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Self-consistent modeling using the stability, transport, equilibrium, and pedestal (STEP) workflow in the OMFIT integrated modeling framework (predicting pedestal with EPED, core profiles with TGYRO, current profile with ONETWO, and EFIT for equilibrium) suggests ITER and future devices such as China Fusion Engineering Test Reactor (CFETR) Zhuang et al (2019 Nucl. Fusion 59 112010) will benefit from high-density operation (Greenwald limit fraction f g w ≈ 0.7−1.3). Regimes with an operational density near the Greenwald limit will likely need peaked density profiles so that the pedestal density remains below the Greenwald limit. Peaked density profiles can be achieved with the help of pellet injection. A flexible Pellet Ablation Module (PAM), which predicts the density source based on a comprehensive analytical pellet ablation model, has been developed for predicting pellet fueling for transport studies, and has been incorporated into the STEP workflow for predictive modeling. This workflow is applied to DIII-D and finds good agreement with experiments. On ITER the effect of pellet fueling is examined in an advanced inductive scenario, where a fusion gain of up to Q  = 9 is predicted with strong central pellet fueling. On CFETR, with a mid-radius density source, an average of 1.5 × 10 22 electrons s −1 are required to achieve the density and temperature profiles necessary for the 1000 MW advanced scenario with a tritium burn-up fraction of ∼ 3 % .

As a promising scenario for fusion reactors, the high poloidal-beta ( βP) scenario is characterized by a strong large radius internal transport barrier (ITB), which significantly enhances the overall confinement quality and the bootstrap current fraction for fully non-inductive operation. It is frequently observed that in the presence of a strong ITB, the pedestal height is lower and is accompanied by small edge localized modes (ELMs), which further improves the compatibility of a high performance core with an edge solution. A mechanism for the formation of the low pedestal is proposed in this paper. It is found that the strong ITB creates an off-axis bootstrap current to clamp the local safety factor q, and thus the magnetic shear in the outer core/pedestal region is increased. Gyrokinetic simulations with the CGYRO code show that the higher magnetic shear brings the experimental profiles into the range where the growth rate of drift-wave instabilities and thus transport is higher, and therefore a lower pedestal gradient is expected. The combination of low pedestal and high magnetic shear further enhances the turbulent transport across the whole pedestal, consistent with power balance analysis. Such a positive feedback mechanism ultimately results in a lower pressure pedestal as observed in experiments. Under such a low pedestal, linear simulations with BOUT++ predict the growth rates of peeling–ballooning modes to be lower across the whole toroidal mode number spectra, and the nonlinear BOUT++ simulation exhibits lower saturated fluctuation intensity as well, consistent with the experimentally observed lower ELM size.

Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments. Zika virus (ZIKV) is an emerging global health issue, but currently no licensed vaccine achieves lasting protective immunity. Here the authors show that a ZIKV vaccine containing the envelop protein without the transmembrane domain and the precursor membrane protein can provide effective protection in mouse models.

Interleukin-2 is a proinflammatory interleukin with a pleiotropic effect on different cell types of the immune system. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH) is up-regulated by interleukin-2 and suppresses interleukin-2 signaling. This study shows that variants of the CISH gene are associated with susceptibility to bacteremia, malaria, and tuberculosis. This study shows that variants of the CISH gene are associated with susceptibility to bacteremia, malaria, and tuberculosis. Tuberculosis, malaria, and invasive bacterial disease together account for more than 5 million deaths annually in the developing world. Although a significant proportion of interindividual variation in disease susceptibility can be attributed to environmental factors such as malnutrition and infection with the human immunodeficiency virus (HIV), a substantial portion is unexplained. Comparative studies involving twins and adopted persons suggest a genetic component, 1 and genes that, when mutated, result in primary immunodeficiency states have been identified. Such immunodeficiencies are extremely rare, however, and the current understanding of common host genetic factors influencing susceptibility to major infectious diseases at the population level . . .

BackgroundThe clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy.MethodsHere, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses.ResultsThe ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells.ConclusionsThese findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.

ObjectivesPopulation ageing and increased care needs lead to adults making consequential medical decisions for others, potentially impacting treatment and end of life. We aim to describe the prevalence of medical decision-making by proxy among the national population and associated demographic and care factors.MethodsWe designed a cross-sectional online survey with a nationally representative adult cohort with an 80% participation rate. 311 Singapore residents completed the survey.Results73% of respondents reported having ever assisted others with medical decisions, while 58% have ever assisted with activities of daily living (ADLs), and 88% with instrumental ADLs (IADLs). Having a digital caregiver account, having a lasting power of attorney as a donee and assisting with ADLs and IADLs are significantly associated with proxy medical decision-making. Gender, ethnicity, income and age did not appear to have a significant impact.ConclusionsA majority of Singapore adults assist others with caregiving tasks and medical decision-making. These helping behaviours are often performed informally, which may increase decisional burden for caregivers and potential abuse of power.

The standard model of particle physics contains parameters—such as particle masses—whose origins are still unknown and which cannot be predicted, but whose values are constrained through their interactions. In particular, the masses of the top quark ( M t ) and W boson ( M W ) 1 constrain the mass of the long-hypothesized, but thus far not observed, Higgs boson. A precise measurement of M t can therefore indicate where to look for the Higgs, and indeed whether the hypothesis of a standard model Higgs is consistent with experimental data. As top quarks are produced in pairs and decay in only about 10 -24  s into various final states, reconstructing their masses from their decay products is very challenging. Here we report a technique that extracts more information from each top-quark event and yields a greatly improved precision (of ± 5.3 GeV/ c 2 ) when compared to previous measurements 2 . When our new result is combined with our published measurement in a complementary decay mode 3 and with the only other measurements available 2 , the new world average for M t becomes 4 178.0 ± 4.3 GeV/ c 2 . As a result, the most likely Higgs mass increases from the experimentally excluded 5 value 6 of 96 to 117 GeV/ c 2 , which is beyond current experimental sensitivity. The upper limit on the Higgs mass at the 95% confidence level is raised from 219 to 251 GeV/ c 2 .