Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma(RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-a subunits (and hence expression of the HIF-a transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (nZ82) and inherited RCC (nZ64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC

Overview over the neutral gas pressures in Wendelstein 7-X during divertor operation under boronized wall conditions

During the first test divertor campaign of the stellarator experiment Wendelstein 7-X (Pedersen et al 2022 Nucl. Fusion 62 042022), OP1.2b, 13 neutral gas pressure gauges collected data in different locations in the plasma vessel, enabling a detailed analysis of the neutral gas pressures, the compression ratios and the particle exhaust rates via the turbomolecular pumps in the different magnetic field configurations. In Wendelstein 7-X, the edge magnetic islands are intersected by the divertor target plates and used to create a plasma-wall interface. As the number and position of the magnetic islands varies in different magnetic field configurations, the position of the strike line on the target plates and thus the neutral gas pressure in the subdivertor differs between the configurations. Neutral gas pressures on the order of few 10−4 mbar were measured in the subdivertor region. The highest neutral gas pressure of $1.75\times 10^{-3}$ mbar was obtained in the so-called high iota configuration featuring four edge magnetic islands per cross section. The neutral particle flux through the pumping gaps into the subdivertor volume was provided by EMC3-EIRENE simulations and allowed to analyze the relation between the particle flux entering the subdivertor and the pressure distribution in the subdivertor. Finite element simulations in ANSYS provide a detailed picture of the pressure distribution in the subdivertor volume and agree with the neutral gas pressure measurements in the subdivertor in the standard configuration featuring an island chain of 5 edge magnetic islands. Surprisingly high neutral gas pressures that were not predicted by the simulation were measured in the subdivertor region away from the main strike line for discharges in the most used magnetic configuration, the standard configuration. While the pressure ratio between the two sections of the subdivertor volume, the low and high iota section is 0.06 in high iota configuration, a ratio of 2–5 was obtained in the other configurations, indicating significant particle loads and exhaust rates on the high iota section of the subdivertor in magnetic configurations with the main strike line on the low iota divertor targets

Single-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a tran- scriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome

Analysis of the neutral fluxes in the divertor region of Wendelstein 7-X under attached and detached conditions using EMC3-EIRENE

This paper analyzes the neutral fluxes in the divertor region of the W7-X standard configuration for different input powers, both under attached and detached conditions. The performed analysis is conducted through EMC3-EIRENE simulations. They show the importance of the horizontal divertor to generate neutrals, and resolve the neutral plugging in the divertor region. Simulations of detached cases show a decrease in the number of generated neutrals compared to the attached simulations, in addition to a higher fraction of the ion flux arriving on the baffles during detachment. As the ionization takes place further inside the plasma during detachment, a larger percentage of the generated neutral particles leave the divertor as neutrals. The leakage in the poloidal and toroidal direction increases, just as the fraction of collected particles at the pumping gap. The fraction of pumped particles increases with a factor two, but stays below one percent. This demonstrates that detachment with the current target geometry, although it improves the power exhaust, is not yet leading to an increased particle exhaust