A high-density and high-confinement tokamak plasma regime for fusion energy.

The tokamak approach, utilizing a toroidal magnetic field configuration to confine a hot plasma, is one of the most promising designs for developing reactors that can exploit nuclear fusion to generate electrical energy1,2. To reach the goal of an economical reactor, most tokamak reactor designs3-10 simultaneously require reaching a plasma line-averaged density above an empirical limit-the so-called Greenwald density11-and attaining an energy confinement quality better than the standard high-confinement mode12,13. However, such an operating regime has never been verified in experiments. In addition, a long-standing challenge in the high-confinement mode has been the compatibility between a high-performance core and avoiding large, transient edge perturbations that can cause very high heat loads on the plasma-facing-components in tokamaks. Here we report the demonstration of stable tokamak plasmas with a line-averaged density approximately 20% above the Greenwald density and an energy confinement quality of approximately 50% better than the standard high-confinement mode, which was realized by taking advantage of the enhanced suppression of turbulent transport granted by high density-gradients in the high-poloidal-beta scenario14,15. Furthermore, our experimental results show an integration of very low edge transient perturbations with the high normalized density and confinement core. The operating regime we report supports some critical requirements in many fusion reactor designs all over the world and opens a potential avenue to an operating point for producing economically attractive fusion energy.

Localized mammary gland changes in milk composition and venous blood metabolite concentrations result from sterile subclinical mastitis.

Subclinical mastitis reduces milk yield and elicits undesirable changes in milk composition, but the mechanisms resulting in reduced milk production in affected mammary glands are incompletely understood. This study investigated the effects of sterile inflammation on mammary gland metabolism by assessing changes in milk and venous blood composition. Mid-lactation primiparous Holstein cows (n = 4) had udder halves randomly allocated to treatments; quarters of 1 udder half were infused with 2 billion cfu of formalin fixed Staphylococcus aureus (FX-STAPH) and quarters of the opposite udder half infused with saline (SAL). Blood samples were collected from the right and left subcutaneous abdominal veins in 2.6 h intervals until 40 h post challenge and analyzed for blood gas and metabolite concentrations. Milk from FX-STAPH udder halves had significantly increased SCS by first milking at 8 h post-challenge. By 16 h post-challenge, FX-STAPH udder halves had increased concentrations of protein and lactate and lower lactose concentrations than SAL udder halves. Milk fat concentrations, milk yields, energy corrected milk yields, and the ferric reducing antioxidant power of milk were not significantly different between SAL and FX-STAPH udder halves. Venous blood of FX-STAPH halves had marginally greater concentrations of saturated O2, partial pressures of O2, and glucose concentrations than SAL halves. Conversely, total and partial pressures of CO2 did not differ between udder half treatments suggesting a shift in local metabolite utilization in FX-STAPH udder halves. These results indicate that changes in milk composition resulting from mastitis are accompanied by changes in some key blood metabolite concentrations. The shift in venous blood metabolite concentrations, along with the marked increase in milk lactate, suggests that local mammary tissue and/or recruited and immune cells alters metabolite usage in mammary tissues. Future studies are needed to quantify the uptake of key milk precursors during mastitis.

Demonstration of improved laser preheat with a cryogenically cooled magnetized liner inertial fusion platform.

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

The immune response to a fungus in pancreatic cancer samples.

Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an .aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 paired tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.

A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

A split influenza vaccine formulated with a combination adjuvant composed of alpha-D-glucan nanoparticles and a STING agonist elicits cross-protective immunity in pigs.

BACKGROUND: Swine influenza A viruses (SwIAVs) pose an economic and pandemic threat, and development of novel effective vaccines is of critical significance. We evaluated the performance of split swine influenza A virus (SwIAV) H1N2 antigens with a plant-derived nanoparticle adjuvant alone (Nano-11) [Nano11-SwIAV] or in combination with the synthetic stimulator of interferon genes (STING) agonist ADU-S100 (NanoS100-SwIAV). Specific pathogen free (SPF) pigs were vaccinated twice via intramuscular (IM) or intradermal (ID) routes and challenged with a virulent heterologous SwIAV H1N1-OH7 virus. RESULTS: Animals vaccinated IM or ID with NanoS100-SwIAV had significantly increased cross-reactive IgG and IgA titers in serum, nasal secretion and bronchoalveolar lavage fluid at day post challenge 6 (DPC6). Furthermore, NanoS100-SwIAV ID vaccinates, even at half the vaccine dose compared to their IM vaccinated counterparts, had significantly increased frequencies of CXCL10+ myeloid cells in the tracheobronchial lymph nodes (TBLN), and IFNγ+ effector memory T-helper/memory cells, IL-17A+ total T-helper/memory cells, central and effector memory T-helper/memory cells, IL-17A+ total cytotoxic T-lymphocytes (CTLs), and early effector CTLs in blood compared with the Nano11-SwIAV group demonstrating a potential dose-sparing effect and induction of a strong IL-17A+ T-helper/memory (Th17) response in the periphery. However, the frequencies of IFNγ+ late effector CTLs and effector memory T-helper/memory cells, IL-17A+ total CTLs, late effector CTLs, and CXCL10+ myeloid cells in blood, as well as lung CXCL10+ plasmacytoid dendritic cells were increased in NanoS100-SwIAV IM vaccinated pigs. Increased expression of IL-4 and IL-6 mRNA was observed in TBLN of Nano-11 based IM vaccinates following challenge. Furthermore, the challenge virus load in the lungs and nasal passage was undetectable in NanoS100-SwIAV IM vaccinates by DPC6 along with reduced macroscopic lung lesions and significantly higher virus neutralization titers in lungs at DPC6. However, NanoS100-SwIAV ID vaccinates exhibited significant reduction of challenge virus titers in nasal passages and a remarkable reduction of challenge virus in lungs. CONCLUSIONS: Despite vast genetic difference (77% HA gene identity) between the H1N2 and H1N1 SwIAV, the NanoS100 adjuvanted vaccine elicited cross protective cell mediated immune responses, suggesting the potential role of this combination adjuvant in inducing cross-protective immunity in pigs.

Outcomes of rapid digital transformation of large-scale communications during the COVID-19 pandemic.

Objective This study examined the content and impact of a new digital communication medium, called a VIDCAST, implemented at a large hospital and health service when the COVID-19 pandemic was announced, and the key concerns held by staff at the time when the health service was preparing for the COVID-19 pandemic to arrive in this health service. Methods A mixed-methods approach was used. Thematic analysis of 20 transcripts of daily VIDCASTS broadcast between 30 March and 24 April 2020 was undertaken, in addition to descriptive analysis of feedback from an anonymous online survey. Results Survey feedback from 322 staff indicated almost universal satisfaction with this new communication method. The VIDCASTS provided a new COVID-safe method for the Executive to connect to staff at a time of uncertainty. Thematic analysis of the content of the VIDCASTS revealed three themes: 'Accurate Information', 'Reassurance and Support' and 'Innovation'. The Executive was able to reassure staff about what the organisation was doing to safeguard the health and wellbeing of all, and enabled an effective response to the pandemic. Conclusions The digital communication channel of VIDCASTS, rapidly operationalised at a major Australian hospital and health service in March 2020, provided important information and support for staff as it prepared for the anticipated COVID-19 surge. What is known about the topic? When the COVID-19 pandemic began, traditional face-to-face staff meetings were disrupted and many hospitals and their staff were left scrambling for information, and for reassurance about their safety, as they prepared to receive increasing numbers of COVID-19 patients. What does this paper add? The implementation of a digital communication tool was able to address many of the concerns raised by hospital staff in other geographic locations dealing with surging COVID-19 cases and underpinned a globally leading COVID-19 response. What are the implications for practitioners? New digitised communication methods provided an effective vehicle to inform and support staff in the early stages of pandemic preparation.

Development of a deuterium-ice extruder for inertial confinement fusion experiments on the Z Facility.

A deuterium-ice extruder has been developed for inertial confinement fusion experiments on the Sandia National Laboratories Z Facility. The screw-driven extruder is filled via desublimation, where a slow flow of deuterium gas enters the extruder cavity and freezes to the walls without entering the liquid phase. Ice generated in this manner is optically clear, demonstrating its high uniformity. When the extruder cavity is filled with ice, the screw is driven downward, closing off the gas-fill line. With the ice cavity isolated, further screw rotation compresses the deuterium through a nozzle, extruding a fiber. Fiber diameters ranging from 200 to 500 µm have been extruded to lengths of 1.5 feet before hitting the vacuum chamber floor. The fiber straightness improves with the nozzle length-to-diameter aspect ratio. Deuterium-ice fibers can persist in high vacuum for more than 10 min before breaking free from the nozzle. The peripheral infrastructure required for Z experimental operations is under development. An in-vacuum stepper-motor-based drive system will allow remote operation, and a translating cathode will ensure proper placement of the fiber in the powerflow hardware.

Organization of mammary blood vessels as affected by mammary parenchymal region and estradiol administration in Holstein heifer calves.

Mammary blood flow is central to mammary growth, development, and productivity, but the development of the vasculature network is poorly understood. The objective of this study was to determine how the vascular system adapts to mammary growth by inducing different levels of mammary growth and examining 2 regions of mammary parenchymal tissue. Holstein heifer calves (n = 12) received daily injections on the days immediately preceding euthanasia at 82 d of age. Treatments were control (CON), short-term estradiol (STE), and long-term estradiol (LTE). The CON calves received corn oil injections, the STE calves received 9 injections of corn oil followed by 3 injections of estradiol, and the LTE calves received 12 estradiol injections. Mammary tissues were collected from the center and edge parenchymal regions of all right rear mammary glands to quantify the tissue area of various tissue structures, the percentage of proliferating epithelial cells, and the number and form of blood vessels. Results showed that LTE calves had a greater tissue area occupied by epithelium than CON and STE calves, and the epithelial area in CON and STE calves was similar. Edge parenchyma had a greater percentage of proliferating epithelial cells than center parenchyma across all treatment groups. In the edge region, LTE calves had the greatest percentage of proliferating epithelial cells, coinciding with greater epithelial area. The number of blood vessels per unit of tissue area was greater in center than in edge parenchyma; the corresponding vessel surface area per unit of tissue area followed the same pattern. Mammary blood vessel measures were not markedly influenced by estradiol treatment. These results highlight the marked difference in the number and organization of blood vessels in different mammary parenchyma regions but indicate that the effects of estradiol on stimulating mammary epithelial proliferation does not directly translate to increasing numbers of blood vessels.

[Novel drug targets and therapeutic perspectives. Towards a precision medicine]. / Nouvelles cibles et perspectives thérapeutiques. Vers une médecine de précision.

A therapeutic target can be defined as the biochemical entity by which a drug exerts its beneficial effects. Historically, most drugs have been used without a precise knowledge of their mechanism of action. The rational drug design for a predefined target has been progressively implemented during the second half of the 20th century. Recent advances in genomics have accelerated the discovery of several targets involved in many pathologies. During the recent period, there has also been a diversification of the types of targets used in therapy. Generally, the proteins modulated by drugs belonged mainly to the families of membrane receptors (receptors coupled to G proteins, ion channels, etc.), nuclear receptors or enzymes. Technological advances in the field of therapeutic antibodies and biotechnologies enabled curative agents to reach previously undruggable targets. In this article, we review these trends and illustrate them by various examples, notably in the field of anticancer drugs, lipid-lowering drugs, gene therapy or antisense therapy.

Une cible thérapeutique est l'entité biochimique grâce à laquelle les substances actives des médicaments exercent leurs effets bénéfiques. Historiquement, la plupart des médicaments ont été utilisés sans que l'on connaisse leur mécanisme d'action. La conception rationnelle de thérapies créées pour agir spécifiquement sur une cible définie à l'avance s'est développée au cours de la seconde moitié du XXème siècle. Les progrès de la génomique ont accéléré la découverte de plusieurs cibles impliquées dans de nombreuses pathologies. Au cours de la période récente, on constate également une diversification de la nature des cibles sur lesquelles agissent les médicaments. Généralement, les protéines contre lesquelles était dirigé l'arsenal thérapeutique appartenaient majoritairement aux familles des récepteurs membranaires (récepteurs couplés aux protéines G, canaux ioniques,…), des récepteurs nucléaires ou bien des enzymes. Les avancées technologiques dans le domaine des anticorps thérapeutiques et des biotechnologies permettent, à présent, de diriger des agents thérapeutiques vers des macromolécules jugées inutilisables auparavant. Dans cet article, nous passons en revue ces tendances illustrées par différents exemples, dans le domaine, notamment, des anticancéreux, des hypolipidémiants, de la thérapie génique ou antisens.

Presence of CD3+ and CD79a+ Lymphocytes in the Pituitary Gland of Dogs at Post-mortem Examination.

Hypophysitis has been reported occasionally in dogs, with most cases resembling primary lymphocytic hypophysitis in man. Although it is generally assumed that lymphocytes are not present normally in the canine pituitary gland, few studies have investigated this hypothesis. However, lymphocytes are recognized in the pituitary gland of people and horses without signs of pituitary disease. It is unknown to what degree lymphocyte infiltration of the pituitary gland might occur as an incidental finding in dogs. The aim of the present study was to investigate the presence and distribution of lymphocytes in the pituitary gland of dogs without clinical suspicion of pituitary disease. Twenty dogs were subjected to routine necropsy examination. Formalin-fixed and paraffin wax-embedded sections of pituitary were stained with haematoxylin and eosin (HE) or subjected to immunohistochemistry (IHC) using primary antibodies specific for the T-cell marker CD3 and the B-cell marker CD79a. The number of CD3+ and CD79a+ cells per area unit (CPA) was determined for different pituitary regions. Two dogs had extensive neoplastic lesions in the pituitary gland and were excluded from analysis. In the remaining 18 dogs, occasional scattered CD3+ cells were found in the pituitary gland. There was a significant difference in CD3+ CPA between pituitary regions (P = 0.001). The highest CD3+ CPA was found in the pars tuberalis (median 41.3 cells/mm2, interquartile range 20.9-50.5 cells/mm2). In six of the 18 dogs (33%), CD79a+ cells were detected in small number (median total cell number 0 cells/section, interquartile range 0-1.0 cells/section). This study shows that T cell, and fewer B cells, may be found in the pituitary gland of dogs without clinical suspicion of pituitary disease. Regional difference in T-cell density, with the highest CD3+ CPA in the pars tuberalis, may imply regional immunoregulatory functions in the canine pituitary gland.

Using city gates as a means of estimating ancient traffic flows.

Despite the recent flurry of interest in various aspects of ancient urbanism, we still know little about how much traffic flowed in and out of ancient cities, in part because of problems with using commodities as proxies for trade. This article investigates another approach, which is to estimate these flows from the built environment, concentrating on transport infrastructure such as city gates. To do this, I begin by discussing a new model for how we would expect this kind of infrastructure to expand with population, before investigating the relationship between the populations of sites and the total numbers and widths of city gates, focusing on the Greek and Roman world. The results suggest that there is indeed a systematic relationship between the estimated populations of cities and transport infrastructure, which is entirely consistent with broader theoretical and empirical expectations. This gives us a new way of exploring the connectivity and integration of ancient cities, contributing to a growing body of general theory about how settlements operate across space and time.

Azimuthal sound source localization of various sound stimuli under different conditions.

AIM: To evaluate azimuthal sound-source localization performance under different conditions, with a view to optimizing a routine sound localization protocol. MATERIAL AND METHOD: Two groups of healthy, normal-hearing subjects were tested identically, except that one had to keep their head still while the other was allowed to turn it. Sound localization was tested without and then with a right ear plug (acute auditory asymmetry) for each of the following sound stimuli: pulsed narrow-band centered on 250Hz, continuous narrowband centered on 2000Hz, 4000Hz and 8000Hz, continuous 4000Hz warble, pulsed white noise, and word ("lac" (lake)). Root mean square error was used to calculate sound-source localization accuracy. RESULTS: With fixed head, localization was significantly disturbed by the earplug for all stimuli (P<0.05). The most discriminating stimulus was continuous 4000Hz narrow-band: area under the ROC curve (AUC), 0.99 [95% CI, 0.95-1.01] for screening and 0.85 [0.82-0.89] for diagnosis. With mobile head, localization was significantly better than with fixed head for 4000 and 8000Hz stimuli (P<0.05). The most discriminating stimulus was continuous 2000Hz narrow-band: AUC, 0.90 [0.83-0.97] for screening and 0.75 [0.71-0.79] for diagnosis. In both conditions, pulsed noise (250Hz narrow-band, white noise or word) was less difficult to localize than continuous noise. CONCLUSION: The test was more sensitive with the head immobile. Continuous narrow-band stimulation centered on 4000Hz most effectively explored interaural level difference. Pulsed narrow-band stimulation centered on 250Hz most effectively explored interaural time difference. Testing with mobile head, closer to real-life conditions, was most effective with continuous narrow-band stimulation centered on 2000Hz.

Playing to live: outcome evaluation of a community-based psychosocial expressive arts program for children during the Liberian Ebola epidemic.

BACKGROUND: This paper reviews the efficacy of a community psychosocial arts program focused on building mental health capacity within post-Ebola Liberia. The aim of this paper was to evaluate the outcome effects of two groups using pre- and post-treatment data. We hypothesized that there would be a difference in symptoms pre- and post-treatment, and the longer program would yield more significant results. METHODS: There was a total of 870 child participants. Of 40 sites, 24 were selected for a 5-month treatment (TG1) while the remaining 16 sites received 3 months of treatment (TG2). Paired t tests and a mixed-model analysis of variance (ANOVA) were used to analyse pre- and post-psychological stress symptoms (PSS) for samples from both groups. RESULTS: Separately, treatment group 1 (TG1) and treatment group 2's (TG2) paired t test yielded significant results (p < 0.001) for the decrease of PSS. The mixed-model ANOVA found that there were significant differences in total pre- and post-test PSS and a significant difference in PSS means over time. CONCLUSIONS: Results indicated that there was a statistically significant decrease in reported symptoms in both treatment groups pre- to post-intervention and a significant difference in total symptoms over time. However, the findings do not indicate that the longer programming was statistically different compared to the shorter programming. The study presented had gaps in data, largely due to limits in research during the crisis. However, this paper provides a unique case study for challenges that can be faced for project evaluation in emergency settings.

Fluorescence Interference Contrast-enabled structures improve the microarrays performance.

Continuous improvements of the fluorescence-based sensitivity and specificity, required for high throughput screening, diagnostics, and molecular biology studies, are usually addressed by better readout systems, or better reporting elements. However, while Fluorescence Interference Contrast (FLIC), which modulates the fluorescence by materials-based parameters, has been used for decades to measure biomolecular interactions at nanometer-precision, e.g., for the study of molecular motors and membrane processes, it has been seldom used for high throughput or diagnostic microdevices. Moreover, the amplification of both the fluorescence signal, modulated by vertically-nano-calibrated structures, and the signal/background, modulated by laterally-micro-calibrated structures, has not been explored. To address this synergy, structures comprising optically transparent silicon oxide, tens of micrometers-wide and with thicknesses in the low hundreds of nanometers, which are able to promote the formation of standing waves if patterned on a reflective material, have been designed, fabricated and tested, for the use in DNA- and protein arrays. The light emitted by a fluorophore placed on top of the structures and reflected by a bottom mirror surface, e.g., silicon, platinum, is physically constrained to a region defined lithographically, both vertically and laterally, i.e., micro-pillars and -wells, resulting in an accurate identification and quantification of fluorescence. The signal/noise ratio on micro-/nano-structured substrates is comparable to that measured on planar substrates, but the physical confinement of the microarray spots results in a considerable increase of the intra-feature uniformity.