SKS Splitting Beneath Mount St. Helens: Constraints on Subslab Mantle Entrainment

Observations of seismic anisotropy can provide direct constraints on the character of mantleflow in subduction zones, critical for our broader understanding of subduction dynamics. Here wepresent over 750 new SKS splitting measurements in the vicinity of Mount St. Helens in the Cascadiasubduction zone using a combination of stations from the iMUSH broadband array and Cascades VolcanoObservatory network. This provides the highest density of splitting measurements yet available inCascadia, acting as a focused“telescope”for seismic anisotropy in the subduction zone. We retrieve spatiallyconsistent splitting parameters (mean fast directionΦ: 74°, mean delay time∂t: 1.0 s) with the azimuthaloccurrence of nulls in agreement with the fast direction of splitting. When averaged across the array, a90° periodicity in splitting parameters as a function of back azimuth is revealed, which has not beenrecovered previously with single‐station observations. The periodicity is characterized by a sawtooth patterninΦwith a clearly defined 45° trend. We present new equations that reproduce this behavior based uponknown systematic errors when calculating shear wave splitting from data with realistic seismic noise.The corrected results suggest a single layer of anisotropy with an ENE‐WSW fast axis parallel to the motionof the subducting Juan de Fuca plate; in agreement with predictions for entrained subslab mantleflow. Thesplitting pattern is consistent with that seen throughout Cascadia, suggesting that entrainment of theunderlying asthenosphere with the subducting slab is coherent and widespread.The broadband seismic component of the iMUSH project was supported by National Science Foundation grants EAR‐1144568, EAR‐1144351, EAR‐1460291, and EAR‐1444275. CME acknowledges support from the Australian Research Council (DE190100062). We thank the 2017 IRIS undergraduate summer intern program for providing support to A. W. to work with E. A. W. at the University of Washington. The facilities of IRIS Data Services, and specifically the IRIS Data Management Center, were used for access to waveforms, related metadata, and/or derived products used in this study. IRIS Data Services are funded through the Seismological Facilities for the Advancement of Geoscience and EarthScope (SAGE) Proposal of the National Science Foundation under Cooperative Agreement EAR‐1261681

Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study

Objective: To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE). Methods: A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37–39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA). Results: Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels. Conclusions: Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing

p62-mediated Selective Autophagy Endows Virus-Transformed Cells With Insusceptibility to DNA Damage Under Oxidative Stress

DNA damage response (DDR) and selective autophagy both can be activated by reactive oxygen/nitrogen species (ROS/RNS), and both are of paramount importance in cancer development. The selective autophagy receptor and ubiquitin (Ub) sensor p62 plays a key role in their crosstalk. ROS production has been well documented in latent infection of oncogenic viruses including Epstein-Barr Virus (EBV). However, p62-mediated selective autophagy and its interplay with DDR have not been investigated in these settings. In this study, we provide evidence that considerable levels of p62-mediated selective autophagy are spontaneously induced, and correlate with ROS-Keap1-NRF2 pathway activity, in virus-transformed cells. Inhibition of autophagy results in p62 accumulation in the nucleus, and promotes ROS-induced DNA damage and cell death, as well as downregulates the DNA repair proteins CHK1 and RAD51. In contrast, MG132-mediated proteasome inhibition, which induces rigorous autophagy, promotes p62 degradation but accumulation of the DNA repair proteins CHK1 and RAD51. However, pretreatment with an autophagy inhibitor offsets the effects of MG132 on CHK1 and RAD51 levels. These findings imply that p62 accumulation in the nucleus in response to autophagy inhibition promotes proteasome-mediated CHK1 and RAD51 protein instability. This claim is further supported by the findings that transient expression of a p62 mutant, which is constitutively localized in the nucleus, in B cell lines with low endogenous p62 levels recaptures the effects of autophagy inhibition on CHK1 and RAD51 protein stability. These results indicate that proteasomal degradation of RAD51 and CHK1 is dependent on p62 accumulation in the nucleus. However, small hairpin RNA (shRNA)-mediated p62 depletion in EBV-transformed lymphoblastic cell lines (LCLs) had no apparent effects on the protein levels of CHK1 and RAD51, likely due to the constitutive localization of p62 in the cytoplasm and incomplete knockdown is insufficient to manifest its nuclear effects on these proteins. Rather, shRNA-mediated p62 depletion in EBV-transformed LCLs results in significant increases of endogenous RNF168-γH2AX damage foci and chromatin ubiquitination, indicative of activation of RNF168-mediated DNA repair mechanisms. Our results have unveiled a pivotal role for p62-mediated selective autophagy that governs DDR in the setting of oncogenic virus latent infection, and provide a novel insight into virus-mediated oncogenesis

Assessment of antibiotic-resistant organism transmission among rooms of hospitalized patients, healthcare personnel, and the hospital environment utilizing surrogate markers and selective bacterial cultures

OBJECTIVE: To assess potential transmission of antibiotic-resistant organisms (AROs) using surrogate markers and bacterial cultures. DESIGN: Pilot study. SETTING: A 1,260-bed tertiary-care academic medical center. PARTICIPANTS: The study included 25 patients (17 of whom were on contact precautions for AROs) and 77 healthcare personnel (HCP). METHODS: Fluorescent powder (FP) and MS2 bacteriophage were applied in patient rooms. HCP visits to each room were observed for 2-4 hours; hand hygiene (HH) compliance was recorded. Surfaces inside and outside the room and HCP skin and clothing were assessed for fluorescence, and swabs were collected for MS2 detection by polymerase chain reaction (PCR) and selective bacterial cultures. RESULTS: Transfer of FP was observed for 20 rooms (80%) and 26 HCP (34%). Transfer of MS2 was detected for 10 rooms (40%) and 15 HCP (19%). Bacterial cultures were positive for 1 room and 8 HCP (10%). Interactions with patients on contact precautions resulted in fewer FP detections than interactions with patients not on precautions (P \u3c .001); MS2 detections did not differ by patient isolation status. Fluorescent powder detections did not differ by HCP type, but MS2 was recovered more frequently from physicians than from nurses (P = .03). Overall, HH compliance was better among HCP caring for patients on contact precautions than among HCP caring for patients not on precautions (P = .003), among nurses than among other nonphysician HCP at room entry (P = .002), and among nurses than among physicians at room exit (P = .03). Moreover, HCP who performed HH prior to assessment had fewer fluorescence detections (P = .008). CONCLUSIONS: Contact precautions were associated with greater HCP HH compliance and reduced detection of FP and MS2

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

Using Gap-Induced Inhibition of the Post-Auricular Muscle Response as an Objective Measure of Tinnitus in Humans

A widely used method for detecting tinnitus in rodents is the gap pre-pulse inhibition of the acoustic startle (GPIAS). One variant uses the Preyer reflex to assess the startle response and a component of this can be measured as a small muscle potential generated by the post-auricular muscle reflex (PAMR). The question was whether the GPIAS method could also be used to identify tinnitus in humans using the PAMR response. We recruited 19 participants with chronic tinnitus and 18 age-matched controls, but 12 tinnitus participants were unable to contribute data to the final result due to hyperacusis or lack of a PAMR. A majority of those tinnitus participants with a detectable PAMR showed some evidence of GPIAS (71%, 5/7). In the control group, most showed a PAMR response (67%, 12/18) and most of these demonstrated GPIAS (67%, 8/12). Our stimulus parameters were not completely optimal for showing a PAMR response so, with further refinement it may be possible to use the PAMR response and GPIAS as an objective method for demonstrating tinnitus in humans

Isolation of SARS-CoV-2 in viral cell culture in immunocompromised patients with persistently positive RT-PCR results

Immunocompromised adults can have prolonged acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive RT-PCR results, long after the initial diagnosis of coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 virus can be recovered in viral cell culture from immunocompromised adults with persistently positive SARS-CoV-2 RT-PCR tests. We obtained 20 remnant SARS-CoV-2 PCR positive nasopharyngeal swabs from 20 immunocompromised adults with a positive RT-PCR test ≥14 days after the initial positive test. The patients\u27