Broadening of the Divertor Heat Flux Profile in High Confinement Tokamak Fusion Plasmas with Edge Pedestals Limited by Turbulence in DIII-D.

Multimachine empirical scaling predicts an extremely narrow heat exhaust layer in future high magnetic field tokamaks, producing high power densities that require mitigation. In the experiments presented, the width of this exhaust layer is nearly doubled using actuators to increase turbulent transport in the plasma edge. This is achieved in low collisionality, high confinement edge pedestals with their gradients limited by turbulent transport instead of large-scale, coherent instabilities. The exhaust heat flux profile width and divertor leg diffusive spreading both double as a high frequency band of turbulent fluctuations propagating in the electron diamagnetic direction doubles in amplitude. The results are quantitatively reproduced in electromagnetic XGC particle-in-cell simulations which show the heat flux carried by electrons emerges to broaden the heat flux profile, directly supported by Langmuir probe measurements.

A closer look at mammalian antiviral condensates.

Several biomolecular condensates assemble in mammalian cells in response to viral infection. The most studied of these are stress granules (SGs), which have been proposed to promote antiviral innate immune signaling pathways, including the RLR-MAVS, the protein kinase R (PKR), and the OAS-RNase L pathways. However, recent studies have demonstrated that SGs either negatively regulate or do not impact antiviral signaling. Instead, the SG-nucleating protein, G3BP1, may function to perturb viral RNA biology by condensing viral RNA into viral-aggregated RNA condensates, thus explaining why viruses often antagonize G3BP1 or hijack its RNA condensing function. However, a recently identified condensate, termed double-stranded RNA-induced foci, promotes the activation of the PKR and OAS-RNase L antiviral pathways. In addition, SG-like condensates known as an RNase L-induced bodies (RLBs) have been observed during many viral infections, including SARS-CoV-2 and several flaviviruses. RLBs may function in promoting decay of cellular and viral RNA, as well as promoting ribosome-associated signaling pathways. Herein, we review these recent advances in the field of antiviral biomolecular condensates, and we provide perspective on the role of canonical SGs and G3BP1 during the antiviral response.

RNase L-induced bodies sequester subgenomic flavivirus RNAs and re-establish host RNA decay.

Subgenomic flavivirus RNAs (sfRNAs) are structured RNA elements encoded in the 3'-UTR of flaviviruses that promote viral infection by inhibiting cellular RNA decay machinery. Herein, we analyze the production of sfRNAs using single-molecule RNA fluorescence in situ hybridization (smRNA-FISH) and super-resolution microscopy during West Nile virus, Zika virus, or Dengue virus serotype 2 infection. We show that sfRNAs are initially localized diffusely in the cytosol or in processing bodies (P-bodies). However, upon activation of the host antiviral endoribonuclease, Ribonuclease L (RNase L), nearly all sfRNAs re-localize to antiviral biological condensates known as RNase L-induced bodies (RLBs). RLB-mediated sequestration of sfRNAs reduces sfRNA association with RNA decay machinery in P-bodies, which coincides with increased viral RNA decay. These findings establish a role of RLBs in promoting viral RNA decay, demonstrating the complex host-pathogen interactions at the level of RNA decay and biological condensation.

Mechanisms and consequences of mRNA destabilization during viral infections.

During viral infection there is dynamic interplay between the virus and the host to regulate gene expression. In many cases, the host induces the expression of antiviral genes to combat infection, while the virus uses "host shut-off" systems to better compete for cellular resources and to limit the induction of the host antiviral response. Viral mechanisms for host shut-off involve targeting translation, altering host RNA processing, and/or inducing the degradation of host mRNAs. In this review, we discuss the diverse mechanisms viruses use to degrade host mRNAs. In addition, the widespread degradation of host mRNAs can have common consequences including the accumulation of RNA binding proteins in the nucleus, which leads to altered RNA processing, mRNA export, and changes to transcription.

G3BP1-dependent condensation of translationally inactive viral RNAs antagonizes infection.

G3BP1 is an RNA binding protein that condenses untranslating messenger RNAs into stress granules (SGs). G3BP1 is inactivated by multiple viruses and is thought to antagonize viral replication by SG-enhanced antiviral signaling. Here, we show that neither G3BP1 nor SGs generally alter the activation of innate immune pathways. Instead, we show that the RNAs encoded by West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 are prone to G3BP1-dependent RNA condensation, which is enhanced by limiting translation initiation and correlates with the disruption of viral replication organelles and viral RNA replication. We show that these viruses counteract condensation of their RNA genomes by inhibiting the RNA condensing function of G3BP proteins, hijacking the RNA decondensing activity of eIF4A, and/or maintaining efficient translation. These findings argue that RNA condensation can function as an intrinsic antiviral mechanism, which explains why many viruses inactivate G3BP proteins and suggests that SGs may have arisen as a vestige of this antiviral mechanism.

Single-cell analysis of RNase L-mediated mRNA decay.

Ribonuclease L (RNase L) is a mammalian endoribonuclease that initiates the mass degradation of cellular mRNAs in response to double-stranded RNA or viral infection. The kinetic rate of mRNA decay upon RNase L activation has been elusive because RNase L is heterogeneously activated with respect to time in individual cells. Herein, we describe a method using immunofluorescence combined with single-molecule fluorescence in situ hybridization (smFISH) to determine single-cell mRNA decay rates upon RNase L activation. Using these approaches, we deduce that the rate of mRNA decay upon RNase L activation is extremely rapid, whereby the half-life of stable mRNAs such as GAPDH mRNA is reduced to ∼15 minutes in individual cells. This allows for RNase L to degrade nearly every mRNA in a cell in less than 1 hour, which is much faster than the decay rate that would be derived using bulk measurement techniques for mRNA levels, such as qRT-PCR. These single-cell approaches can generally be employed to resolve mRNA decay kinetics in additional contexts.

Profile of and risk factors for early unplanned readmissions in patients with acute necrotizing pancreatitis.

INTRODUCTION: Acute necrotizing pancreatitis (ANP) complicates up to 15% of acute pancreatitis cases. ANP has historically been associated with a significant risk for readmission, but there are currently no studies exploring factors that associate with risk for unplanned, early (<30-day) readmissions in this patient population. METHODS: We performed a retrospective review of all consecutive patients presenting to hospitals in the Indiana University (IU) Health system with pancreatic necrosis between December 2016 and June 2020. Patients younger than 18 years of age, without confirmed pancreatic necrosis and those that suffered in-hospital mortality were excluded. Logistic regression was performed to identify potential predictors of early readmission in this group of patients. RESULTS: One hundred and sixty-two patients met study criteria. 27.7% of the cohort was readmitted within 30-days of index discharge. The median time to readmission was 10 days (IQR 5-17 days). The most frequent reason for readmission was abdominal pain (75.6%), followed by nausea and vomiting in (35.6%). Discharge to home was associated with 93% lower odds of readmission. We found no additional clinical factors that predicted early readmission. CONCLUSION: Patients with ANP have a significant risk for early (<30 days) readmission. Direct discharge to home, rather than short or long-term rehabilitation facilities, is associated with lower odds of early readmission. Analysis was otherwise negative for independent, clinical predictors of early unplanned readmissions in ANP.

Glucagon-like peptide-1 secretion in people with versus without type 2 diabetes: a systematic review and meta-analysis of cross-sectional studies.

AIMS/HYPOTHESIS: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. METHODS: A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1TOTAL and GLP-1TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). RESULTS: Pooled across 18 studies, the overall SMD in GLP-1TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L-1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L-1·min) was very small, not statistically significant and heterogenous across studies (g = -0.15, p = 0.43, PI: -1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = -0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L-1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L-1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: -1.55, 2.02). CONCLUSIONS: Differences in fasting GLP-1TOTAL and GLP-1TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID: CRD42020195612.

Measurements of multiple heat flux components at the divertor target by using surface eroding thermocouples (invited).

The Surface Eroding Thermocouple (SETC) is a robust diagnostic utilized in DIII-D to provide fast, edge-localized modes (ELMs) resolved heat flux measurements, in particular in geometric regions that are too shadowed for traditional infrared thermography. In order to further investigate the power dissipation in the divertor region, a combination of flush-mounted and recessed SETCs was developed to assess the effect on surface heating from non-charged particles at the divertor target. Utilizing the Divertor Materials Evaluation System sample exposure platform, the first demonstration of the feasibility of using this new method to distinguish between the heat flux from charged particles and that from neutrals and radiative heating was achieved. This paper details the process of using the combination of flush SETCs and recessed SETCs to measure the multiple heat flux components at the divertor target and further discusses how to determine two important ratios, α (ratio of heat flux from charged particles deposit on recessed SETC to that deposit on flush SETC) and ß (ratio of heat flux from non-charged particles deposit on recessed SETC to that deposit on flush SETC), in the estimation of the heat flux from non-charged particle sources. Using a time dependent ratio α, it was found that ∼50% of the total incident heat flux is attributable to the non-charged particles in the fully detached open divertor in DIII-D. Finally, the new application of similar SETC diagnostics in the Small Angle Slot divertor with a V-like configuration and partial tungsten coated surface (SAS-VW) is also introduced.

An Engineered Monovalent Anti-TNF-α Antibody with pH-Sensitive Binding Abrogates Immunogenicity in Mice following a Single Intravenous Dose.

Therapeutic Abs directed toward TNF-α display significant immunogenicity in humans, frequently leading to lower serum concentrations of the Ab that are associated with lower treatment efficacy. The enhanced incidence of immunogenicity observed with this class of therapeutics may be mediated by the expression of TNF-α as a homotrimer, both as a soluble serum protein and as a membrane-associated protein (mTNF-α) on the surface of dendritic cells. The TNF-α homotrimer enables the formation of polyvalent Ab-TNF-α immune complexes (ICs) that enhance binding to FcR and neonatal FcR. Polyvalent ICs and Ab bound to mTNF-α on the surface of dendritic cells can internalize, traffic to the lysosomes, and be processed for presentation by MHC molecules. To diminish immunogenicity caused by trafficking of ICs and mTNF-α to the lysosomes, we engineered a monovalent format of adalimumab with pH-sensitive binding to TNF-α. The engineered variant, termed AF-M2637, did not cross-link TNF-α trimers and consequently formed small, nonprecipitating ICs only. AF-M2637 bound TNF-α with high affinity at pH 7.4 (EC50 = 1.1 nM) and displayed a significantly faster dissociation rate than adalimumab at pH 6.0. No immune response to AF-M2637 was detected in mice following a single i.v. dose. In contrast, rapid immunization was detected following the injection of a single i.v. dose of adalimumab, monovalent adalimumab, or the bivalent form of the pH-sensitive variant. These data suggest that ICs and mTNF-α both contribute to the immunogenicity of adalimumab in mice and provide a general strategy for engineering less immunogenic therapeutic TNF-α Abs.

An epidemiological investigation of COVID-19 outbreaks in a group of care homes in Wales, UK: a retrospective cohort study.

BACKGROUND: This study describes the epidemiology of COVID-19 outbreaks in four care homes in terms of spread, severity, presentation and interventions. METHODS: Participants were 100 residents and 102 staff from four co-located care homes in Wales. Data were collected from the homes and Public Health Wales, including demographics, presentations, test status and results, hospital admissions and deaths. Genomic sequencing of confirmed case samples was completed, where possible. Epi-curves, crude attack rates, a Kaplan-Meier survival curve and adjusted hazard ratios were calculated using R. RESULTS: About 14 confirmed and 43 possible resident cases, 23 confirmed and 47 possible staff cases occurred. Crude attack rates of possible and confirmed cases were 57% (residents) and 69% (staff). Genomic sequencing for 10 confirmed case PCR samples identified at least 5 different UK lineages of COVID-19.42 (42%) residents died, 23 (55%) with COVID-19 or suspected COVID-19 recorded on the death certificate. The hazard ratio for death amongst resident possible and confirmed cases compared to null cases, adjusting for age and sex, was 13.26 (95% CI 5.61-31.34). CONCLUSIONS: There were extensive outbreaks of COVID-19 in these homes with high crude attack rates and deaths. Universal testing and early isolation of residents are recommended.

Langmuir probe array for the small angle slot divertor in DIII-D.

The DIII-D small angle slot (SAS) divertor is designed for divertor physics studies with enhanced neutral confinement and special target geometries in a closed divertor. The closed nature of the SAS makes optical diagnostic measurements difficult, so a specially designed, multipurpose array of Langmuir probes has been implemented to study the plasma conditions in and around the slot. The probes are spaced to provide at least 2 mm resolution (shorter than the energy decay length) of the near scrape-off layer when mapped to the outer mid-plane. Due to space limitations at the bottom of the slot, a novel spring-loaded probe and tile design was developed to clamp several short rooftop probe tips and insulators to the cooled baseplate. Initial probe measurements revealed tile to tile edge shadowing, especially where magnetic field line surface angles were less than 1°. Additionally, it was found, using three Langmuir probes (at 90°, 180°, and 270°), that the strike point variation of ±5 mm radially around the torus was not well aligned with the circular slot geometry [Watkins et al., Nucl. Mater. Energy 18, 46 (2019)]. These issues were resolved by (1) designing tiles with all probes mounted near the tile center instead of near the edges and (2) aligning these new custom tiles to the measured strike point toroidal surface with a very accurate laser scanning alignment tool. Post-alignment Langmuir probe measurements and plasma behavior demonstrated close agreement at two separate toroidal locations that were 45° apart.

Integration of full divertor detachment with improved core confinement for tokamak fusion plasmas.

Divertor detachment offers a promising solution to the challenge of plasma-wall interactions for steady-state operation of fusion reactors. Here, we demonstrate the excellent compatibility of actively controlled full divertor detachment with a high-performance (ßN ~ 3, H98 ~ 1.5) core plasma, using high-ßp (poloidal beta, ßp > 2) scenario characterized by a sustained core internal transport barrier (ITB) and a modest edge transport barrier (ETB) in DIII-D tokamak. The high-ßp high-confinement scenario facilitates divertor detachment which, in turn, promotes the development of an even stronger ITB at large radius with a weaker ETB. This self-organized synergy between ITB and ETB, leads to a net gain in energy confinement, in contrast to the net confinement loss caused by divertor detachment in standard H-modes. These results show the potential of integrating excellent core plasma performance with an efficient divertor solution, an essential step towards steady-state operation of reactor-grade plasmas.

First Evidence of Local E×B Drift in the Divertor Influencing the Structure and Stability of Confined Plasma near the Edge of Fusion Devices.

The structure of the edge plasma in a magnetic confinement system has a strong impact on the overall plasma performance. We uncover for the first time a magnetic-field-direction dependent density shelf, i.e., local flattening of the density radial profile near the magnetic separatrix, in high confinement plasmas with low edge collisionality in the DIII-D tokamak. The density shelf is correlated with a doubly peaked density profile near the divertor target plate, which tends to occur for operation with the ion B×∇B drift direction away from the X-point, as currently employed for DIII-D advanced tokamak scenarios. This double-peaked divertor plasma profile is connected via the E×B drifts, arising from a strong radial electric field induced by the radial electron temperature gradient near the divertor target. The drifts lead to the reversal of the poloidal flow above the divertor target, resulting in the formation of the density shelf. The edge density shelf can be further enhanced at higher heating power, preventing large, periodic bursts of the plasma, i.e., edge-localized modes, in the edge region, consistent with ideal magnetohydrodynamics calculations.

Prenatal infection with Mycoplasma pulmonis in rats exaggerates the angiotensin II pressor response in adult offspring.

Exposure to different stressors in utero is linked to adult diseases such as obesity and hypertension. In this study, the impact of prenatal infection (PNI) on adult body weight and cardiovascular function was evaluated using a naturally occurring rodent pathogen, Mycoplasma pulmonis (MP). Pregnant Sprague-Dawley rats were infected with MP on gestationalday 14 and gave birth naturally. Adult PNI offspring weighed more than controls, but resting mean arterial pressure (MAP) was unchanged. Subcutaneous injection of angiotensin II (10 µg/kg) elicited a rise in MAP that was greater in both male and female PNI offspring compared with controls (P < 0.03). The accompanying reflex bradycardia was similar to the controls, suggesting that PNI induced baroreflex dysfunction. Subcutaneous nicotine administration, a potent cardiorespiratory stimulus, also elicited a transient rise in MAP that was generally greater in the PNI group, but the change in MAP from baseline was only significant in the PNI females compared with controls (P < 0.03). Elevated body weight and cardiovascular reactivity in the PNI offspring was associated with an increase in the ratio of hypothalamic corticotrophin-releasing hormone receptors type 1 to type 2 gene expression in both sexes compared with controls. These findings support previous studies demonstrating that PNI induces alterations in cardiovascular function and body weight. Yet, unlike previous studies utilizing other models of PNI (e.g., endotoxin), MP PNI did not induce resting hypertension. Thus, our study provides a foundation for future studies evaluating the cardiovascular risks of offspring exposed to microbial challenges in utero.

The 1980s: D-AP5, LTP and a Decade of NMDA Receptor Discoveries.

In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of D-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.

Imaging divertor strike point splitting in RMP ELM suppression experiments in the DIII-D tokamak.

Fast visible imaging of the lower divertor from above is used to study the structure and dynamics of lobes induced by resonant magnetic perturbations (RMPs) in Edge-Localized Mode (ELM) suppression experiments in DIII-D. The best compromise between the amount of light and sharp imaging was obtained using emission at 601 nm from Fulcher band molecular deuterium. Multiple spatially resolved peaks in the D2 emission, taken as a proxy for the particle flux, are readily resolved during RMPs, in contrast to the heat flux measured by infrared cameras, which shows little spatial structure in ITER-like conditions. The 25 mm objective lens provides high spatial resolution (2-4 mm/pixel) from the centerpost to the outer shelf over 40° toroidally that overlaps the field of view of the IRTV that measures the divertor heat flux, allowing direct comparison in non-axisymmetric discharges. The image is coupled to a Phantom 7.3 camera using a Schott wound fiber bundle, providing high temporal resolution that allows the lobe dynamics to be resolved between ELMs and across ELM suppression onset. These measurements are used to study the heat and particle flux in 3D magnetic fields and to validate models for the plasma response to RMPs.

The surface eroding thermocouple for fast heat flux measurement in DIII-D.

A novel type of surface eroding thermocouple (SETC) has been tested and demonstrated in the small angle slot (SAS) divertor of DIII-D for fast local heat flux measurements. The thermojunction of the SETC is formed between two thin (10 µm) ribbons, which are filed over to create microfiber junctions. These thermocouples are able to be exposed directly to the plasma at surface temperatures exceeding 2000 °C and are capable of sub-10 ms time resolution. Before installation in SAS, the SETCs were exposed in the lower DIII-D divertor during L-mode and H-mode discharges, from which results are presented. In preliminary tests, SETCs proved to be a qualified diagnostic to accurately measure both the intra-edge localized mode (ELM) and inter-ELM heat flux during H-mode shots with high frequency ELMs (hundreds of Hz) and to resolve heat flux profiles during strike point sweeps. The heat fluxes measured by using SETCs are consistent with the heat fluxes measured by using IR cameras and Langmuir probes. These new diagnostic capabilities will complement the existing IR camera measurements and will be of particularly significant value to measure surface heat flux in the SAS divertor or other regions where the IR camera lacks line of sight.

Brachionus leydigii (Monogononta: Ploima) reported from the western basin of Lake Erie.

Several species of non-indigenous planktonic invertebrates have historically been introduced to the Laurentian Great Lakes. Previous introductions of non-indigenous planktonic invertebrates to the Great Lakes have been crustacean zooplankton, specifically Cladocera and Copepoda. This report documents the first known occurrence of Brachionus leydigii var. tridentatus (Zernov, 1901) in Lake Erie and possibly the first detection of a non-indigenous rotifer species in the Laurentian Great Lakes. The specimen was collected from a U.S. EPA monitoring station in the western basin of Lake Erie on April 4, 2016.