Evaluation of the role of innate lymphoid cells following viral vector vaccination

Over the past decade, studies in our laboratory have established that i) compared to systemic route of delivery, mucosal delivery of recombinant fowlpox virus (rFPV) prime can induce excellent high avidity mucosal/systemic HIV-specific CD8+ T cell immunity, ii) this was associated with IL-4/IL-13 cytokine milieu and iii) transient inhibition of IL-13 at the vaccination site can recruit unique lung dendritic cell (DC) subsets, responsible for the induction of high quality CD8+ T cell immunity. Therefore, to understand which cells at the vaccination site was the predominant source of IL-13 was assessed by evaluating the different cells at the vaccination site, specifically innate lymphoid cells (ILC) following rFPV vaccination with and without transient inhibition of IL-13. These studies for the first time revealed that ILC2 were the main source of IL-13 at the vaccination site (24 h post vaccination) responsible for inducing high quality T and B cells immune responses reported previously. Intranasal vaccination induced ST2/IL-33R+ ILC2 in lung, whilst intramuscular vaccination exclusively induced IL-25R+ ILC2 in muscle. Moreover, adjuvants that transiently inhibited IL-13 at the vaccination site significantly influenced the IFN-γ expression by ILC1/ILC3 indicating that ILC2-derived IL-13 at the vaccination site also modulated ILC1/ILC3 function/activity. As intranasal and intramuscular vaccinations induced different ILC2 subsets, two rFPV vaccines co-expressing adjuvants that transiently sequestered IL-25 and IL-33 at the vaccination site (rFPV-IL-12BP and rFPV-IL-33BP) were used to further evaluate ILC development following vaccination. Unlike IL-13 inhibitor vaccination conditions, intranasal delivery of IL-25BP adjuvanted vaccine induced not only ST2/IL-33R+ ILC2 but also IL-25R+ and TSLPR+ ILC2 subsets that were able to express IL-13. Moreover TSLPR+ ILC2 subset was also able to express IL-4. Interestingly, intranasal delivery of IL-25BP also induced significantly elevated number of NKp46+/- ILC1/ILC3 expressing IL-17A compared to IFN-γ, unlike the unadjuvanted or IL-13 inhibitor conditions. Taken together, these inhibitor studies indicated that IL-25 play a fundamental role in early ILC development than IL-33, suggesting that there is a hierarchical regulation of ILC development, where IL-25 is most likely the master regulator of ILC. Data also revealed that ILC and their cytokine expression profiles were vastly different during permanent verses transient blockage of IL-13, and STAT6 at the vaccination site. STAT6-/- mice given the FPV-HIV vaccine showed elevated ST2/IL-33R+ ILC2-driven IL-13 expression whilst reduced IFN-γ expression by both NKp46+/- ILC1/ILC3, unlike transient blockage of STAT6 which showed the opposing effect. When IL-13-/- mice were vaccinated with FPV-HIV significantly elevated lung lineage- ST2/IL-33R+ ILC2s were detected compared to BALB/c mice given the FPV-HIV-IL-13Rα2 adjuvanted vaccine (transient inhibition of IL-13), and their NKp46+/- ILC1/ILC3-driven IFN-γ expression was significantly lower compared to transient inhibition of STAT6. In previous studies when IL-13 was inhibited, no or low antibody differentiation has been reported, unlike STAT6 inhibition. Thus, current data further corroborated that ST2/IL-33R+ ILC2-derived IL-13 play a crucial role in modulating downstream B cell immune outcomes. Specifically, co-regulation of ST2/IL-33R+ ILC2-derived IL-13 and NKp46+/- ILC1/ILC3-derived IFN-γ may play an important role in modulating antibody differentiation process in a STAT6 independent manner via the IL-13Rα2 pathway. When trying to understand the molecular mechanism involved in this process, data revealed that the expression of IL-13Rα2, type I and II IL-4Rs on ST2/IL-33R+ ILC2 and NKp46- ILC1/ILC3 were co-regulated 24 h post intranasal rFPV vaccination. Inhibition of STAT6 signalling significantly impacted the IL-13Rα2 expression on both ST2/IL-33R+ ILC2 and NKp46- ILC1/ILC3, unlike IL-13 inhibition, suggesting that under STAT6 inhibition conditions, IL-13 could signal via IL-13Rα2 pathway. As elevated number of ST2/IL-33R+ ILC2 expressing IL-13Rα2 were detected in BALB/c mice given the FPV-HIV-IL-4R antagonist vaccine, this also indicated an autocrine regulation of IL-13 at the ILC2 via IL-13Rα2. The Il-4/IL-13 receptor expression profile on NKp46+ ILC1/ILC3 and NKp46- ILC1/ILC3 were vastly different, suggesting that these cells may play different roles in downstream immune outcomes. Collectively, findings in this thesis demonstrated that i) ILC activity is significantly modulated by route of vaccine delivery and vaccine adjuvants early as 24 h post vaccination, ii) When designing vaccines against chronic pathogens, understanding the fundamental roles of ILC at the vaccination site may help design better vaccines in the future, iii) IL-25 regulated initial development/differentiation of all ILCs and IL-33 most likely only play a role in ILC2 homing to the lung mucosae, iv) Post viral vector vaccination ILC-derived IL-13 and IFN-γ balance was crucial for shaping the downstream immune outcomes, v) The IL-13 regulation at the ILC level occurred via an STAT6 independent pathway, most likely IL-13Rα2 (due to low IL-13 conditions). In conclusion, this work has provided unique insights into ILC function and activity during viral vector vaccination, that could be used to tailor vaccine vectors to induce effective immune outcomes against target pathogens (for example TB verses an HIV vaccine)

STAT3 determines IL-4 signalling outcomes in naïve T cells

IL-4 production is associated with low-avidity, poorly cytotoxic T cell induction that contributes to viral immune evasion and the failure of T cell-based vaccines. Yet, the precise mechanisms that regulate IL-4 signalling in T cells remain elusive. Mounting evidence indicates that cells can dynamically alter their IL-4/IL-13 receptor signature to modulate downstream immune outcomes upon pathogen encounter. Here, we describe how naïve (CD62L+CD44lo–mid) CD4 and CD8 T cells distinctly engage both STAT6 and STAT3 in response to IL-4. We further show that IL-4R⍺ expression is both time- and IL-4 concentration-dependent. Remarkably, our findings reveal that STAT3 inhibition can ablate IL-4R⍺ and affect transcriptional expression of other Stat and Jak family members. By extension, the loss of STAT3 lead to aberrant STAT6 phosphorylation, revealing an inter-regulatory relationship between the two transcription factors. Moreover, IL-4 stimulation down-regulated TGF-β1 and IFN-γR1 expression on naïve T cells, possibly signifying the broad regulatory implications of IL-4 in conditioning lineage commitment decisions during early infection. Surprisingly, naïve T cells were unresponsive to IL-13 stimulation, unlike dendritic cells. Collectively, these findings could be exploited to inform more efficacious vaccines, as well as design treatments against IL-4/IL-13-associated disease conditions

On the seed population of solar energetic particles in the inner heliosphere

Particles measured in large gradual solar energetic particle (SEP) events are believed to be predominantly accelerated at shocks driven by coronal mass ejections (CMEs). Ion charge state and composition analyses suggest that the origin of the seed particle population for the mechanisms of particle acceleration at CME-driven shocks is not the bulk solar wind thermal material, but rather a suprathermal population present in the solar wind. This suprathermal population could result from remnant material accelerated in prior solar flares and/or preceding CME-driven shocks. In this work, we examine the distribution of this suprathermal particle population in the inner heliosphere by combining a magnetohydrodynamic (MHD) simulation of the solar wind and a Monte-Carlo simulation of particle acceleration and transport. Assuming that the seed particles are uniformly distributed near the Sun by solar flares of various magnitudes, we study the longitudinal distribution of the seed population at multiple heliocentric distances. We consider a non-uniform background solar wind, consisting of fast and slow streams that lead to compression and rarefaction regions within the solar wind. Our simulations show that the seed population at a particular location (e.g., 1 au) is strongly modulated by the underlying solar wind configuration. Corotating interaction regions (CIRs) and merged interactions regions (MIRs) can strongly alter the energy spectra of the seed particle populations. In addition, cross-field diffusion plays an important role in mitigating strong variations of the seed population in both space and energy.Comment: 20 pages, 7 figure

MRI characteristics of lumbosacral dural arteriovenous fistulas

Background and purposeSpinal dural arteriovenous fistulas located in the lumbosacral region are rare and present with nonspecific clinical signs. The purpose of this study was to find out the specific radiologic features of these fistulas.MethodsWe retrospectively reviewed the clinical and radiological data of 38 patients diagnosed with lumbosacral spinal dural arteriovenous fistulas in our institution from September 2016 to September 2021. All patients underwent time-resolved contrast-enhanced three-dimensional MRA and DSA examinations, and were treated with either endovascular or neurosurgical strategies.ResultsMost of the patients (89.5%) had motor or sensory disorders in both lower limbs as the first symptoms. On MRA, the dilated filum terminale vein or radicular vein was seen in 23/30 (76.7%) patients with lumbar spinal dural arteriovenous fistulas and 8/8 (100%) patients with sacral spinal dural arteriovenous fistulas. T2W intramedullary abnormally high signal intensity areas were found in all lumbosacral spinal dural arteriovenous fistula patients, with involvement of the conus present in 35/38 (92.1%) patients. The “missing piece sign” in the intramedullary enhancement area was seen in 29/38 (76.3%) patients.ConclusionDilatation of the filum terminale vein or radicular vein is powerful evidence for diagnosis of lumbosacral spinal dural arteriovenous fistulas, especially for sacral spinal dural arteriovenous fistulas. T2W intramedullary hyperintensity in the thoracic spinal cord and conus, and the missing-piece sign could be indicative of lumbosacral spinal dural arteriovenous fistula

A High Precision and Multifunctional Electro‐Optical Conversion Efficiency Measurement System for Metamaterial‐Based Thermal Emitters

In this study, a multifunctional high-vacuum system was established to measure the electro-optical conversion efficiency of metamaterial-based thermal emitters with built-in heaters. The system is composed of an environmental control module, an electro-optical conversion measurement module, and a system control module. The system can provide air, argon, high vacuum, and other conventional testing environments, combined with humidity control. The test chamber and sample holder are carefully designed to minimize heat transfer through thermal conduction and convection. The optical power measurements are realized using the combination of a water-cooled KBr flange, an integrating sphere, and thermopile detectors. This structure is very stable and can detect light emission at the μW level. The system can synchronously detect the heating voltage, heating current, optical power, sample temperatures (both top and bottom), ambient pressure, humidity, and other environmental parameters. The comprehensive parameter detection capability enables the system to monitor subtle sample changes and perform failure mechanism analysis with the aid of offline material analysis using scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction. Furthermore, the system can be used for fatigue and high-low temperature impact tests

Modelling two Energetic Storm Particle Events Observed by Solar Orbiter Using the Combined EUHFORIA and iPATH Models

By coupling the EUropean Heliospheric FORcasting Information Asset (EUHFORIA) and the improved Particle Acceleration and Transport in the Heliosphere (iPATH) model, two energetic storm particle (ESP) events, originating from the same active region (AR 13088) and observed by Solar Orbiter (SolO) on August 31 2022 and September 05 2022, are modelled. While both events originated from the same active region, they exhibited notable differences, including: 1) the August ESP event lasted for 7 hours, while the September event persisted for 16 hours; 2) The time intensity profiles for the September event showed a clear cross-over upstream of the shock where the intensity of higher energy protons exceeds those of lower energy protons, leading to positive (``reverse'') spectral indices prior to the shock passage. For both events, our simulations replicate the observed duration of the shock sheath, depending on the deceleration history of the CME. Imposing different choices of escaping length scale, which is related to the decay of upstream turbulence, the modelled time intensity profiles prior to the shock arrival also agree with observations. In particular, the cross-over of this time profile in the September event is well reproduced. We show that a ``reverse'' upstream spectrum is the result of the interplay between two length scales. One characterizes the decay of upstream shock accelerated particles, which are controlled by the energy-dependent diffusion coefficient, and the other characterizes the decay of upstream turbulence power, which is related to the process of how streaming protons upstream of the shock excite Alfv\'{e}n waves. Simulations taking into account real-time background solar wind, the dynamics of the CME propagation, and upstream turbulence at the shock front are necessary to thoroughly understand the ESP phase of large SEP events.Comment: Accepted by A&A. 16 pages, 11 figure

Ultrahigh-charge electron beams from laser-irradiated solid surface

Compact acceleration of a tightly collimated relativistic electron beam with high charge from a laser–plasma interaction has many unique applications. However, currently the well-known schemes, including laser wakefield acceleration from gases and vacuum laser acceleration from solids, often produce electron beams either with low charge or with large divergence angles. In this work, we report the generation of highly collimated electron beams with a divergence angle of a few degrees, nonthermal spectra peaked at the megaelectronvolt level, and extremely high charge (∼100 nC) via a powerful subpicosecond laser pulse interacting with a solid target in grazing incidence. Particle-in-cell simulations illustrate a direct laser acceleration scenario, in which the self-filamentation is triggered in a large-scale near–critical-density plasma and electron bunches are accelerated periodically and collimated by the ultraintense electromagnetic field. The energy density of such electron beams in high-Z materials reaches to ∼1012 J/m3, making it a promising tool to drive warm or even hot dense matter states

Towards prediction of ordered phases in rechargeable battery chemistry via group–subgroup transformation

Abstract: The electrochemical thermodynamic and kinetic characteristics of rechargeable batteries are critically influenced by the ordering of mobile ions in electrodes or solid electrolytes. However, because of the experimental difficulty of capturing the lighter migration ion coupled with the theoretical limitation of searching for ordered phases in a constrained cell, predicting stable ordered phases involving cell transformations or at extremely dilute concentrations remains challenging. Here, a group-subgroup transformation method based on lattice transformation and Wyckoff-position splitting is employed to predict the ordered ground states. We reproduce the previously reported Li0.75CoO2, Li0.8333CoO2, and Li0.8571CoO2 phases and report a new Li0.875CoO2 ground state. Taking the advantage of Wyckoff-position splitting in reducing the number of configurations, we identify the stablest Li0.0625C6 dilute phase in Li-ion intercalated graphite. We also resolve the Li/La/vacancy ordering in Li3xLa2/3−xTiO3 (0 < x < 0.167), which explains the observed Li-ion diffusion anisotropy. These findings provide important insight towards understanding the rechargeable battery chemistry

Validity and applicability of the global leadership initiative on malnutrition criteria in non-dialysis patients with chronic kidney disease

IntroductionThere are no standardized assessment criteria for selecting nutritional risk screening tools or indicators to assess reduced muscle mass (RMM) in the Global Leadership Initiative on Malnutrition (GLIM) criteria. We aimed to compare the consistency of different GLIM criteria with Subjective Global Assessment (SGA) and protein-energy wasting (PEW).MethodsIn this study, nutritional risk screening 2002 first four questions (NRS-2002-4Q), Nutritional Risk Screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), and Mini-Nutritional Assessment Short-Form (MNA-SF) tools were used as the first step of nutritional risk screening for the GLIM. The RMM is expressed using different metrics. The SGA and PEW were used to diagnose patients and classify them as malnourished and non-malnourished. Kappa (κ) tests were used to compare the concordance between the SGA, PEW, and GLIM of each combination of screening tools.ResultsA total of 157 patients were included. Patients with Chronic kidney disease (CKD) stage 1–3 accounted for a large proportion (79.0%). The prevalence rates of malnutrition diagnosed using the SGA and PEW were 18.5% and 19.7%, respectively. The prevalence of GLIM-diagnosed malnutrition ranges from 5.1% to 37.6%, depending on the different screening methods for nutritional risk and the different indicators denoting RMM. The SGA was moderately consistent with the PEW (κ = 0.423, p &lt; 0.001). The consistency among the GLIM, SGA, and PEW was generally low. Using the NRS-2002-4Q to screen for nutritional risk, GLIM had the best agreement with SGA and PEW when skeletal muscle index (SMI), fat-free mass index (FFMI), and hand grip strength (HGS) indicated a reduction in muscle mass (SGA: κ = 0.464, 95% CI 0.28–0.65; PEW: κ = 0.306, 95% CI 0.12–0.49).ConclusionThe concordance between the GLIM criteria and the SGA and PEW depended on the screening tool used in the GLIM process. The inclusion of RMM in the GLIM framework is important. The addition of HGS could further improve the performance of the GLIM standard compared to the use of body composition measurements