More than two billion people worldwide have suffered thyroid disorders from either iodine deficiency or excess. By creating the national map of groundwater iodine throughout China, we reveal the ...spatial responses of diverse health risks to iodine in continental groundwater. Greater non-carcinogenic risks relevant to lower iodine more likely occur in the areas of higher altitude, while those associated with high groundwater iodine are concentrated in the areas suffered from transgressions enhanced by land over-use and intensive anthropogenic overexploitation. The potential roles of groundwater iodine species are also explored: iodide might be associated with subclinical hypothyroidism particularly in higher iodine regions, whereas iodate impacts on thyroid risks in presence of universal salt iodization exhibit high uncertainties in lower iodine regions. This implies that accurate iodine supply depending on spatial heterogeneity and dietary iodine structure optimization are highly needed to mitigate thyroid risks in iodine-deficient and -excess areas globally.
HLA-A*11:01 is one of the most prevalent human leukocyte antigens (HLAs), especially in East Asian and Oceanian populations. It is also highly expressed in Indigenous people who are at high risk of ...severe influenza disease. As CD8+ T cells can provide broadly cross-reactive immunity to distinct influenza strains and subtypes, including influenza A, B and C viruses, understanding CD8+ T cell immunity to influenza viruses across prominent HLA types is needed to rationally design a universal influenza vaccine and generate protective immunity especially for high-risk populations. As only a handful of HLA-A*11:01-restricted CD8+ T cell epitopes have been described for influenza A viruses (IAVs) and epitopes for influenza B viruses (IBVs) were still unknown, we embarked on an epitope discovery study to define a CD8+ T cell landscape for HLA-A*11:01-expressing Indigenous and non-Indigenous Australian people. Using mass-spectrometry, we identified IAV- and IBV-derived peptides presented by HLA-A*11:01 during infection. 79 IAV and 57 IBV peptides were subsequently screened for immunogenicity in vitro with peripheral blood mononuclear cells from HLA-A*11:01-expressing Indigenous and non-Indigenous Australian donors. CD8+ T cell immunogenicity screening revealed two immunogenic IAV epitopes (A11/PB2320-331 and A11/PB2323-331) and the first HLA-A*11:01-restricted IBV epitopes (A11/M41-49, A11/NS1186-195 and A11/NP511-520). The immunogenic IAV- and IBV-derived peptides were >90% conserved among their respective influenza viruses. Identification of novel immunogenic HLA-A*11:01-restricted CD8+ T cell epitopes has implications for understanding how CD8+ T cell immunity is generated towards IAVs and IBVs. These findings can inform the development of rationally designed, broadly cross-reactive influenza vaccines to ensure protection from severe influenza disease in HLA-A*11:01-expressing individuals.
Summary Objective Leptin has been found highly expressed in human osteoarthritis. We aimed to explore the possible effects and mechanisms of leptin on the apoptosis and autophagy of chondrocytes ...during osteoarthritis pathogenesis. Methods Gene expression profile from osteoarthritis affected and preserved cartilage were downloaded from NCBI’s Gene Expression Omnibus database (GSE57218). Lysyl oxidase-like 3 (LOXL3) mRNA expression in cartilage tissues and leptin concentration in joint synovial fluid (SF) was measured in samples from 45 osteoarthritis patients and 25 healthy donors by real-time PCR and radioimmunoassay, respectively. Rat osteoarthritis model was induced by anterior cruciate ligament transection (ACLT). The expression of apoptosis regulators and autophagy markers were detected by Western blot. Cell survival and cell apoptosis were identified by CCK-8 and flow cytometry, respectively. Results Re-analysis on GSE57218 indicated that LOXL3 mRNA was upregulated in osteoarthritis affected cartilage. LOXL3 mRNA was upregulated in osteoarthritis patients, which was positively correlated with SF leptin concentration. Similar results were obtained in rat osteoarthritis model. Moreover, ACLT surgery led to a significant increase in the protein levels of cleaved caspase 3, and a notable decrease in the protein levels of Bcl-2, LC3 II/LC3 I and Beclin1. Silencing of LOXL3 in ACLT and leptin treated primary chondrocytes significantly inhibited cell apoptosis, and promoted cell proliferation and autophagy. Moreover, overexpression of LOXL3 remarkably inhibited autophagy of chondrocytes via activating mTORC1. Conclusions LOXL3, a downstream of leptin, stimulated the apoptosis, but inhibited the autophagy of chondrocytes. LOXL3 is a potential therapy target for osteoarthritis.
Crystal plasticity has been applied to model the cyclic constitutive behaviour of a polycrystalline nickel-based superalloy at elevated temperature using finite element analyses. A representative ...volume element, consisting of randomly oriented grains, was considered for the finite element analyses under periodic boundary constraints. Strain-controlled cyclic test data at 650
°C were used to determine the model parameters from a fitting process, where three loading rates were considered. Model simulations are in good agreement with the experimental results for stress–strain loops, cyclic hardening behaviour and stress relaxation behaviour. Stress and strain distributions within the representative volume element are of heterogeneous nature due to the orientation mismatch between neighbouring grains. Stress concentrations tend to occur within “hard” grains while strain concentrations tend to locate within “soft” grains, depending on the orientation of grains with respect to the loading direction. The model was further applied to study the near-tip deformation of a transgranular crack in a compact tension specimen using a submodelling technique. Grain microstructure is shown to have an influence on the von Mises stress distribution near the crack tip, and the gain texture heterogeneity disturbs the well-known butterfly shape obtained from the viscoplasticity analysis at continuum level. The stress–strain response near the crack tip, as well as the accumulated shear deformation along slip system, is influenced by the orientation of the grain at the crack tip, which might dictate the subsequent crack growth through grains. Individual slip systems near the crack tip tend to have different amounts of accumulated shear deformation, which was utilised as a criterion to predict the crack growth path.
Summary
Background
Multiphoton microscopy (MPM) is a novel imaging technology that has recently become applicable for diagnostic purposes. The use of (near) infrared light in MPM allows for deep ...tissue imaging. In addition, this modality exploits the autofluorescent nature of extracellular matrix fibres within the skin.
Objectives
To quantitate the structure and abundance of elastic fibres in human dermis in three dimensions utilizing autofluorescent signals generated by MPM for the objective examination of elastin‐related skin disorders.
Methods
Cross‐sections of skin samples from elastin‐related disorders were analysed by MPM and correlated to histopathology. In situ visualization of elastic fibres by MPM was conducted by en face imaging of ex vivo skin samples through the intact epidermis. Image analysis software was used to quantify elastic fibres in three dimensions.
Results
Based on the MPM‐detected elastin‐specific autofluorescence, we developed the Dermal Elastin Morphology Index (DEMI), calculated as the ratio of elastic fibre surface area and volume. This enabled objective three‐dimensional quantification of elastic fibres. Quantitative scoring of sun‐damaged skin using DEMI correlated with qualitative histopathological grading of the severity of solar elastosis. Furthermore, this approach was applied to changes in elastic fibre architecture in other disorders, such as pseudoxanthoma elasticum (PXE), PXE‐like syndrome, elastofibroma, focal dermal elastosis, anetoderma, mid‐dermal elastolysis and striae distensae. We imaged elastic fibres in intact ex vivo skin imaged en face through the epidermis, indicating that this approach could be used in vivo.
Conclusions
MPM has the potential for noninvasive in vivo visualization of elastic fibres in the dermis with near histological resolution. DEMI allows objective assessment of elastic fibres to support diagnosis and monitoring of disease progress or therapy of elastin‐related skin disorders.
What's already known about this topic?
Multiphoton microscopy has been used on tissue sections and in patients to assess skin pathologies.
Autofluorescent structures within the skin, including elastic fibres, can be visualized using multiphoton imaging without the need for histochemical or antibody staining.
What does this study add?
Development of the Dermal Elastin Morphology Index (DEMI) to enable objective three‐dimensional quantification of elastic fibres.
Use of DEMI is demonstrated in elastin‐related skin disorders.
DEMI can be used on tissue sections, where it correlates with histopathology, but in contrast to histopathology it allows in vivo application.
► Ratchetting near and ahead of a crack tip is a characteristic of the crack tip field. ► The phenomenon does not appear to be sensitive to constitutive formulation. ► Ratchetting strain is sensitive ...to grain orientation. ► Ratchetting strain is related to accumulated plastic strain. ► A crack growth criterion is proposed based on the concept of ratchetting.
Ratchetting deformation has significant implications on material damage and fatigue life of components under service loading conditions. In this work, we explore the concept of ratchetting strain as a driving force in controlling crack growth, both time-independent and time-dependent, utilising elasto-plastic, visco-plastic and crystal-plasticity constitutive models. Characteristics of crack tip deformation were examined for both stationary and growing cracks using the finite element method. Whilst the strain range and the stress range remained largely unchanged throughout the loading cycles, distinctive strain ratchetting behaviour near the crack tip occurred in all cases, leading to progressive accumulation of tensile strain normal to the crack growth plane. It seems plausible that this tensile strain, or ratchetting strain, may be responsible for material separation leading to crack growth. The effects of material constitutive model, grain orientation and loading frequency on the development of ratchetting strain were also examined. Ratchetting strain was found to be related to accumulated plastic strain; and both were used in a crack growth criterion with which the crack growth rates of a nickel alloy were predicted. The preliminary results seem to be encouraging.
An experimental investigation of spatio-temporal characteristics of the Portevin–Le Châtelier (PLC) effect in austenitic steel with twinning induced plasticity (TWIP) is presented. Post-processing of ...high resolution digital images captured from specimens in quasi-static, room temperature tensile tests was conducted with a digital image correlation (DIC) method. This provided direct measurement of strain fields during all stages of the tests. Variable rate digital image capture, enabled with a custom image acquisition algorithm, guaranteed a suitable number of images recorded during serrations in load–time records. Nucleation, propagation, and morphology of individual PLC bands in both straight gage and tapered specimens were quantified with strain rate contours computed with a backward differentiation scheme. Time histories of strain evolution in the PLC band wakes were extracted from cumulative strain contours. Of the three types of PLC bands, only the continuously propagating Type A bands were observed. Band nucleation, which occurred at serration crests in flow curves derived from the DIC results, was not limited to regions of geometry-induced stress concentrations. Due to its importance in finite element springback predictions and to support theoretical model development of inelastic behavior in TWIP steel, we measured Young’s modulus variation with strain in periodic loading–unloading tests. Implications of the experimental results for theoretical modeling of the PLC effect in TWIP steel are discussed.
Regeneration gas CO2 concentration distribution along the bed in the heat blowing process by pure nitrogen desorption. The regeneration time tR is from 1 min to 5 min, and the regeneration partition ...zone III (Re-adsorption Area) is not formed. The CO2 concentration curve has no significant peak, and the CO2 regeneration rate slows down at this point. In 5–9 min: the regeneration mass partition zone is basically formed, the CO2 regeneration rate of speed increases, the CO2 concentration curve reaches a peak. In 9–17 min: the regeneration zones III and IV gradually disappear, the CO2 breakthrough curve reaches a peak, and the volume fraction is 9250 × 10−6. In 17–25 min: the value of the CO2 concentration peak decreases, and the volume fraction of CO2 becomes 1064 × 10−6. When tR exceeds 25 min, the CO2 that remains in the 13× molecular sieve bed is completely precipitated and discharged from the absorber.
Display omitted
•The three-bed temperature swing adsorption air pre-purification unit was proposed.•The partition theory was proposed, and the 13× molecular sieve was divided into four zones.•The waste heat recovery from the heat-blowing stage was verified via experiment.•The maximum saving energy of the three-bed TSA recovery strategy was up to 51.1%.•The regenerative heat mass transfers of the three- and two-bed were distinguished.
A novel three-bed temperature swing adsorber was built to recover low-temperature waste heat from heat- and cold-blowing stages in a double molecular sieve of an air pre-purification system. The regenerative mass transfer in the adsorption bed was divided, and the temperature and concentration breakthrough curves of the adsorber regenerator were obtained via an experiment. Experimental results show that the relationship between the starting point and the energy of waste heat recovery is parabolic. However, energy saving reached the peak at 52.5% when the starting point of heat recovery was 23 min; this result would yield additional H2O and CO2 into the bed, thereby affecting the purification effect of the absorbers. The starting time of exhaust gas recycling for limit waste heat recovery strategy was 26 min, which resulted in 51.1% energy savings by recycling different stages of regeneration exhaust. The starting time of exhaust gas recycling for the optimal heat recovery strategy was 29 min, in which energy saving reached 46.5%. The starting time of exhaust gas recycling for the best regeneration strategy was 35 min, which generated energy saving of 29.8%.
We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we ...characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c(+) major histocompatibility complex (MHC) class II(hi)) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T(H)17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple T(H)1, T(H)2, and T(H)17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4(+) T lymphocytes. Loss of T and B lymphocytes in Rag1(-/-) × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1(-/-), indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/T(H)17 response, similar to that of human ulcerative colitis.
Advanced microscopy characterisation and numerical modelling have been carried out to investigate oxygen diffusion and crack growth in a nickel-based superalloy under fatigue-oxidation conditions. ...Penetration of oxygen into the material and the associated internal oxidation, which leads to material embrittlement and failure, have been found from Focused Ion Beam (FIB) examinations. Applied fatigue loading tends to enhance the extent of internal oxidation for temperatures at 750°C and above. Using a submodelling technique, finite element analyses of oxygen penetration at grain level have been carried out to quantify the fatigue-oxidation damage and calibrate the diffusion parameters based on the measurements of maximum depth of internal oxidation. The grain microstructure was considered explicitly in the finite element model, where the grain boundary was taken as the primary path for oxygen diffusion. A sequentially coupled mechanical-diffusion analysis was adopted to account for the effects of deformation on diffusion during fatigue loading, for which the material constitutive behaviour was described by a crystal plasticity model at grain level. Prediction of oxidation-assisted crack growth has also been carried out at elevated temperature from the finite element analyses of oxygen diffusion near a fatigue crack tip. A failure curve for crack growth has been constructed based on the consideration of both oxygen concentration and accumulated inelastic strain near the crack tip. The predictions from the fatigue-oxidation failure curve compared well with the experimental results for triangular and dwell loading waveforms, with significant improvement achieved over those predicted from the viscoplastic model alone.
PDF
