Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis

Loss of functional RAB18 causes the autosomal recessive condition Warburg Micro syndrome. To better understand this disease, we used proximity biotinylation to generate an inventory of potential RAB18 effectors. A restricted set of 28 RAB18 interactions were dependent on the binary RAB3GAP1–RAB3GAP2 RAB18–guanine nucleotide exchange factor complex. Twelve of these 28 interactions are supported by prior reports, and we have directly validated novel interactions with SEC22A, TMCO4, and INPP5B. Consistent with a role for RAB18 in regulating membrane contact sites, interactors included groups of microtubule/membrane-remodeling proteins, membrane-tethering and docking proteins, and lipid-modifying/transporting proteins. Two of the putative interactors, EBP and OSBPL2/ORP2, have sterol substrates. EBP is a Δ8-Δ7 sterol isomerase, and ORP2 is a lipid transport protein. This prompted us to investigate a role for RAB18 in cholesterol biosynthesis. We found that the cholesterol precursor and EBP-product lathosterol accumulates in both RAB18-null HeLa cells and RAB3GAP1-null fibroblasts derived from an affected individual. Furthermore, de novo cholesterol biosynthesis is impaired in cells in which RAB18 is absent or dysregulated or in which ORP2 expression is disrupted. Our data demonstrate that guanine nucleotide exchange factor–dependent Rab interactions are highly amenable to interrogation by proximity biotinylation and may suggest that Micro syndrome is a cholesterol biosynthesis disorder

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Disclosure of complementary health approaches among low income and racially diverse safety net patients with diabetes

OBJECTIVE: Patient-provider communication about complementary health approaches can support diabetes self-management by minimizing risk and optimizing care. We sought to identify sociodemographic and communication factors associated with disclosure of complementary health approaches to providers by low-income patients with diabetes. METHODS: We used data from San Francisco Health Plan's SMARTSteps Program, a trial of diabetes self-management support for low-income patients (n=278) through multilingual automated telephone support. Interviews collected use and disclosure of complementary health approaches in the prior month, patient-physician language concordance, and quality of communication. RESULTS: Among racially, linguistically diverse participants, half (47.8%) reported using complementary health practices (n=133), of whom 55.3% disclosed use to providers. Age, sex, race/ethnicity, nativity, education, income, and health literacy were not associated with disclosure. In adjusted analyses, disclosure was associated with language concordance (AOR=2.21, 95% CI: 1.05, 4.67), physicians' interpersonal communication scores (AOR=1.50, 95% CI: 1.03, 2.19), shared decision making (AOR=1.74, 95% CI: 1.33, 2.29), and explanatory-type communication (AOR = 1.46, 95% CI: 1.03, 2.09). CONCLUSION: Safety net patients with diabetes commonly use complementary health approaches and disclose to providers with higher patient-rated quality of communication. PRACTICE IMPLICATIONS: Patient-provider language concordance and patient-centered communication can facilitate disclosure of complementary health approaches

Thermal (wimps) and the scale of new physics: global fits of Dirac dark matter effective field theories

We assess the status of a wide class of WIMP dark matter (DM) models in light of the latest experimental results using the global fitting framework GAMBIT. We perform a global analysis of effective field theory (EFT) operators describing the interactions between a gauge-singlet Dirac fermion and the Standard Model quarks, the gluons and the photon. In this bottom-up approach, we simultaneously vary the coefficients of 14 such operators up to dimension 7, along with the DM mass, the scale of new physics and several nuisance parameters. Our likelihood functions include the latest data from Planck, direct and indirect detection experiments, and the LHC. For DM masses below 100 GeV, we find that it is impossible to satisfy all constraints simultaneously while maintaining EFT validity at LHC energies. For new physics scales around 1 TeV, our results are influenced by several small excesses in the LHC data and depend on the prescription that we adopt to ensure EFT validity. Furthermore, we find large regions of viable parameter space where the EFT is valid and the relic density can be reproduced, implying that WIMPs can still account for the DM of the universe while being consistent with the latest data.GAMBIT Collaboration, Peter Athron, Neal Avis Kozar, Csaba Balázs, Ankit Beniwal, a, Sanjay Bloor, b, Torsten Bringmann, Joachim Brod, Christopher Chang, Jonathan M. Cornell, Ben Farmer, Andrew Fowlie, Tomás E. Gonzalo, c, Will Handley, Felix Kahlhoefer, d, Anders Kvellestad, Farvah Mahmoudi, Markus T. Prim, Are Raklev, Janina J. Renk, Andre Scaffidi, Pat Scott, Patrick Stöcker, Aaron C. Vincent, Martin White, Sebastian Wild, Jure Zupa

Impact of nitrogen seeding on confinement and power load control of a high-triangularity JET ELMy H-mode plasma with a metal wall

This paper reports the impact on confinement and power load of the high-shape 2.5MA ELMy H-mode scenario at JET of a change from an all carbon plasma facing components to an all metal wall. In preparation to this change, systematic studies of power load reduction and impact on confinement as a result of fuelling in combination with nitrogen seeding were carried out in JET-C and are compared to their counterpart in JET with a metallic wall. An unexpected and significant change is reported on the decrease of the pedestal confinement but is partially recovered with the injection of nitrogen.Comment: 30 pages, 16 figure