Deimmunizing substitutions in Pseudomonas exotoxin domain III perturb antigen processing without eliminating T-cell epitopes

© 2019 Moss et al. Effective adaptive immune responses depend on activation of CD4 T cells via the presentation of antigen peptides in the context of major histocompatibility complex (MHC) class II. The structure of an antigen strongly influences its processing within the endolysosome and potentially controls the identity of peptides that are presented to T cells. A recombinant immunotoxin, comprising exotoxin A domain III (PE-III) from Pseudomonas aeruginosa and a cancer-specific antibody fragment, has been developed to manage cancer, but its effectiveness is limited by the induction of neutralizing antibodies. Here, we observed that this immunogenicity is substantially reduced by substituting six residues within PE-III. Although these substitutions targeted T-cell epitopes, we demonstrate that reduced conformational stability and protease resistance were responsible for the reduced antibody titer. Analysis of mouse T-cell responses coupled with biophysical studies on single-substitution versions of PE-III suggested that modest but comprehensible changes in T-cell priming can dramatically perturb antibody production. The most strongly responsive PE-III epitope was well-predicted by a structure-based algorithm. In summary, single-residue substitutions can drastically alter the processing and immunogenicity of PE-III but have only modest effects on CD4 T-cell priming in mice. Our findings highlight the importance of structure-based processing constraints for accurate epitope prediction

Multiscale architectured materials with composition and grain size gradients manufactured using high-pressure torsion

The concept of multiscale architectured materials is established using composition and grain size gradients. Composition-gradient nanostructured materials are produced from coarse grained interstitial free steels via carburization and high-pressure torsion. Quantitative analyses of the dislocation density using X-ray diffraction and microstructural studies clearly demonstrate the gradients of the dislocation density and grain size. The mechanical properties of the gradient materials are compared with homogeneous nanostructured carbon steel without a composition gradient in an effort to investigate the gradient effect. Based on the above observations, the potential of multiscale architecturing to open a new material property is discussed.111010Ysciescopu

Prostate-specific extracellular vesicles as a novel biomarker in human prostate cancer

Extracellular vesicles (EVs) may play an important role in cancer development and progression. We aimed to investigate the prognostic potential of prostate-specific EVs in prostate cancer (PCa) patients. Plasma and prostate tissue were collected from patients who underwent surgery for PCa (n = 82) or benign prostatic hyperplasia (BPH, n = 28). To analyze the quantity of EVs in prostate, we performed transmission electron microscopy (TEM), immuno-TEM with CD63 and prostate-specific membrane antigen (PSMA), and immunofluorescence staining. After EV isolation from plasma, CD63 and PSMA concentration was measured using ELISA kits. PSMA-positive areas in prostate differed in patients with BPH, and low-, intermediate-, and high-risk PCa (2.4, 8.2, 17.5, 26.5%, p < 0.001). Plasma PSMA-positive EV concentration differed in patients with BPH, and low-, intermediate-, and high-risk PCa (21.9, 43.4, 49.2, 59.9 ng/mL, p < 0.001), and ROC curve analysis indicated that plasma PSMA-positive EV concentration differentiated PCa from BPH (AUC 0.943). Patients with lower plasma PSMA-positive EV concentration had greater prostate volume (50.2 vs. 33.4 cc, p < 0.001) and lower pathologic Gleason score (p = 0.025). During the median follow-up of 18 months, patients with lower plasma PSMA-positive EV concentration tended to have a lower risk of biochemical failure than those with higher levels of prostate-specific EVs (p = 0.085).11910Ysciescopu

Topological phase transition and quantum spin Hall edge states of antimony few layers

While two-dimensional (2D) topological insulators (TI&apos;s) initiated the field of topological materials, only very few materials were discovered to date and the direct access to their quantum spin Hall edge states has been challenging due to material issues. Here, we introduce a new 2D TI material, Sb few layer films. Electronic structures of ultrathin Sb islands grown on Bi2Te2Se are investigated by scanning tunneling microscopy. The maps of local density of states clearly identify robust edge electronic states over the thickness of three bilayers in clear contrast to thinner islands. This indicates that topological edge states emerge through a 2D topological phase transition predicted between three and four bilayer films in recent theory. The non-trivial phase transition and edge states are confirmed for epitaxial films by extensive density-functional-theory calculations. This work provides an important material platform to exploit microscopic aspects of the quantum spin Hall phase and its quantum phase transition.1187Ysciescopu

Cardiovascular health status between standard and nonstandard workers in Korea

OBJECTIVES: The effect of employment insecurity on employee health is an important public health issue due to the recent effects of neoliberalism and the global financial crisis (2007-2008) on labor markets. This study aims to evaluate the differences in cardiovascular health status and the use of preventive screening services between standard and nonstandard workers. METHODS: Waged employees (N = 5,338) between the ages of 20 and 64 were grouped into standard (full-time, permanent) and nonstandard (part-time, temporary, or daily) employees. Data from the Fourth Korea National Health and Nutrition Examination Survey, 2007-2009, a nationwide representative survey, were examined, including cardiovascular health risk behaviors (tobacco, alcohol, physical inactivity), measured morbidities (blood pressure, blood glucose level, lipid profiles, body mass index), and the use of screening services for hypertension and diabetes mellitus. RESULTS: Female nonstandard employees tended to have higher blood pressure than did female standard employees (adjusted odds ratio, aOR 1.42, 95% confidence interval, CI 1.02 to 1.98). However, nonstandard employees (both men and women) were less likely to use preventive screening services for hypertension (aOR 0.72, 95% CI 0.54 to 0.94 in men; aOR 0.56, 95% CI 0.43 to 0.73 in women) and diabetes (aOR 0.58, 95% CI 0.43 to 0.79 in men; aOR 0.55, 95% CI 0.43 to 0.71 in women). CONCLUSION: Nonstandard work is associated with the underuse of screening services and poorer cardiovascular health in a specific population. Policies to reduce employment insecurity and encourage nonstandard employees to receive health screening services should be prioritized

Strangeness in the nucleon and the ratio of proton-to-neutron neutrino-induced quasi-elastic yield

The electroweak form factors of the nucleon as obtained within a three flavor pseudoscalar vector meson soliton model are employed to predict the ratio of the proton and neutron yields from $^{12}C$, which are induced by quasi-elastic neutrino reactions. These predictions are found to vary only moderately in the parameter space allowed by the model. The antineutrino flux of the up-coming experiment determining this ratio was previously overestimated. The corresponding correction is shown to have only a small effect on the predicted ratio. However, it is found that the experimental result for the ratio crucially depends on an accurate measurement of the energy of the knocked out nucleon.Comment: 17 pages, LaTeX, 2 tables, 4 figures, Discussion on shape of strange form factors added, Z. Phys. A, to be publishe

Latent tuberculosis infection screening and treatment in congregate settings (TB FREE COREA): protocol for a prospective observational study in Korea

IntroductionSouth Korea regards tuberculosis (TB) incidence in congregate settings as a serious problem. To this end, systematic latent TB infection (LTBI) diagnosis and treatment were provided to approximately 1.2 million individuals in high-risk congregate settings.Methods and analysisWe designed a prospective cohort study of individuals tested for LTBI, based on the data collected on all persons screened for LTBI as part of the 2017 congregate settings programme in South Korea. Four types of databases are kept: LTBI screening database (personal information and LTBI test results), national health information (NHI) database (socio-demographic data and comorbidities), public healthcare information system (PHIS) database, and the Korean national TB surveillance system database (TB outcomes). Information regarding LTBI treatment at private hospitals and public health centres is collected from NHI and PHIS databases, respectively. The screening data are cleaned, duplicates are removed, and, where appropriate, re-coded to analyse specific exposures and outcomes. The primary objective is to compare the number of active TB cases prevented within 2 years between participants undergoing treatment and not undergoing treatment in the LTBI screening programme in congregate settings. Cascade of care for LTBI diagnosis and treatment will be evaluated among those with a positive LTBI test result. A Cox proportional hazards model will be applied to determine the risk factors for developing active TB.Ethics and disseminationThe protocol is approved by the institutional review boards of Incheon St. Mary’s Hospital, the Catholic University of Korea. Study results will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberKCT000390