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In the longitudinal seismic deformation method for shield tunnels, one of the most commonly used is the longitudinal equivalent stiffness beam model (LES) for simulating the mechanical behavior of the lining. In this model, axial deformation and bending deformation are independent, so the equivalent stiffness is a constant value. However, the actual situation is that axial deformation and bending deformation occur simultaneously, which is not considered in LES. At present, we are not clear about the effect on the calculation results when axial deformation and bending deformation occur simultaneously. Therefore, in this paper, we improve the traditional LES by taking the relative deformation as a load and considering the coordinated deformation of axial and bending degrees of freedom. This improved model is called DNLES, and its neutral axis equations are an explicit expression. Then, we propose an iterative algorithm to solve the calculation model of the DNLES-based longitudinal seismic deformation method. Through a calculation example, we find that the internal forces based on LES are notably underestimated than those of DNLES in the compression bending zone, while are overestimated in the tension bending zone. When considering the combined effect, the maximum bending moment reached 13.7 times that of the LES model, and the axial pressure and tension were about 1.14 and 0.96 times, respectively. Further analysis reveals the coordinated deformation process in the axial and bending directions of the shield tunnel, which leads to a consequent change in equivalent stiffness. This explains why, in the longitudinal seismic deformation method, the traditional LES may result in unreasonable calculation results.

Abstract Biological sex is a crucial variable in neuroscience studies where sex differences have been documented across cognitive functions and neuropsychiatric disorders. While gross statistical differences have been previously documented in macroscopic brain structure such as cortical thickness or region size, less is understood about sex-related cellular-level microstructural differences which could provide insight into brain health and disease. Studying these microstructural differences between men and women paves the way for understanding brain disorders and diseases that manifest differently in different sexes. Diffusion MRI is an important in vivo, non-invasive methodology that provides a window into brain tissue microstructure. Our study develops multiple end-to-end classification models that accurately estimates the sex of a subject using volumetric diffusion MRI data and uses these models to identify white matter regions that differ the most between men and women. 471 male and 560 female healthy subjects (age range, 22–37 years) from the Human Connectome Project are included. Fractional anisotropy, mean diffusivity and mean kurtosis are used to capture brain tissue microstructure characteristics. Diffusion parametric maps are registered to a standard template to reduce bias that can arise from macroscopic anatomical differences like brain size and contour. This study employ three major model architectures: 2D convolutional neural networks, 3D convolutional neural networks and Vision Transformer (with self-supervised pretraining). Our results show that all 3 models achieve high sex classification performance (test AUC 0.92–0.98) across all diffusion metrics indicating definitive differences in white matter tissue microstructure between males and females. We further use complementary model architectures to inform about the pattern of detected microstructural differences and the influence of short-range versus long-range interactions. Occlusion analysis together with Wilcoxon signed-rank test is used to determine which white matter regions contribute most to sex classification. The results indicate that sex-related differences manifest in both local features as well as global features / longer-distance interactions of tissue microstructure. Our highly consistent findings across models provides new insight supporting differences between male and female brain cellular-level tissue organization particularly in the central white matter.

BackgroundPopulus simonii, a notable native tree species in northern China, demonstrates impressive resistance to stress, broad adaptability, and exceptional hybridization potential. DOF family is a class of specific transcription factors that only exist in plants, widely participating in plant growth and development, and also playing an important role in abiotic stress response. To date, there have been no reported studies on the DOF gene family in P. simonii, and the expression levels of this gene family in different tissues of poplar, as well as its expression patterns under cold, heat, and other stress conditions, remain unclear.MethodsIn this study, DOF gene family were identified from the P. simonii genome, and various bioinformatics data on the DOF gene family, gene structure, gene distribution, promoters and regulatory networks were analyzed. Quantitative real time PCR technology was used to verify the expression patterns of the DOF gene family in different poplar tissues.ResultsThis research initially pinpointed 41 PSDOF genes in P. simonii genome. The chromosomal localization results revealed that the PSDOF genes is unevenly distributed among 19 chromosomes, with the highest number of genes located on chromosomes 4, 5, and 11. A phylogenetic tree was constructed based on the homology between Arabidopsis thaliana and P. simonii, dividing the 41 PSDOF genes into seven subgroups. The expression patterns of PSDOF genes indicated that specific genes are consistently upregulated in various tissues and under different stress conditions, suggesting their pivotal involvement in both plant development and response to stress. Notably, PSDOF35 and PSDOF28 serve as pivotal hubs in the interaction network, playing a unique role in coordinating with other genes within the family.ConclusionThe analysis enhances our comprehension of the functions of the DOF gene family in tissue development and stress responses within P. simonii. These findings provide a foundation for future exploration into the biological roles of DOF gene family.

With the rapid increase in the number of vehicles on the road, minor traffic accidents have become more frequent, contributing significantly to traffic congestion and disruptions. Traditional methods for determining responsibility in such accidents often require human intervention, leading to delays and inefficiencies. This study proposed a fully intelligent method for liability determination in minor accidents, utilizing collision detection and large language models. The approach integrated advanced vehicle recognition using the YOLOv8 algorithm coupled with a minimum mean square error filter for real-time target tracking. Additionally, an improved global optical flow estimation algorithm and support vector machines were employed to accurately detect traffic accidents. Key frames from accident scenes were extracted and analyzed using the GPT4-Vision-Preview model to determine liability. Simulation experiments demonstrated that the proposed method accurately and efficiently detected vehicle collisions, rapidly determined liability, and generated detailed accident reports. The method achieved the fully automated AI processing of minor traffic accidents without manual intervention, ensuring both objectivity and fairness.

Objectives: To quantify the seasonal and antigenic characteristics of influenza to help understand influenza activity and inform vaccine recommendations. Methods: We employed a generalized linear model with harmonic terms to quantify the seasonal pattern of influenza in China from 2005-2017, including amplitude (circulatory intensity), semiannual periodicity (given two peaks a year), annual peak time, and epidemic duration. The antigenic differences were distinguished as antigenic similarity between 2009 and 2020. We categorized regions above 33° N, between 27° N and 33° N, and below 27° N as the north, central, and south regions, respectively. Results: We estimated that the amplitude in the north region (median: 0.019, 95% CI: 0.018-0.021) was significantly higher than that in the central region (median: 0.011, 95% CI: 0.01-0.012, P

Abstract Background Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers. Methods Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer. Results WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis. Conclusion The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.

Enterovirus A71 (EV-A71) infection is a major cause of severe hand, foot and mouth disease (HFMD) in young children. The characteristics of EV-A71 neutralizing antibodies in HFMD patients are not well understood. In this study, we identified and cloned EV-A71-neutralizing antibodies by single cell RNA and B cell receptor sequencing of peripheral blood mononuclear cells. From 145 plasmablasts, we identified two IgG1 monoclonal antibodies (mAbs) and six IgM mAbs that neutralized EV-A71. Four of the IgM mAbs harbor germline variable sequences and neutralize EV-A71 potently. Two genetically similar IgM antibodies from two patients have recurrent heavy chain variable domain gene usage and similar complementarity-determining region 3 sequences. We mapped the residues of EV-A71 critical for neutralization through selection of virus variants resistant to antibody neutralization in the presence of neutralizing mAbs. The residues critical for neutralization are conserved among EV-A71 genotypes. Epitopes for the two genetically similar antibodies overlap with the SCARB2 binding site of EV-A71. We used escape variants to measure the epitope-specific antibody response in acute phase serum samples from EV-A71 infected HFMD patients. We found that these epitopes are immunogenic and contributed to the neutralizing antibody response against the virus. Our findings advance understanding of antibody response to EV-A71 infection in young children and have translational potential: the IgM mAbs could potentially be used for prevention or treatment of EV-A71 infections.

The inherent short‐term transience of renewable energy sources causes significant challenges for the electricity grids. Energy storage systems that can simultaneously provide high power and high energy efficiency are required to accommodate the intermittent renewables. Herein, an ultrafast and high‐capacity aqueous proton battery is developed based on the organic pyrene‐4,5,9,10‐tetraone (PTO) anode. The co‐insertion of H2O molecules and proton into the PTO organic anode effectively reduces the interfacial resistance between the anode and electrolytes, and achieves an unprecedented rate capability up to 250 C and as short as 7 s per charge/discharge. A PTO‐based full cell exhibits an outstanding power density (>104 W kg−1) comparable to supercapacitors. The full utilization of the four C=O groups in PTO molecule during cycling enables the highest capacity (85 mAh g−1) reported for proton batteries to date. This study represents a significant leap forward in the exploitation of ultrafast electrochemical energy storage and accelerates the development of intermittent grid‐scale energy storage technologies.

Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1–3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.

Three ultracompact integrated photonic devices are proposed, assisted by etched structures. A mode-order converter (MOC) is achieved with a footprint of 0.85 × 1.4 μm2, which exhibits high performances with insertion loss (IL) below 0.34 dB and mode purity (MP) above 90% within 100 nm waveband. Moreover, a mode blocking filter (MBF) is proposed based on a subwavelength grating with a footprint of 0.8 × 4.12 μm2, which allows the propagation of TM0 mode but blocks the TM1 mode with a remarkably high extinction ratio of 31.6 dB at the wavelength of 1550 nm. Finally, a compact reciprocal optical diode (ROD) is presented by cascading the abovementioned MOC and MBF with a footprint of 0.85 × 5.9 μm2. This ROD enables one-way transmissions for both TM0 mode and TM1 mode with contrast ratios of 19.74 dB and 32.04 dB, respectively. The design methodology paves a new way for mode manipulation in integrated multimode photonic circuits.

With the COVID-19 pandemic, life satisfaction among college students has become a key issue at universities and in society. The current study explores the effects of belief in a just world and resilience on the relationship between relative deprivation and life satisfaction. A total of 787 college students from universities in China completed online questionnaires. Results showed that relative deprivation was negatively correlated with life satisfaction. Belief in a just world and resilience separately mediated the relationship between relative deprivation and life satisfaction. Moreover, a serial mediating effect of belief in a just world and resilience was observed between relative deprivation and life satisfaction. These findings suggest that relative deprivation may impair individuals' beliefs in a just world. Moreover, less belief in a just world may lower resilience and consequently decrease life satisfaction. This study enriches the research field of relative deprivation theory in the context of the COVID-19 pandemic, and provides a new interpretation and intervention perspective for improving college students' life satisfaction.

Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.

During January–February 2020, coronavirus disease (COVID-19) and tuberculosis were diagnosed for 3 patients in Wuhan, China. All 3 patients had COVID-19 pneumonia. One severely ill patient died after acute respiratory distress syndrome developed. Clinicians and public health officials should be aware of underlying chronic infections such as tuberculosis in COVID-19 patients.

Abstract Objectives To (i) use a mandibular advancement appliance in rats to investigate the role of the stromal cell-derived factor/CXC receptor 4 (SDF-1/CXCR4) signaling pathway in temporomandibular joint osteoarthritis (TMJ OA) induced by overloaded functional orthopedics (OFO) and (ii) provide a cellular and molecular basis for efficacious treatment of skeletal class-II malocclusion and avoidance of TMJ OA. Method Male Sprague-Dawley rats (6 weeks) were divided randomly into control + normal saline (NS), EXP + ADM3100 (SDF-1 antagonist), EXP + NS, and control + ADM3100 groups. Changes in articular cartilage and subchondral bone after TMJ OA in these four groups were observed by hematoxylin and eosin (H&E), immunofluorescence double staining (IDS), Safranin-O staining, immunohistochemical (IHC) staining, real-time polymerase chain reaction, and micro-computed tomography at 2, 4, and 8 weeks. Results OFO led to increased expression of SDF-1, CXCR4, and matrix metalloproteinase (MMP) 13 and decreased expression of collagen II. The thickness of the hypertrophic cartilage layer was reduced at 4 weeks in the EXP + NS group, and damage to subchondral bone was observed at 2 weeks. Using ADM3100 to inhibit SDF-1 signaling could attenuate expression of MMP13, cartilage damage, and osteoblast differentiation. IDS showed that the areas of expression of SDF-1 and OSX in subchondral bone overlapped. Conclusions Overloaded functional orthopedics (OFO) induced TMJ OA. The destruction of subchondral bone in TMJ OA caused by OFO occurred before damage to cartilage. SDF-1/CXCR4 may induce the osteogenic differentiation and cause cartilage degradation in TMJ OA caused by OFO.

The advent of graphene opens up the research into two-dimensional (2D) materials, which are considered revolutionary materials. Due to its unique geometric structure, graphene exhibits a series of exotic physical and chemical properties. In addition, single-element-based 2D materials (Xenes) have garnered tremendous interest. At present, 16 kinds of Xenes (silicene, borophene, germanene, phosphorene, tellurene, etc.) have been explored, mainly distributed in the third, fourth, fifth, and sixth main groups. The current methods to prepare monolayers or few-layer 2D materials include epitaxy growth, mechanical exfoliation, and liquid phase exfoliation. Although two Xenes (aluminene and indiene) have not been synthesized due to the limitations of synthetic methods and the stability of Xenes, other Xenes have been successfully created via elaborate artificial design and synthesis. Focusing on elemental 2D materials, this review mainly summarizes the recently reported work about tuning the electronic, optical, mechanical, and chemical properties of Xenes via surface modifications, achieved using controllable approaches (doping, adsorption, strain, intercalation, phase transition, etc.) to broaden their applications in various fields, including spintronics, electronics, optoelectronics, superconducting, photovoltaics, sensors, catalysis, and biomedicines. These advances in the surface modification of Xenes have laid a theoretical and experimental foundation for the development of 2D materials and their practical applications in diverse fields.

Abstract Background Snake venoms are complex mixtures of toxic proteins or peptides encoded by various gene families that function synergistically to incapacitate prey. In the present study, in order to unravel the proteomic repertoire of Deinagkistrodon acutus venom, some trace abundance components were analyzed. Methods Shotgun proteomic approach combined with shotgun nano-LC-ESI-MS/MS were employed to characterize the medically important D. acutus venom, after collected samples were enriched with the combinatorial peptide ligand library (CPLL). Results This avenue helped us find some trace components, undetected before, in D. acutus venom. The results indicated that D. acutus venom comprised 84 distinct proteins from 10 toxin families and 12 other proteins. These results are more than twice the number of venom components obtained from previous studies, which were only 29 distinct proteins obtained through RP-HPLC for the venom of the same species. The present results indicated that in D. acutus venom, the most abundant components (66.9%) included metalloproteinases, serine proteinases, and C-type lectin proteins; the medium abundant components (13%) comprised phospholipases A2 (PLA2) and 5’-nucleotidases and nucleases; whereas least abundant components (6%) were aminopeptidases, L-amino acid oxidases (LAAO), neurotoxins and disintegrins; and the trace components. The last were undetected before the use of conventional shotgun proteomics combined with shotgun nano-LC-ESI-MS/MS, such as cysteine-rich secretory proteins Da-CRPa, phospholipases B-like 1, phospholipases B (PLB), nerve growth factors (NGF), glutaminyl-peptide cyclortransferases (QC), and vascular non-inflammatory molecules 2 (VNN2). Conclusion These findings demonstrated that the CPLL enrichment method worked well in finding the trace toxin proteins in D. acutus venom, in contrast with the previous venomic characterization of D. acutus by conventional LC-MS/MS. In conclusion, this approach combined with the CPLL enrichment was effective for allowing us to explore the hidden D. acutus venomic profile and extended the list of potential venom toxins.

Background: Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) poses a serious threat to children's health. Kinetics of the neutralising antibody (NAb) response in EV-A71 infected HFMD patients remains unclear. The ideal sampling time of paired serum samples for serological diagnosis of EV-A71 infection is not well defined. Methods: HFMD inpatients admitted to Henan Children's Hospital between February 15, 2017 and February 15, 2018 were enrolled. Serial serum samples collected during hospitalisation and up to 1.5 years after discharge were tested for NAb against EV-A71. Random intercept modelling with B-spline was conducted to characterize the kinetics of the EV-A71 NAb response over time after illness onset. Findings: A total of 524 serum samples from 264 EV-A71 RNA positive HFMD inpatients were collected. NAb titres of EV-A71 infected patients were estimated to increase from 40 (95% CI: 9-180) at the day of onset to the peak of 2417 (95% CI: 1859-3143) at day 13, then remained above 1240 until 26 months. For serological diagnosis of EV-A71 infection, if at least a 4-fold rise in titre was used as the criteria, the acute phase serum should be collected at 0-4 days, the corresponding convalescent serum should be collected 14.9 days (95% CI: 9.1-23.8) after illness onset. Interpretation: EV-A71 infection induced a strong and persistent humoral immune response in HFMD patients. The findings provide a scientific support for determining the collection time of paired serum samples for serological diagnosis of EV-A71 infected HFMD patients. Funding: National Science Fund for Distinguished Young Scholars

Quantum droplets have recently emerged as a novel liquid state of matter in a mixture of two-component ultracold Bose gases under the equilibrium condition between the competing attractive inter- and repulsive intraspecies forces. Quantum droplets represent a self-bound liquid state in purely nonlinear systems and as such there is not any management applied to their study up to now. We here introduce the nonlinear management via space-periodic Feshbach resonance technique to a binary Bose–Einstein condensate and investigate theoretically the structure, property and dynamics of the one-dimensional quantum droplets therein, three findings are made: small droplets with single hump (solitonlike), moderate droplets composed of two solitons, large droplets feature a modulated flat-top shape. Particularly, by means of linear-stability and direct perturbed simulations, we prove that the droplets have a much wider stable region than their counterparts without taking the nonlinear management. The variational approximation is adopted and validated with numerical results in terms of small droplets. The results predicted here may be realized in the frontier ultracold atoms experiments aided by Feshbach-resonance, opening up a new channel to the quantum droplets studies.

Objective Critically ill patients often require emergency endotracheal intubation and mechanical ventilation. When esophageal intubation is not confirmed early, treatment may be delayed, even for life-threatening conditions. We examined the accuracy of bedside real-time airway ultrasonography in confirming the endotracheal tube (ETT) position during emergency endotracheal intubation in patients in the intensive care unit (ICU). Methods This single-center prospective observational study included 118 patients who underwent urgent endotracheal intubation in the ICU of Taizhou Hospital of Integrated Traditional Chinese and Western Medicine. Tracheal ultrasonography was used to confirm the ETT position during endotracheal intubation, after which fiberoptic bronchoscopy was performed. The accuracy of bedside real-time tracheal ultrasonography in determining the ETT position was examined. Results Twelve (10.2%) patients underwent endotracheal intubation. The kappa value was 0.844, indicating perfect consistency between tracheal ultrasonography and fiberoptic bronchoscopy in identifying esophageal intubation. The sensitivity, specificity, and positive and negative predictive values of tracheal ultrasonography in determining the ETT position were 75.0%, 100%, 100%, and 97.2%, respectively. Conclusions Bedside real-time tracheal ultrasonography accurately assesses the ETT position in the ICU and can identify the ETT position during intubation. These findings have important clinical applications and are of great significance for treatment of ICU patients.

Few researches have been focused on the treatment delay of rural-to-urban migrants in China. Our study aimed to investigate the effect of migration duration on treatment delay among rural-to-urban migrants in tertiary hospitals. A cross-sectional study was conducted based on a sample of 727 patients and surveyed factors including sociodemographics, medical costs, migration, treatment delay, and health cost-coping strategies. Totally, 727 patients were included, of which 61 delayed their treatment and 666 had no treatment delay. Statistically significant differences were found between different migration duration groups in marital status, education, insurance, family annual income, residency, payment before treatment, reported disease, and migration duration ( P < .05). The results from multiple logistic regression showed that migration between 1 and 5 years (adjusted odds ratio [OR] = 7.24; 95% confidence interval [CI] = 1.59-32.87; P < .05) was considered the significant contributing risk factor for treatment delay after adjusting for age, sex, and other variables. To cope with their health expenditure, patients with treatment delay tended to use less savings and borrow more money than those without. Rural-to-urban migrants with 1 to 5 years of migration were the most vulnerable group of having treatment delay. Migrants were more likely to borrow money to cope with the health expenditure. Targeted services should be provided to meet different needs of migrants according to migration duration.

Abstract Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.

Soluble microneedles (MNs) have recently become an efficient and minimally invasive tool in transdermal drug delivery because of their excellent biocompatibility and rapid dissolution. However, direct monitoring of structural and functional changes of MNs in vivo to estimate the efficiency of insulin delivery is difficult. We monitored the dissolution of MNs to obtain structural imaging of MNs’ changes by using optical coherence tomography (OCT). We also observed the effect of MNs on microvascular conditions with laser speckle contrast imaging (LSCI) and measured the blood perfusion of skin to obtain functional imaging of MNs. We determined the performance of two soluble MN arrays made from polyvinyl alcohol (PVA) and polyvinyl alcohol/polyvinylpyrolidone (PVA/PVP) by calculating the cross-sectional areas of the microchannels in mouse skin as a function of time. Moreover, the change in blood glucose before and after using MNs loaded with insulin was evaluated as an auxiliary means to demonstrate the ability of the soluble MNs to deliver insulin. Results showed that the structural imaging of these MNs could be observed in vivo via OCT in real time and the functional imaging of MNs could be showed using LSCI. OCT and LSCI are potential tools in monitoring MNs structural and functional changes.

Enterovirus 71 (EV71) is an RNA virus that causes hand-foot-mouth disease (HFMD), and even fatal encephalitis in children. Although EV71 pathogenesis remains largely obscure, host immune responses may play important roles in the development of diseases. Recognition of pathogens mediated by Toll-like receptors (TLRs) induces host immune and inflammatory responses. Intracellular TLRs must traffic from the endoplasmic reticulum (ER) to the endolysosomal network from where they initiate complete signaling, leading to inflammatory response. This study reveals a novel mechanism underlying the regulation of TLR7 signaling during EV71 infection. Initially, we show that multiple cytokines are differentially expressed during viral infection and demonstrate that EV71 infection induces the production of proinflammatory cytokines through regulating TLR7-mediated p38 MAPK, and NF-κB signaling pathways. Further studies reveal that the expression of the endosome-associated protein hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is upregulated and highly correlated with the expression of TLR7 in EV71 infected patients, mice, and cultured cells. Virus-induced HRS subsequently enhances TLR7 complex formation in early- and late-endosome by interacting with TLR7 and TAB1. Moreover, HRS is involved in the regulation of the TLR7/NF-κB/p38 MAPK and the TLR7/NF-κB/IRF3 signaling pathways to induce proinflammatory cytokines and interferons, respectively, resulting in the orchestration of inflammatory and immune responses to the EV71 infection. Therefore, this study demonstrates that HRS acts as a key component of TLR7 signaling to orchestrate immune and inflammatory responses during EV71 infection, and provides new insights into the mechanisms underlying the regulation of host inflammation and innate immunity during EV71 infection.

Upon recognition of viral components by pattern recognition receptors, such as the toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like helicases, cells are activated to produce type I interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. In this study, we revealed a novel mechanism in which hepatitis C virus (HCV) evades the immune surveillance system to proliferate by activating microRNA-21 (miR-21). We demonstrated that HCV infection upregulates miR-21, which in turn suppresses HCV-triggered type I IFN production, thus promoting HCV replication. Furthermore, we demonstrated that miR-21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. HCV-mediated activation of miR-21 expression requires viral proteins and several signaling components. Moreover, we identified a transcription factor, activating protein-1 (AP-1), which is partly responsible for miR-21 induction in response to HCV infection through PKCε/JNK/c-Jun and PKCα/ERK/c-Fos cascades. Taken together, our results indicate that miR-21 is upregulated during HCV infection and negatively regulates IFN-α signaling through MyD88 and IRAK1 and may be a potential therapeutic target for antiviral intervention.