Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition.

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

Plasmoid Formation and Strong Radiative Cooling in a Driven Magnetic Reconnection Experiment.

We present the first experimental study of plasmoid formation in a magnetic reconnection layer undergoing rapid radiative cooling, a regime relevant to extreme astrophysical plasmas. Two exploding aluminum wire arrays, driven by the Z machine, generate a reconnection layer (S_{L}≈120) in which the cooling rate far exceeds the hydrodynamic transit rate (τ_{hydro}/τ_{cool}>100). The reconnection layer generates a transient burst of >1 keV x-ray emission, consistent with the formation and subsequent rapid cooling of the layer. Time-gated x-ray images show fast-moving (up to 50 km s^{-1}) hotspots in the layer, consistent with the presence of plasmoids in 3D resistive magnetohydrodynamic simulations. X-ray spectroscopy shows that these hotspots generate the majority of Al K-shell emission (around 1.6 keV) prior to the onset of cooling, and exhibit temperatures (170 eV) much greater than that of the plasma inflows and the rest of the reconnection layer, thus providing insight into the generation of high-energy radiation in radiatively cooled reconnection events.

Performance Scaling in Magnetized Liner Inertial Fusion Experiments.

We present experimental results from the first systematic study of performance scaling with drive parameters for a magnetoinertial fusion concept. In magnetized liner inertial fusion experiments, the burn-averaged ion temperature doubles to 3.1 keV and the primary deuterium-deuterium neutron yield increases by more than an order of magnitude to 1.1×10^{13} (2 kJ deuterium-tritium equivalent) through a simultaneous increase in the applied magnetic field (from 10.4 to 15.9 T), laser preheat energy (from 0.46 to 1.2 kJ), and current coupling (from 16 to 20 MA). Individual parametric scans of the initial magnetic field and laser preheat energy show the expected trends, demonstrating the importance of magnetic insulation and the impact of the Nernst effect for this concept. A drive-current scan shows that present experiments operate close to the point where implosion stability is a limiting factor in performance, demonstrating the need to raise fuel pressure as drive current is increased. Simulations that capture these experimental trends indicate that another order of magnitude increase in yield on the Z facility is possible with additional increases of input parameters.

Experimental Demonstration of the Stabilizing Effect of Dielectric Coatings on Magnetically Accelerated Imploding Metallic Liners.

Enhanced implosion stability has been experimentally demonstrated for magnetically accelerated liners that are coated with 70 µm of dielectric. The dielectric tamps liner-mass redistribution from electrothermal instabilities and also buffers coupling of the drive magnetic field to the magneto-Rayleigh-Taylor instability. A dielectric-coated and axially premagnetized beryllium liner was radiographed at a convergence ratio [CR=Rin,0/Rin(z,t)] of 20, which is the highest CR ever directly observed for a strengthless magnetically driven liner. The inner-wall radius Rin(z,t) displayed unprecedented uniformity, varying from 95 to 130 µm over the 4.0 mm axial height captured by the radiograph.

Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence. METHODS: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression. RESULTS: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001). CONCLUSIONS: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.

Experimental demonstration of fusion-relevant conditions in magnetized liner inertial fusion.

This Letter presents results from the first fully integrated experiments testing the magnetized liner inertial fusion concept [S. A. Slutz et al., Phys. Plasmas 17, 056303 (2010)], in which a cylinder of deuterium gas with a preimposed 10 Taxial magnetic field is heated by Z beamlet, a 2.5 kJ, 1 TW laser, and magnetically imploded by a 19 MA, 100 ns rise time current on the Z facility. Despite a predicted peak implosion velocity of only 70 km = s, the fuel reaches a stagnation temperature of approximately 3 keV, with T(e) ≈ T(i), and produces up to 2 x 10(12) thermonuclear deuterium-deuterium neutrons. X-ray emission indicates a hot fuel region with full width at half maximum ranging from 60 to 120 µm over a 6 mm height and lasting approximately 2 ns. Greater than 10(10) secondary deuterium-tritium neutrons were observed, indicating significant fuel magnetization given that the estimated radial areal density of the plasma is only 2 mg = cm(2).

Understanding fuel magnetization and mix using secondary nuclear reactions in magneto-inertial fusion.

Magnetizing the fuel in inertial confinement fusion relaxes ignition requirements by reducing thermal conductivity and changing the physics of burn product confinement. Diagnosing the level of fuel magnetization during burn is critical to understanding target performance in magneto-inertial fusion (MIF) implosions. In pure deuterium fusion plasma, 1.01 MeV tritons are emitted during deuterium-deuterium fusion and can undergo secondary deuterium-tritium reactions before exiting the fuel. Increasing the fuel magnetization elongates the path lengths through the fuel of some of the tritons, enhancing their probability of reaction. Based on this feature, a method to diagnose fuel magnetization using the ratio of overall deuterium-tritium to deuterium-deuterium neutron yields is developed. Analysis of anisotropies in the secondary neutron energy spectra further constrain the measurement. Secondary reactions also are shown to provide an upper bound for the volumetric fuel-pusher mix in MIF. The analysis is applied to recent MIF experiments [M. R. Gomez et al., Phys. Rev. Lett. 113, 155003 (2014)] on the Z Pulsed Power Facility, indicating that significant magnetic confinement of charged burn products was achieved and suggesting a relatively low-mix environment. Both of these are essential features of future ignition-scale MIF designs.

Anti-IL-23p19 therapy inhibits the adoptive transfer of syngeneic graft-versus-host disease.

Syngeneic graft-versus-host disease (SGVHD), a chronic inflammatory disease, develops following irradiation, syngeneic bone marrow transplantation (BMT) and treatment with the immunosuppressive agent cyclosporine A (CsA). We have shown that TH1 and TH17 cytokine responses are increased during the development of SGVHD. The current study was designed to further investigate the involvement of TH17 immunity in SGVHD-associated colitis. IL-23 is a TH17 cytokine responsible for maintaining the effector functions of TH17 cells. The administration of anti-mouse IL-23p19 was shown to significantly reduce the clinical symptoms of primary and secondary SGVHD-associated colitis resulting in a significant reduction in both TH1 and TH17 associated cytokine expression. These results demonstrate that the TH17-associated cytokine, IL-23, may prove to be a beneficial therapeutic target in the treatment of chronic colon inflammation.

Pressure and energy balance of stagnating plasmas in z-pinch experiments: implications to current flow at stagnation.

Detailed spectroscopic diagnostics of the stagnating plasma in two disparate z pinches allow, for the first time, the examination of the plasma properties within a 1D shock wave picture, demonstrating a good agreement with this picture. The conclusion is that for a wide range of imploding-plasma masses and current amplitudes, in experiments optimizing non-Planckian hard radiation yields, contrary to previous descriptions the stagnating plasma pressure is balanced by the implosion pressure, and the radiation energy is provided by the imploding-plasma kinetic energy, rather than by the magnetic-field pressure and magnetic-field-energy dissipation, respectively.

Observations of modified three-dimensional instability structure for imploding z-pinch liners that are premagnetized with an axial field.

Novel experimental data are reported that reveal helical instability formation on imploding z-pinch liners that are premagnetized with an axial field. Such instabilities differ dramatically from the mostly azimuthally symmetric instabilities that form on unmagnetized liners. The helical structure persists at nearly constant pitch as the liner implodes. This is surprising since, at the liner surface, the azimuthal drive field presumably dwarfs the axial field for all but the earliest stages of the experiment. These fundamentally 3D results provide a unique and challenging test for 3D-magnetohydrodynamics simulations.

Murine syngeneic graft-versus-host disease is responsive to broad-spectrum antibiotic therapy.

Murine syngeneic graft-versus-host disease (SGVHD) initiates colon and liver inflammation following lethal irradiation, reconstitution with syngeneic bone marrow transplantation, and therapy with the immunosuppressive agent cyclosporine A. Previous studies have demonstrated that the inducible disease is mediated by CD4(+) T cells with increased reactivity of peripheral and liver-associated lymphocytes against intestinal microbial Ags. In the current report, studies were performed to analyze the specificity of the CD4(+) T cell response of T cells isolated from diseased animals and to determine the in vivo role of the microbiota to the development of SGVHD. Increased major histocompatibility Ag (MHC) class II-restricted responsiveness of SGVHD CD4(+) T cells against microbial Ags isolated from the ceca of normal animals was observed. The enhanced proliferative response was observed in the CD62L(-) memory population of CD4(+) T cells. To determine the role of the bacterial microbiota in the development of murine SGVHD, control and CsA-treated bone marrow transplantation animals were treated with broad-spectrum antibiotics (metronidazole, ciprofloxacin) after transplantation. Cyclosporine A-treated animals that were given antibiotic therapy failed to develop clinical symptoms and pathological lesions in the target tissues characteristic of SGVHD. Furthermore, the reduction in intestinal bacteria resulted in the elimination of the enhanced antimicrobial CD4(+) T cell response and significantly reduced levels of the inflammatory cytokines, IFN-γ, IL-17, and TNF-α. The elimination of the disease-associated inflammatory immune responses and pathology by treatment with broad-spectrum antibiotics definitively links the role of the microbiota and microbial-specific immunity to the development of murine SGVHD.

Near infrared reactance for the estimation of body fatness in regularly exercising individuals.

Near infrared reactance (NIR) is used to measure body fat percentage (BF%), but there is little data on its use in non-obese, regularly exercising individuals. Therefore, this study aimed to examine the limits of agreement between NIR compared to dual x-ray absorptiometry (DXA) for the measurement of BF% in 2 cohorts of regularly exercising individuals. BF% was measured using DXA and NIR in a regular exercising (≥3 sessions/week), healthy active cohort (HA; n=57), and in a regularly exercising and resistance trained (≥2 sessions/week) cohort (RT; n=59). The RT cohort had lower BF% than the HA cohort (15.3±5.5% and 25.8±7.1%, P<0.001). In the HA and RT cohorts, NIR BF% was associated with DXA BF% (R2=0.72, SEE=3.7, p<0.001 and R2=0.50, SEE=4.1 p<0.001, respectively). In the HA cohort, NIR tended to under-predict BF% (mean difference: - 1.3%; 95% limits of agreement (LOA); - 8.8 to 6.2%) whereas in the RT cohort, NIR tended to over-predict BF% compared to DXA (mean difference: 1.1; 95% LOA; - 8.1 to 10.3%). In conclusion, NIR and DXA yield similar average BF% measurements in 2 cohorts of non-obese regularly exercising individuals. However, the rather broad LOA of NIR need to be considered when using NIR to screen for overweight and obesity, or measure and track changes in body composition.

Evaluating the perceptions of workplace-based assessments in surgical training: a systematic review.

INTRODUCTION: Workplace-based assessments (WBAs) are intended to maximise learning opportunities in surgical training. There is speculation as to whether mandatory assessments in this form contribute to a tick-box culture. The objective of this review was to investigate surgical trainees' attitudes towards WBAs. METHODS: This systematic review of qualitative studies was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement. The literature was searched on the Medline®, Embase™, PubMed and Web of Science™ databases on 22 March 2022. RESULTS: Sixteen studies were included in the review, mostly carried out on users of the Intercollegiate Surgical Curriculum Programme portfolio in the UK. Trainees felt that WBAs were educationally useful, providing opportunity for feedback, but this was overshadowed by a pressure to reach a set annual quota for WBAs and achieve high scores. Other themes included inaccurate recording of WBAs, the role of WBAs as formative or summative assessments, engagement and accessibility of trainers, and lack of time to complete WBAs. CONCLUSIONS: Negative perceptions about WBAs were widespread among surgical trainees despite a recognition of their capacity to facilitate learning. This review supports the recent removal of the annual quota for WBAs in UK surgical training programmes.

Illness perceptions and health literacy are strongly associated with health-related quality of life, anxiety, and depression in patients with coronary heart disease: results from the EUROASPIRE V cross-sectional survey.

AIMS: To (1) Describe the sociodemographic and risk factor profiles of a sample of patients with coronary disease, (2) Explore associations between illness perceptions and health literacy with sociodemographic characteristics and risk factors, health-related quality of life (HRQoL), anxiety, and depression. METHODS AND RESULTS: Conducted as part of the ESC Prevention of CVD Project and EUROASPIRE V survey, patients were consecutively and retrospectively identified 6 months to 2 years after an acute event or elective procedure from 12 countries and interviewed. Three thousand four hundred and eight participants (76% male, mean age 64 years) were recruited, 16% were smokers, 38% obese, 60% physically inactive, and 41% hypertensive. Forty percent had attended cardiac rehabilitation. More threatening illness perceptions were associated with female gender (P < 0.0001), lower income (P < 0.0001), lower education (P = 0.02), obesity (P < 0.0001), sedentary behaviour (P < 0.0001), and diabetes (P < 0.0001). Poorer health literacy was associated with obesity (P = 0.02) and sedentary behaviour (P = 0.0001). Threatening illness perceptions were strongly associated with anxiety, depression, and poorer ratings of HRQoL after multivariable adjustment (all P < 0.001). Poor health literacy was associated with anxiety and depression (P < 0.0001) and poorer ratings of HRQoL (HeartQol scores P = 0.03). Results were consistent across regions of Europe, age, gender, and socio-economic strata. CONCLUSIONS: Interventions like cardiac rehabilitation should be targeted at vulnerable groups given the strong associations between more threatening illness perceptions, lower health literacy, lower HRQoL, and higher levels of anxiety and depression. The delivery and content of these interventions should be accessible for those with low health literacy.

Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia.

In daylight, demand for visual chromophore (11-cis-retinal) exceeds supply by the classical visual cycle. This shortfall is compensated, in part, by the retinal G-protein-coupled receptor (RGR) photoisomerase, which is expressed in both the retinal pigment epithelium (RPE) and in Müller cells. The relative contributions of these two cellular pools of RGR to the maintenance of photoreceptor light responses are not known. Here, we use a cell-specific gene reactivation approach to elucidate the kinetics of RGR-mediated recovery of photoreceptor responses following light exposure. Electroretinographic measurements in mice with RGR expression limited to either cell type reveal that the RPE and a specialized subset of Müller glia contribute both to scotopic and photopic function. We demonstrate that 11-cis-retinal formed through photoisomerization is rapidly hydrolyzed, consistent with its role in a rapid visual pigment regeneration process. Our study shows that RGR provides a pan-retinal sink for all-trans-retinal released under sustained light conditions and supports rapid chromophore regeneration through the photic visual cycle.

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.

Investigation of high-temperature bright plasma X-ray sources produced in 5-MA X-pinch experiments.

Using solid, machined X-pinch targets driven by currents rising from 0 to 5-6 MA in 60 ns, we observed bright spots of 5-9-keV continuum radiation from 5±2-µm diameter regions. The >6-keV radiation is emitted in about 0.4 ns, and the bright spots are roughly 75 times brighter than the bright spots measured at 1 MA. A total x-ray power of 10 TW peak and yields of 165±20 kJ were emitted from a 3-mm height. The 3-5-keV continuum radiation had a 50-90-GW peak power and 0.15-0.35-kJ yield. The continuum is plausibly from a 1275±75-eV blackbody or alternatively from a 3500±500-eV bremsstrahlung source.

Penetrating radiography of imploding and stagnating beryllium liners on the Z accelerator.

The implosions of initially solid beryllium liners (tubes) have been imaged with penetrating radiography through to stagnation. These novel radiographic data reveal a high degree of azimuthal correlation in the evolving magneto-Rayleigh-Taylor structure at times just prior to (and during) stagnation, providing stringent constraints on the simulation tools used by the broader high energy density physics and inertial confinement fusion communities. To emphasize this point, comparisons to 2D and 3D radiation magnetohydrodynamics simulations are also presented. Both agreement and substantial disagreement have been found, depending on how the liner's initial outer surface finish was modeled. The various models tested, and the physical implications of these models are discussed. These comparisons exemplify the importance of the experimental data obtained.

Accumulation of CD4+ T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation.

Syngeneic graft vs. host disease (SGVHD) was first described as a graft vs. host disease-like syndrome that developed in rats following syngeneic bone marrow transplantation (BMT) and cyclosporin A (CsA) treatment. SGVHD can be induced by reconstitution of lethally irradiated mice with syngeneic bone marrow cells followed by 21 days of treatment with the immunosuppressive agent CsA. Clinical symptoms of the disease appear 2-3 wk following cessation of CsA therapy, and disease-associated inflammation occurs primarily in the colon and liver. CD4(+) T cells have been shown to play an important role in the inflammatory response observed in the gut of SGVHD mice. Time-course studies revealed a significant increase in migration of CD4(+) T cells into the colon during CsA therapy, as well as significantly elevated mRNA levels of TNF-α, proinflammatory chemokines, and cell adhesion molecules in colonic tissue of CsA-treated animals compared with BMT controls, as early as day 14 post-BMT. Homing studies revealed a greater migration of labeled CD4(+) T cells into the gut of CsA-treated mice at day 21 post-BMT than control animals via CsA-induced upregulation of mucosal addressin cell adhesion molecule. This study demonstrates that, during the 21 days of immunosuppressive therapy, functional mechanisms are in place that result in increased homing of CD4(+) T effector cells to colons of CsA-treated mice.