Here, we identify ADP-ribosylation factor (ARF)-like 7 (ARL7) as the only ARF- and ARL-family member whose mRNA-expression is induced by liver X-receptor/retinoid X-receptor agonists or cholesterol loading in human macrophages. Moreover, subcellular distribution of mutant and wild type ARL7-enhanced green fluorescent protein (EGFP) supports that ARL7 may be involved in a vesicular transport step between a perinuclear compartment and the plasma membrane. Therefore, we investigated the effect of ARL7 over-expression on the cholesterol secretory pathway. We found that expression of wild type and dominant active ARL7-EGFP stimulated the rate of apolipoprotein AI-specific cholesterol efflux 1.7- and 2.8-fold. In contrast, expression of the dominant negative form of ARL7-EGFP led to approximately 50% inhibition of cholesterol efflux. This data is consistent with a model in which ARL7 is involved in transport between a perinuclear compartment and the plasma membrane apparently linked to the ABCA1-mediated cholesterol secretion pathway.

Using data from the IceCube Neutrino Observatory, we searched for high-energy neutrino emission from the gravitational-wave events detected by the advanced LIGO and Virgo detectors during their third observing run. We did a low-latency follow-up on the public candidate events released during the detectors’ third observing run and an archival search on the 80 confident events reported in the GWTC-2.1 and GWTC-3 catalogs. An extended search was also conducted for neutrino emission on longer timescales from neutron star containing mergers. Follow-up searches on the candidate optical counterpart of GW190521 were also conducted. We used two methods; an unbinned maximum likelihood analysis and a Bayesian analysis using astrophysical priors, both of which were previously used to search for high-energy neutrino emission from gravitational-wave events. No significant neutrino emission was observed by any analysis, and upper limits were placed on the time-integrated neutrino flux as well as the total isotropic equivalent energy emitted in high-energy neutrinos.

Objectives Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset juvenile idiopathic arthritis (SJIA) from infectious diseases is difficult. Biomarkers are needed supporting the diagnostic work-up. The aim of this study was to validate the usefulness of MRP8/14 measurements in the diagnostic wok-up of febrile children and transfer it to clinical practice. Methods Data of 1,110 paediatric patients were included and divided into two cohorts: (A) For validation of MRP8/14 test performance with 3 different testing systems: the experimental enzyme-linked immunosorbent sandwich assay (ELISA), commercial ELISA and an innovative (POCT) lateral flow immunoassay (LFIA); (B) to validate the diagnostic accuracy with the two latter assays. Results In cohort A (n = 940), MRP8/14 was elevated in SJIA (12110±2650 ng/ml mean ± 95% CI) compared to other diagnoses (including infections and autoinflammatory diseases; 2980±510 ng/ml) irrespective of fever and anti-inflammatory treatment (p < 0.001). In untreated patients with fever (n = 195) MRP8/14 levels in SJIA (19740±5080 ng/ml) were even higher compared to other diagnoses (4590±1160 ng/ml) (p < 0.001, sensitivity 73%, specificity 90%). In cohort B1, the performance of the tests was confirmed in untreated patients with fever (n = 170): commercial ELISA (sensitivity 79%, specificity 89%) and LFIA (sensitivity 84%, specificity 81%). Compared with ferritin, IL-18, ESR, sIL2-R, and procalcitonin, MRP8/14 showed the best accuracy. Conclusion MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children. The results could be confirmed with commercial ELISA and LFIA enabling a rapid diagnostic point-of-care screening test.

IceCube, a cubic-kilometer array of optical sensors built to detect atmospheric and astrophysical neutrinos between 1 GeV and 1 PeV, is deployed 1.45 km to 2.45 km below the surface of the ice sheet at the South Pole. The classification and reconstruction of events from the in-ice detectors play a central role in the analysis of data from IceCube. Reconstructing and classifying events is a challenge due to the irregular detector geometry, inhomogeneous scattering and absorption of light in the ice and, below 100 GeV, the relatively low number of signal photons produced per event. To address this challenge, it is possible to represent IceCube events as point cloud graphs and use a Graph Neural Network (GNN) as the classification and reconstruction method. The GNN is capable of distinguishing neutrino events from cosmic-ray backgrounds, classifying different neutrino event types, and reconstructing the deposited energy, direction and interaction vertex. Based on simulation, we provide a comparison in the 1 GeV–100 GeV energy range to the current state-of-the-art maximum likelihood techniques used in current IceCube analyses, including the effects of known systematic uncertainties. For neutrino event classification, the GNN increases the signal efficiency by 18% at a fixed background rate, compared to current IceCube methods. Alternatively, the GNN offers a reduction of the background (i.e. false positive) rate by over a factor 8 (to below half a percent) at a fixed signal efficiency. For the reconstruction of energy, direction, and interaction vertex, the resolution improves by an average of 13%–20% compared to current maximum likelihood techniques in the energy range of 1 GeV–30 GeV. The GNN, when run on a GPU, is capable of processing IceCube events at a rate nearly double of the median IceCube trigger rate of 2.7 kHz, which opens the possibility of using low energy neutrinos in online searches for transient events.

Galactic PeV cosmic-ray accelerators (PeVatrons) are Galactic sources theorized to accelerate cosmic rays up to PeV in energy. The accelerated cosmic rays are expected to interact hadronically with nearby ambient gas or the interstellar medium, resulting in γ-rays and neutrinos. Recently, the Large High Altitude Air Shower Observatory (LHAASO) identified 12 γ-ray sources with emissions above 100 TeV, making them candidates for PeVatrons. While at these high energies the Klein–Nishina effect exponentially suppresses leptonic emission from Galactic sources, evidence for neutrino emission would unequivocally confirm hadronic acceleration. Here, we present the results of a search for neutrinos from these γ-ray sources and stacking searches testing for excess neutrino emission from all 12 sources as well as their subcatalogs of supernova remnants and pulsar wind nebulae with 11 yr of track events from the IceCube Neutrino Observatory. No significant emissions were found. Based on the resulting limits, we place constraints on the fraction of γ-ray flux originating from the hadronic processes in the Crab Nebula and LHAASO J2226+6057.