ($u,d,s$) events from $Z^0$ decays measured in the SLD experiment. Impact parameters of charged tracks were used to select enriched samples of $b$ and light quark events, and reconstructed charmed mesons were used to select $c$ quark events. We measured the charged multiplicities: $\bar{n}_{uds} = 20.21 \pm 0.10 (\rm{stat.})\pm 0.22(\rm{syst.})$, $\bar{n}_{c} = 21.28 \pm 0.46(\rm{stat.}) ^{+0.41}_{-0.36}(\rm{syst.})$ $\bar{n}_{b} = 23.14 \pm 0.10(\rm{stat.}) ^{+0.38}_{-0.37}(\rm{syst.})$, from which we derived the differences between the total average charged multiplicities of $c$ or $b$ quark events and light quark events: $\Delta \bar{n}_c = 1.07 \pm 0.47(\rm{stat.})^{+0.36}_{-0.30}(\rm{syst.})$ and $\Delta \bar{n}_b = 2.93 \pm 0.14(\rm{stat.})^{+0.30}_{-0.29}(\rm{syst.})$. We compared these measurements with those at lower center-of-mass energies and with perturbative QCD predictions. These combined results are in agreement with the QCD expectations and disfavor the hypothesis of flavor-independent fragmentation.Comment: 19 pages LaTex, 4 EPS figures, to appear in Physics Letters

Flux-rope twist in eruptive flares and CMEs : due to zipper and main-phase reconnection

Funding: UK Science and Technology Facilities CouncilThe nature of three-dimensional reconnection when a twisted flux tube erupts during an eruptive flare or coronal mass ejection is considered. The reconnection has two phases: first of all, 3D “zipper reconnection” propagates along the initial coronal arcade, parallel to the polarity inversion line (PIL); then subsequent quasi-2D “main phase reconnection” in the low corona around a flux rope during its eruption produces coronal loops and chromospheric ribbons that propagate away from the PIL in a direction normal to it. One scenario starts with a sheared arcade: the zipper reconnection creates a twisted flux rope of roughly one turn (2π radians of twist), and then main phase reconnection builds up the bulk of the erupting flux rope with a relatively uniform twist of a few turns. A second scenario starts with a pre-existing flux rope under the arcade. Here the zipper phase can create a core with many turns that depend on the ratio of the magnetic fluxes in the newly formed flare ribbons and the new flux rope. Main phase reconnection then adds a layer of roughly uniform twist to the twisted central core. Both phases and scenarios are modeled in a simple way that assumes the initial magnetic flux is fragmented along the PIL. The model uses conservation of magnetic helicity and flux, together with equipartition of magnetic helicity, to deduce the twist of the erupting flux rope in terms the geometry of the initial configuration. Interplanetary observations show some flux ropes have a fairly uniform twist, which could be produced when the zipper phase and any pre-existing flux rope possess small or moderate twist (up to one or two turns). Other interplanetary flux ropes have highly twisted cores (up to five turns), which could be produced when there is a pre-existing flux rope and an active zipper phase that creates substantial extra twist.PostprintPublisher PDFPeer reviewe

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure : an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Death in hospital following ICU discharge : insights from the LUNG SAFE study

Background: To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. Methods: The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments (‘treatment limitations’), and the subpopulations with treatment limitations. Results: 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. Conclusions: A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration: ClinicalTrials.gov NCT02010073

Stochastic Acceleration by Turbulence

The subject of this paper is stochastic acceleration by plasma turbulence, a process akin to the original model proposed by Fermi. We review the relative merits of different acceleration models, in particular the so called first order Fermi acceleration by shocks and second order Fermi by stochastic processes, and point out that plasma waves or turbulence play an important role in all mechanisms of acceleration. Thus, stochastic acceleration by turbulence is active in most situations. We also show that it is the most efficient mechanism of acceleration of relatively cool non relativistic thermal background plasma particles. In addition, it can preferentially accelerate electrons relative to protons as is needed in many astrophysical radiating sources, where usually there are no indications of presence of shocks. We also point out that a hybrid acceleration mechanism consisting of initial acceleration by turbulence of background particles followed by a second stage acceleration by a shock has many attractive features. It is demonstrated that the above scenarios can account for many signatures of the accelerated electrons, protons and other ions, in particular $^3$He and $^4$He, seen directly as Solar Energetic Particles and through the radiation they produce in solar flares.Comment: 29 pages 7 figures for proceedings of ISSI-Bern workshop on Particle Acceleration 201

The Origin, Early Evolution and Predictability of Solar Eruptions

Coronal mass ejections (CMEs) were discovered in the early 1970s when space-borne coronagraphs revealed that eruptions of plasma are ejected from the Sun. Today, it is known that the Sun produces eruptive flares, filament eruptions, coronal mass ejections and failed eruptions; all thought to be due to a release of energy stored in the coronal magnetic field during its drastic reconfiguration. This review discusses the observations and physical mechanisms behind this eruptive activity, with a view to making an assessment of the current capability of forecasting these events for space weather risk and impact mitigation. Whilst a wealth of observations exist, and detailed models have been developed, there still exists a need to draw these approaches together. In particular more realistic models are encouraged in order to asses the full range of complexity of the solar atmosphere and the criteria for which an eruption is formed. From the observational side, a more detailed understanding of the role of photospheric flows and reconnection is needed in order to identify the evolutionary path that ultimately means a magnetic structure will erupt

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch