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Abstract Depression frequently comorbidities with cancer, adversely affecting survivors’ quality of life. Liver dysfunction is also prevalent among cancer survivors. However, the association between these two conditions remains unclear. This study aimed to explore the relationship between depression and liver function biomarkers in US cancer survivors. A cross-sectional study was conducted utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2005–2020. Cancer survivors were screened and depression was assessed using the Patient Health Questionnaire-9 (PHQ-9), and 18 liver function biomarkers were included. Survey-weighted generalized linear models with multiple covariables adjusted were employed to examine the associations between depression and liver function biomarkers. A total of 4118 cancer survivors were included, representing a weighted population of 21 501 237. After adjusted with age, gender, race, marital status, education level, family income-to-poverty ratio, and number of cancer types, 8 biomarkers demonstrated positive correlations with depression in cancer survivors, included alanine aminotransferase (ALT, OR = 1.007, 95% CI: 1.000 to 1.013), alkaline phosphatase (ALP, 1.006 [1.002, 1.010]), gamma glutamyl transferase (GGT, 1.004 [1.001, 1.007]), lactate dehydrogenase (LDH, 1.004 [1.000, 1.009]), total protein (TP, 1.040 [1.009, 1.072]), globulin (GLB, 1.060 [1.030, 1.091]), total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) ratio (1.162 [1.050, 1.286]), and low-density lipoprotein cholesterol (LDL-C) to HDL-C ratio (1.243 [1.012, 1.526]); while 4 other biomarkers exhibited negative correlations, included HDL-C (0.988 [0.980, 0.997]), total bilirubin (TBi, 0.501 [0.284, 0.883]), aspartate aminotransferase (AST) to ALT ratio (0.588 [0.351, 0.986]), albumin (ALB) to GLB ratio (0.384 [0.229, 0.642]). Following sensitivity analysis, 5 biomarkers included LDH, HDL-C, TBi, AST/ALT and LDL-C/HDL-C lost their statistical significance for the association. This study identified certain associations between 7 liver function biomarkers and depression in US cancer survivors. Further research, particularly prospective longitudinal studies, is warranted to elucidate the causal relationships and explore the potential of improving liver function for the management of depression in cancer patients.

Abstract Background How to reduce the high incidence rate and mortality of colorectal cancer (CRC) effectively is the focus of current research. Endoscopic treatment of early-stage CRC and colorectal adenomas (CAC) has a high success rate, but although several treatments are available for advanced CRC, such as surgery, radiotherapy, chemotherapy, and immunotherapy, the 5-year survival rate remains low. In view of the high incidence rate and mortality of CRC, early rational drug prevention for high-risk groups and exploration of alternative treatment modalities are particularly warranted. Summary Gut microbiota is the target of and interacts with probiotics, prebiotics, aspirin, metformin, and various Chinese herbal medicines (CHMs) for the prevention of CRC. In addition, the anti-cancer mechanisms of probiotics differ widely among bacterial strains, and both bacterial strains and their derivatives and metabolites have been found to have anti-cancer effects. Gut microbiota plays a significant role in early drug prevention of CRC and treatment of CRC in its middle and late stages, targeting gut microbiota may be a new strategy for colorectal cancer treatment.

Abstract Reactor pressure vessel (RPV) studs are key components of nuclear reactors, and their connection with flange ensures the sealing of the RPV under high-pressure and high-temperature conditions. In the present work, the external threads of the RPV stud were prepared by triaxial rolling, and the texture evolution of the external thread root material of an RPV stud was predicted by finite element analysis coupled with viscoplastic self-consistent simulations. The microstructure of the external thread root material of RPV stud was characterized by scanning electron microscope and electron back-scattered diffraction. The installation characteristics of the turned and rolled parts of the RPV stud were tested by installation and pretightening tests. It was found that the dynamic recrystallization at the external thread root formed ultrafine tempered sorbite grains, high-angle grain boundaries (47%), and strong {111} and {111} textures. In the installation and pretightening test, the residual elongation of rolled parts was reduced by 6% under the same loading pressure. The triaxial rolling process distributed the microstructure of the external thread root of the RPV stud in a gradient manner, resulting in improved stud installation characteristics.

Abstract To investigate whether peritumoral edema (PE) could enhance deep learning radiomic (DLR) model in predicting axillary lymph node metastasis (ALNM) burden in breast cancer. Invasive breast cancer patients with preoperative MRI were retrospectively enrolled and categorized into low (

Abstract Preoperatively predicting extensive intraductal component in invasive breast cancer through imaging is crucial for informed decision-making, guiding surgical planning to mitigate risks of incomplete resection or re-operation for positive margins in breast-conserving surgery. This study aimed to characterize intra- and peri-tumor heterogeneity using high-spatial resolution ultrafast DCE-MRI to predict the extensive intraductal component in invasive breast cancer (IBC-EIC) preoperatively. A retrospective analysis included invasive breast cancer patients who underwent preoperative high-spatial resolution ultrafast DCE-MRI, categorized based on intraductal component status (IBC-EIC vs. IBC without EIC). Propensity score matching (PSM) was employed to balance clinicopathological covariates between the groups. Personalized kinetic intra-tumor heterogeneity (ITHkinetic) and peri-tumor heterogeneity (PTHkinetic) scores were quantified using clustered voxels with similar enhancement patterns. An image combined model, incorporating MRI features, ITHkinetic, and PTHkinetic scores, was developed and assessed. Of 368 patients, 26.4% (97/368) had IBC-EIC. PSM yielded well-matched pairs of 97 patients each. After PSM, ITHkinetic and PTHkinetic scores were significantly higher in the IBC-EIC group (ITHkinetic: 0.68 ± 0.23; PTHkinetic: 0.58 ± 0.19) compared to IBC without EIC (ITHkinetic: 0.32 ± 0.25; PTHkinetic: 0.42 ± 0.18; p

Abstract The agriculture Internet of Things (IoT) has been widely applied in assisting pear farmers with pest and disease prediction, as well as precise crop management, by providing real-time monitoring and alerting capabilities. To enhance the effectiveness of agriculture IoT monitoring applications, clustering protocols are utilized in the data transmission of agricultural wireless sensor networks (AWSNs). However, the selection of cluster heads is a NP-hard problem, which cannot be solved effectively by conventional algorithms. Based on this, This paper proposes a novel AWSNs clustering model that comprehensively considers multiple factors, including node energy, node degree, average distance and delay. Furthermore, a novel high-performance cluster protocol based on Gaussian mutation and sine cosine firefly algorithm (GSHFA-HCP) is proposed to meet the practical requirements of different scenarios. The innovative Gaussian mutation strategy and sine–cosine hybrid strategy are introduced to optimize the clustering scheme effectively. Additionally, an efficient inter-cluster data transmission mechanism is designed based on distance between nodes, residual energy, and load. The experimental results show that compared with other four popular schemes, the proposed GSHFA-HCP protocol has significant performance improvement in reducing network energy consumption, extending network life and reducing transmission delay. In comparison with other protocols, GSHFA-HCP achieves optimization rates of 63.69%, 17.2%, 19.56%, and 35.78% for network lifespan, throughput, transmission delay, and packet loss rate, respectively.

BackgroundPreschoolers’ lifestyles have become physically inactive and sedentary, their eating habits have become unhealthy, and their sleep routines have become increasingly disturbed. Parent-based interventions have shown promise to improve physical activity (PA), improve dietary behavior (DB), and reduce sleep problems among preschoolers. However, because of the recognized obstacles of face-to-face approaches (eg, travel costs and time commitment), easy access and lower costs make eHealth interventions appealing. Previous studies that examined the effectiveness of parent-based eHealth for preschoolers’ PA, DB, and sleep have either emphasized 1 variable or failed to balance PA, DB, and sleep modules and consider the intervention sequence during the intervention period. There is an acknowledged gap in parent-based eHealth interventions that target preschoolers raised in Chinese cultural contexts. ObjectiveThis study aims to investigate the effectiveness of a parent-based eHealth intervention for PA, DB, and sleep problems among Chinese preschoolers. MethodsThis 2-arm, parallel, randomized controlled trial comprises a 12-week intervention with a 12-week follow-up. A total of 206 parent-child dyads will be randomized to either an eHealth intervention group or a control group. Participants allocated to the eHealth intervention group will receive 12 interactive modules on PA, DB, and sleep, with each module delivered on a weekly basis to reduce the sequence effect on variable outcomes. The intervention is grounded in social cognitive theory. It will be delivered through social media, where parents can obtain valid and updated educational information, have a social rapport, and interact with other group members and facilitators. Participants in the control group will receive weekly brochures on PA, DB, and sleep recommendations from kindergarten teachers, but they will not receive any interactive components. Data will be collected at baseline, 3 months, and 6 months. The primary outcome will be preschoolers’ PA. The secondary outcomes will be preschoolers’ DB, preschoolers’ sleep duration, preschoolers’ sleep problems, parents’ PA, parenting style, and parental feeding style. ResultsParent-child dyads were recruited in September 2023. Baseline and posttest data collection occurred from October 2023 to March 2024. The follow-up data will be obtained in June 2024. The results of the study are expected to be published in 2025. ConclusionsThe parent-based eHealth intervention has the potential to overcome the barriers of face-to-face interventions and will offer a novel approach for promoting a healthy lifestyle among preschoolers. If this intervention is found to be efficacious, the prevalence of unhealthy lifestyles among preschoolers may be alleviated at a low cost, which not only has a positive influence on the health of individuals and the well-being of the family but also reduces the financial pressure on society to treat diseases caused by poor lifestyle habits. Trial RegistrationClinicalTrials.gov NCT06025019; https://clinicaltrials.gov/study/NCT06025019 International Registered Report Identifier (IRRID)DERR1-10.2196/58344

Abstract Detecting the water deficit status of vertical greenery plants rapidly and accurately is a significant challenge in the process of cultivating and planting greenery plants. Currently, the mainstream method involves utilizing a single target detection algorithm for this task. However, in complex real-world scenarios, the accuracy of detection is influenced by factors such as image quality and background environment. Therefore, we propose a multi-stage progressive detection method aimed at enhancing detection accuracy by gradually filtering, processing, and detecting images through a multi-stage architecture. Additionally, to reduce the additional computational load brought by multiple stages and improve overall detection efficiency, we introduce a Swin Transformer based on mobile windows and hierarchical representations for feature extraction, along with global feature modeling through a self-attention mechanism. The experimental results demonstrate that our multi-stage detection approach achieves high accuracy in vertical greenery plants detection tasks, with an average precision of 93.5%. This represents an improvement of 19.2%, 17.3%, 13.8%, and 9.2% compared to Mask R-CNN (74.3%), YOLOv7 (76.2%), DETR (79.7%), and Deformable DETR (84.3%), respectively.

Abstract Background Digital histopathology provides valuable information for clinical decision-making. We hypothesized that a deep risk network (DeepRisk) based on digital pathology signature (DPS) derived from whole-slide images could improve the prognostic value of the tumor, node, and metastasis (TNM) staging system and offer chemotherapeutic benefits for gastric cancer (GC). Methods DeepRisk is a multi-scale, attention-based learning model developed on 1120 GCs in the Zhongshan dataset and validated with two external datasets. Then, we assessed its association with prognosis and treatment response. The multi-omics analysis and multiplex Immunohistochemistry were conducted to evaluate the potential pathogenesis and spatial immune contexture underlying DPS. Results Multivariate analysis indicated that the DPS was an independent prognosticator with a better C-index (0.84 for overall survival and 0.71 for disease-free survival). Patients with low-DPS after neoadjuvant chemotherapy responded favorably to treatment. Spatial analysis indicated that exhausted immune clusters and increased infiltration of CD11b+CD11c+ immune cells were present at the invasive margin of high-DPS group. Multi-omics data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) hint at the relevance of DPS to myeloid derived suppressor cells infiltration and immune suppression. Conclusion DeepRisk network is a reliable tool that enhances prognostic value of TNM staging and aid in precise treatment, providing insights into the underlying pathogenic mechanisms.

Abstract Background Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity. Methods We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments. Results The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients. Conclusions Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1 P409L , ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Abstract Background This study investigates the accuracy of 3D-printed dental stents in intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC) and their dosimetric effects on normal tissues. Methods We selected 60 patients with OPC who underwent IMRT in the Department of Oncology, Special Medical Center of Army Medical University. These patients were randomly assigned into 3D-printed oral stent, simple glass bottle, and nonstent groups (20 patients/group). The positioning error was analyzed with the onboard imaging system once a week after 5 fractions of IMRT. The conformity index (CI), homogeneity index (HI), radiation dose of organs at risk (OARs), and oral mucosal reaction were compared among the three groups. Results No significant difference was observed in the conformity and uniformity of the target dose and the dose received by the spinal cord, larynx, and bilateral parotid glands among the three groups (P > 0.05). Meanwhile, the dose received by the upper cheek, hard palate, and soft palate of patients was significantly lower in the 3D-printed oral stent group than in the nonstent group (P 0.05). When compared with the nonstent group, the simple glass bottle group showed a markedly lower dose received by the upper cheek (P 0.05). According to Common Terminology Criteria for Adverse Events v.5.0, the adverse response rate of the hard palate mucosa was lower in the 3D-printed oral stent group than in the simple glass bottle and nonstent groups (P

Abstract Background Several observational studies have suggested an association between low serum bilirubin levels and Behçet's disease uveitis. However, the causal inference between bilirubin level and juvenile idiopathic arthritis‐associated uveitis (JIAU) remains ambiguous. We investigated the potential causal relationship between serum bilirubin levels and JIAU using a bidirectional two‐sample Mendelian randomization (MR) framework. Methods We systemically integrated summary‐level data from published large‐scale genome‐wide association studies on bilirubin level and JIAU in a Caucasian British population. To determine the causal effect of bilirubin level on JIAU, we constructed strong instrumental variables using 47 and 80 single‐nucleotide polymorphisms (SNPs) specific to direct bilirubin and total bilirubin levels, respectively. For reverse causal inference, seven SNPs associated with JIAU were included in our study. Multiple complementary methods were further performed to evaluate the robustness of MR estimates. Results The inverse‐variance weighted estimate did not show any significant causal associations of genetically predicted serum direct or total bilirubin level with the risk of JIAU (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 0.750–1.359, p = 0.947; OR: 0.867, 95% CI: 0.688–1.093; p = 0.227, respectively). MR–Egger and weighted median methods also obtained similar associations. Additionally, the results of reverse MR analyses using JIAU as exposure showed no associations of genetically predicted risk of JIAU with serum bilirubin levels (p > 0.05). In sensitivity analysis, the causal estimate between serum bilirubin levels and JIAU did not differ when SNPs associated with possible confounders were omitted. Conclusion Genetic evidence from our bidirectional analysis did not support a causal association between serum bilirubin levels and JIAU risk in the Caucasian British population. Future large‐scale studies should be conducted to validate these findings and explore any causal effects on the disease process.

Detecting green fruits presents significant challenges due to their close resemblance in color to the leaves in an orchard environment. We designed GreenFruitDetector, a lightweight model based on an improved YOLO v8 architecture, specifically for green fruit detection. In the Backbone network, we replace ordinary convolution with Deformable Convolution to enhance the extraction of geometric features. Additionally, we designed MCAG-DC (Multi-path Coordinate Attention Guided Deformer Convolution) to replace the convolution in C2f, enhancing the Backbone's feature extraction capability when encountering occlusion problems. For the Neck part of the algorithm, we designed a Fusion-neck structure that integrates spatial detail information from feature maps at different scales, thereby enhancing the network's ability to extract multi-scale information. Additionally, we devised a new detection head that incorporates multi-scale information, significantly improving the detection of small and distant objects. Finally, we applied channel pruning techniques to reduce the model size, parameter count, and FLOPs to 50%, 55%, and 44% of the original, respectively. We trained and evaluated the improved model on three green fruit datasets. The accuracy of the improved model reached 94.5%, 84.4%, and 85.9% on the Korla Pear, Guava, and Green Apple datasets, respectively, representing improvements of 1.17%, 1.1%, and 1.77% over the baseline model. The mAP@0.5 increased by 0.72%, 6.5%, and 0.9%, respectively, and the recall rate increased by 1.97%, 1.1%, and 0.49%, respectively.

AbstractBackground This study aimed to evaluate the diagnostic value of a non-invasive methylation gene test in clinical colorectal tumour screening.Method The quantitative methylation-specific PCR technique was used to detect faecal methylated syndecan-2 (mSDC2) in patients who received the screening of colorectal cancer (CRC).To evaluate the positive predictive value (PPV) of mSDC2 in patients with colorectal cancer, advanced adenoma (AA), and colorectal tumor (CRN) in risk factor stratification.Results The PPV of CRC, CRC + AA and CRN in male patients were 28.03%, 43.55% and 56.24%, respectively, which were higher than female patients. The positive detection rate of mSDC2 and the PPV of CRC gradually increased with age; The PPV in patients aged over 80 years was up to 78.05%, which was more significant than in younger patients with CRC. The PPV of CRC, AA and CRN were 37.10%, 11.80% and 63.37%, respectively. mSDC2 has a high detection rate of 85–100% in AA with intramucosal carcinoma alone or in combination with severe atypical hyperplasia or villous adenoma.Conclusion The mSDC2 test has a higher PPV in patients with colorectal cancer and colorectal adenoma (AD), especially in high-risk groups over 50 years of age, and may help in the early diagnosis of colorectal tumours in the future.

Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated the immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6], or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T-cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as the positive and negative control, respectively. Upon challenge with virulent Wa HRV, a significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG antibody-secreting cells in the ileum, spleen, and blood seven days post-challenge, as well as VP8*-specific IFN-γ-producing T-cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to the P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and the significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for the further development of mRNA-based rotavirus vaccines.

Abstract We evaluated how different degrees of air pollution affect the ocular surface of a cohort of human subjects in Beijing by correlating in-patient test outcomes with tear cytokines. A cross-sectional study involving 221 volunteers was carried out in different districts of Beijing. Air pollution indices were recorded for 7 d (including the visit day). The indices recorded were the air quality index (AQI), which is a dimensionless measure that quantitatively describes the state of air quality, concentrations of particulate matter smaller than 2.5 μm (PM2.5) and 10 μm (PM10), sulfur dioxide (SO2), ozone (O3), and nitrogen dioxide (NO2). The Ocular Symptom Disease Index (OSDI) questionnaire provided. Subsequently, subjects underwent slit-lamp examination, which included meibomian gland examination, conjunctival congestion score, conjunctivochalasis grade, tear meniscus height (TMH), tear breakup time (TBUT), corneal fluorescein staining (CFS), Schirmer I test, and conjunctival impression cytology. The concentrations of vascular endothelial growth factor (VEGF), interleukins (IL)-1β, IL-6 and IL-8 in tears were measured by microsphere-based immunoassay analysis. According to the value of the AQI, participants are divided into a slightly polluted (SP) group (n = 103) which the AQI value is less than or equal to 100 and a heavily polluted (HP) group (n = 118) whose AQI value is more than 100. Air pollution is related to ocular discomfort based on tear cytokine concentrations. PM2.5, PM10 and NO2 were positively correlated with OSDI, MG expressibility, meibum score, meiboscore, conjunctival congestion score, Schirmer I test value, TMH, goblet-cell density, concentrations of IL-6, and VEGF were negatively correlated with TBUT. PM2.5 and PM10 appear to be the major risk factors to the ocular surface, with NO2 being another important risk factor based on this study. The symptoms and signs of eye discomfort in the SP group were significantly less severe than those in the HP group, and tear cytokine concentrations (IL-6 and VEGF) were lower. Air pollution degrees were significantly correlated with tear cytokine concentrations, indicating an alteration of cytokine balance at the ocular surface under different degrees of air pollution.

Abstract Hematopoietic stem cells show biological manifestations of aging, diminished hematopoietic function and abnormal differentiation, which can lead to leukemia. It is therefore important to explore the mechanism underlying hematopoietic stem cell aging to develop strategies for delaying the process. Our evaluations revealed that the number of bone marrow hematopoietic cells (BMHCs) started to decrease significantly after 45 years of age, and the number of senescent BMHCs, as determined by senescence-associated beta-galactosidase staining, gradually increased with age. In addition, BMHCs from individuals over 45 years of age presented with notably reduced proliferative capacity, increased G1-phase cell cycle arrest, and significantly decreased generation of mixed colony forming units, which suggests that BMHCs enter senescence during middle age. Furthermore, we observed significantly lower antioxidant capacity and a significant increase in oxidative damage products, a gradual increase in the expression of senescence-associated proteins and genes, and a gradual decrease in the expression of cell cycle related proteins in BMHCs after middle age. Taken together, these findings offer both a theoretical and experimental basis for better understanding of the senescence progression of BMHCs and the optimal timing for anti-senescence drug interventions in clinical practice.

Abstract Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

Abstract This work focuses on the nature of magnetic anisotropy in 2.5–16 micron thick films of nickel ferrite (NFO) grown by liquid phase epitaxy (LPE). The technique, ideal for rapid growth of epitaxial oxide films, was utilized for films on (100) and (110) substrates of magnesium gallate (MGO). The motivation was to investigate the dependence of the growth induced anisotropy field on film thickness since submicron films of NFO were reported to show a very high anisotropy. The films grown at 850–875 C and subsequently annealed at 1000 C were found to be epitaxial, with the out-of-plane lattice constant showing unanticipated decrease with increasing film thickness and the estimated in-plane lattice constant increasing with the film thickness. The uniaxial anisotropy field H σ , estimated from X-ray diffraction data, ranged from 2.8–7.7 kOe with the films on (100) MGO having a higher H σ value than for the films on (110) MGO. Ferromagnetic resonance (FMR) measurements for in-plane and out-of-plane static magnetic field were utilized to determine both the magnetocrystalline the anisotropy field H 4 and the uniaxial anisotropy field H a . Values of H 4 range from −0.24 to −0.86 kOe. The uniaxial anisotropy field H a was an order of magnitude smaller than H σ and it decreased with increasing film thickness for NFO films on (100) MGO, but H a increased with film thickness for films on (110) MGO substrates. These observations indicate that the origin of the induced anisotropy could be attributed to several factors including (i) strain due to mismatch in the film-substrate lattice constants, (ii) possible variations in the bond lengths and bond angles in NFO during the growth process, and (iii) the strain arising from mismatch in the thermal expansion coefficients of the film and the substrate due to the high growth and annealing temperatures involved in the LPE technique. The LPE films of NFO on MGO substrates studied in this work are of interest for use in high frequency devices.

Abstract SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage–CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Abstract To investigate the value of the star-VIBE sequence in dynamic contrast-enhanced magnetic resonance imaging of esophageal carcinoma under free breathing conditions. From February 2019 to June 2020, 60 patients with esophageal carcinoma were prospectively enrolled to undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the K-space golden-angle radial stack-of-star acquisition scheme (star-VIBE) sequence (Group A) or conventional 3D volumetric-interpolated breath-hold examination (3D-VIBE) sequence (Group B), completely randomized grouping. The image quality of DCE-MRI was subjectively evaluated at five levels and objectively evaluated according to the image signal-to-noise ratio (SNR) and contrast-noise ratio (CNR). The DCE-MRI parameters of volume transfer constant (Ktrans), rate constant (Kep) and vascular extracellular volume fraction (Ve) were calculated using the standard Tofts double-compartment model in the post-perfusion treatment software TISSUE 4D (Siemens). Each group included 30 randomly selected cases. There was a significant difference in subjective classification between the groups (35.90 vs 25.10, p = 0.009). The study showed that both the SNR and CNR of group A were significantly higher than those of group B (p = 0.004 and 0.05). The star-VIBE sequence can be applied in DCE-MRI examination of esophageal carcinoma, which can provide higher image quality than the conventional 3D-VIBE sequence in the free breathing state.

Introduction Low anterior resection syndrome (LARS) involves bowel dysfunction after sphincter-preserving surgery for rectal resection that significantly impacts patients’ quality of life (QoL). The improvement of LARS largely depends on patient self-management behaviour; however, insufficient information about supportive care and weak awareness of self-management lead to poor self-management behaviour. Motivational interviewing (MIs) explore and change patients’ ambivalence during the conversation, thereby changing and maintaining healthy behaviours to enhance effective participation. In recent years, mobile health has been widely used in clinical practice, providing continuous information support and remote interaction. However, current online information on LARS is suboptimal, websites are highly variable, important content is often lacking and the material is too complex for patients. Therefore, this study will evaluate the impacts of a remote LARS interaction management intervention based on a WeChat applet (‘e-bowel safety’) and MIs on patients with LARS.Methods and analysis This study will be a single-blind, two-arm randomised controlled trial involving patients with LARS in three tertiary grade A general hospitals who will be randomised into two groups. The intervention group will use the ‘e-bowel safety’ applet and the intervention team will conduct a monthly MI about syndrome management. The control group will receive an information booklet that contains the same information as that provided in the ‘e-bowel safety’ informational module. The intervention will last for 3 months, followed by 3 months of follow-up. The primary outcome will be global QoL; the secondary outcomes will include bowel function, social support, self-management measured at the baseline, 3 months and 6 months for three times and patients’ thinkings at the end of the intervention (at 3 months).Ethics and dissemination Ethics approval was granted by the Clinical Medical Research Ethics Committee of the First Affiliated Hospital of Anhui Medical University (PJ2022-07-53).Trial registration number Chinese Clinical Trial Registry (ChiCTR2200061317).

Abstract Bean dregs can be prepared into organic fertilizer by microbial fermentation. Geobacillus toebii GT-02, which has promoting effect on bean dregs fermentation, was isolated from horse dung and it grows within a range of 40–75 °C and pH 6.50–9.50. The effectiveness of GT-02 addition on composition transformations and the microbial community in bean dregs thermophilic fermentation at 70 °C for 5 days was investigated (T1). Fermentation of bean dregs without GT-02 served as control (CK). The results showed that T1 (the germination index (GI) = 95.06%) and CK (GI = 86.42%) reached maturity (defined by GI ≥ 85%) on day 3 and day 5, respectively. In addition, the total nitrogen loss of T1 (18.46%) on day 3 was lower than that in CK (24.12%). After thermophilic fermentation, the total organic carbon and dry matter loss of T1 (53.51% and 54.16%) was higher than that in CK (41.72% and 42.82%). The mean microbial number in T1 was 4.94 × 107 CFUs/g dry matter, which was 5.37 times higher than that in CK. 16S rDNA sequencing identified Bacillus, Geobacillus and Thermobacillus as dominant in CK, while Bacillus, Ammoniibacillus and Geobacillus were dominant in T1. A canonical correspondence analysis showed that Geobacillus and Ammoniibacillus were positively correlated with the GI. Thus, thermophilic fermentation with GT-02 can promote the maturity of bean dregs, which indicated the potential application value of GT-02 in thermophilic fermentation.

Abstract The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

Objectives The COVID-19 outbreak beginning in late 2019 has resulted in negative emotions among the public. However, many healthcare workers risked their lives by voluntarily travelling to the worst-hit area, Hubei Province, to support antipandemic work. This study explored the mental health changes in these healthcare workers and tried to discover the influencing factors.Design A longitudinal online survey was begun on 8 February 2020, using the snowball sampling method, and this first phase ended on 22 February 2020 (T1). The follow-up survey was conducted from 8 February to 22 February 2021 (T2).Setting Healthcare workers from outside of the Hubei area who went to the province to provide medical assistance.Participants 963 healthcare workers who completed both surveys.Measures Self-Rating Scale of Sleep (SRSS), Generalised Anxiety Scale (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9).Results There were no significant differences in the SRSS scores or in the GAD-7 scores between T1 and T2 (t=0.994, 0.288; p>0.05). However, the PHQ-9 score at T2 was significantly higher than the score at T1 (t=−10.812, p

Human rotavirus (HRV) is the causative agent of severe dehydrating diarrhea in children under the age of five, resulting in up to 215,000 deaths each year. These deaths almost exclusively occur in low- and middle-income countries where vaccine efficacy is the lowest due to chronic malnutrition, gut dysbiosis, and concurrent enteric viral infection. Parenteral vaccines for HRV are particularly attractive as they avoid many of the concerns associated with currently used live oral vaccines. In this study, a two-dose intramuscular (IM) regimen of the trivalent, nanoparticle-based, nonreplicating HRV vaccine (trivalent S60-VP8*), utilizing the shell (S) domain of the capsid of norovirus as an HRV VP8* antigen display platform, was evaluated for immunogenicity and protective efficacy against P[6] and P[8] HRV using gnotobiotic pig models. A prime–boost strategy using one dose of the oral Rotarix® vaccine, followed by one dose of the IM trivalent nanoparticle vaccine was also evaluated. Both regimens were highly immunogenic in inducing serum virus neutralizing, IgG, and IgA antibodies. The two vaccine regimens failed to confer significant protection against diarrhea; however, the prime–boost regimen significantly shortened the duration of virus shedding in pigs challenged orally with the virulent Wa (G1P[8]) HRV and significantly shortened the mean duration of virus shedding, mean peak titer, and area under the curve of virus shedding after challenge with Arg (G4P[6]) HRV. Prime–boost-vaccinated pigs challenged with P[8] HRV had significantly higher P[8]-specific IgG antibody-secreting cells (ASCs) in the spleen post-challenge. Prime–boost-vaccinated pigs challenged with P[6] HRV had significantly higher numbers of P[6]- and P[8]-specific IgG ASCs in the ileum, as well as significantly higher numbers of P[8]-specific IgA ASCs in the spleen post-challenge. These results suggest the promise of and warrant further investigation into the oral priming and parenteral boosting strategy for future HRV vaccines.

Abstract Background Percutaneous vertebroplasty (PVP) has been demonstrated to be effective in the treatment of acute osteoporotic vertebral fracture (AOVF). However, bilateral puncture takes more time to accept more X-ray irradiation; some scholars apply unilateral puncture PVP, but the cement cannot be symmetrically distributed in the vertebral body, so we use a flexible cement injector that undergoes PVP through the unilateral pedicle puncture. This research aims to compare the clinical results of PVP for AOVF with unilateral pedicle puncture using a straight bone cement injector and a bendable cement injector, determine the value of a bendable cement injector. Methods We undertook a retrospective analysis of patients with thoracic and lumbar compression fracture treated with unilateral pedicle puncture percutaneous vertebroplasty from our institution from June 2013 to July 2015. Operation time, radiation exposure, bone cement injection amount, and the incidence of bone cement leakage were recorded on presentation, the cement leakage was measured by X-ray and computed tomography scan. The patients were followed up postoperatively and were assessed mainly with regard to clinical and radiological outcomes. Results There was no significant difference in the operation time, radiation exposure time and incidence of bone cement leakage between the two groups. There was significant difference in the amount of bone cement injection and the difference between the two groups. There were no significant differences in VAS and the relative height of the vertebral body and local Cobb angle and QUALEFFO between the two groups at 1 week after PVP, significant difference was observed only 12 months after operation. Conclusions Application of flexible cement injector is safe and feasible, compared with the application of straight bone cement injector, without prolonging the operative time, radiation exposure time and the incidence of bone cement leakage; it has the advantages of good long-term effect and low incidence of vertebral fracture recurrence.

This study was aimed to evaluate the effects of post-transportation vitamin E (VE) supplementation on health condition, blood biochemical parameters, blood antioxidant indices and blood metabolomics in yak. Five yaks were used in this study. After 2100 km of highway transportation from Riwoqe county to Rongchang County, Chongqing, blood was collected immediately after arrival and these samples served as the baseline (control, CON_VE). A VE injection (40 mg/kg) was then performed and blood samples were collected 10 days later. Injection of VE led to lower serum VE concentration. Relative to the CON_VE, VE injection led to greater concentrations of creatinine and lower concentrations of glutamate pyruvic transaminase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, indirect bilirubin, direct bilirubin, UREA and glucose. Compared with CON_VE, VE injection led the lower serum level of malondialdehydeand greater serum level of glutathione s-transferase, glutathione peroxidase, glutathione reductase and glutathione peroxidase 4. Based on metabolomics analysis, 119 differentially altered serum metabolites (P1.0) were identified with VE injection relative to CON_VE. VE injection resulted in changes of lysophosphatidylethanolamine, lysophosphatidylcholine, phosphocholine, choline, malate, citrate, α-Oxo-glutarate, phenylalanine, 3-Phenylpropanoic acid and 3-(3-Hydroxyphenyl) propanoic acid. These metabolites are associated with lipid metabolism, tricarboxylic acid cycle and oxidative stress. Overall, our study indicates that VE injection can alleviate transportation stress in yak partly through protecting liver and kidney, and improving antioxidant defense systems.

The research expects to evaluate the capital market risk and resource allocation ability of green credit business exploration based on neural network algorithm by deep learning in the context of the Internet of things, increase the funds flowing to green environmental protection industry, accelerate the development of real economy and stabilize China's market economy. On the basis of previous studies, the research takes the credit business in the capital market as the research object, and improves the ability of resource allocation by optimizing the financial transaction structure. On this basis, through comparative analysis, the grey system model is implemented. back propagation neural network model under deep learning is used to evaluate the capital market risk of green credit business exploration, and the data of different provinces in China from 2009 to 2019 are taken as an example to verify. The model is used to measure the relationship between green credit business and industrial structure. Additionally, it also analyzes the main factors affecting the efficiency of green credit. The results show that green credit mainly affects the industrial structure through enterprise capital and financing channels. China's overall green credit adjustment has had a significant upgrading effect on the industrial structure. The impact of green credit on industrial structure adjustment is different in the east, middle, and west regions. Optimizing the project capital structure, promoting seasonal financial transformation, setting up the function of innovation platform, and improving the internal governance structure of enterprises can improve financing efficiency and realize green and sustainable economic development in the future. The research results can provide a theoretical basis for the green development of China's financial market and the application of deep learning neural network algorithm under the background of Internet of things.

Recommendation algorithms save a lot of valuable time for people to get the information they are interested in. However, the feature calculation and extraction process of each machine learning or deep learning recommendation algorithm are different, so how to obtain various features with different dimensions, i.e., how to integrate the advantages of each model and improve the model inference efficiency, becomes the focus of this paper. In this paper, a better deep learning model is obtained by integrating several cutting-edge deep learning models. Meanwhile, to make the integrated learning model converge better and faster, the parameters of the integrated module are initialized, constraints are imposed, and a new activation function is designed for better integration of the sub-models. Finally, the integrated large model is distilled for knowledge distillation, which greatly reduces the number of model parameters and improves the model inference efficiency.

The overall purpose of this study is to explore and examine whether high-performance work systems (HPWS) can impact thriving at work and job burnout via resilience at work among nurses in Chinese public hospitals. Specifically, it draws on social exchange theory to conceptualize a positive relationship between HPWS and resilience at work. Then, based on a socially embedded model of thriving at work and knowledge about job burnout in the literature, it further proposes the differentiated mediation roles of resilience at work in the relationship of HPWS to thriving at work and job burnout. A time-lagged survey involving three rounds of data collection with self-reported online questionnaires was employed. A total of 160 nurses from 20 public hospitals in China were invited to participate in the research. Finally, a sample of 845 responses was obtained. The response rate was 52.8%. Multiple regression analyses were conducted to test the hypotheses. It was found that HPWS (time 1) positively impacted resilience at work (time 2). The results also demonstrated that HPWS (time1) enhanced thriving at work (time 3) and reduced job burnout (time 3) via developing resilience at work (time 2). To conclude, being resilient in the workplace is crucial for nurses to enhance thriving at work, and inhabit job burnout among nurses. HPWS is a valid management tool that can be used to cultivate a nurse’s resilience at work, which further reduces job burnout and enhance thriving at work.

Background: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models. Methods: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models. Findings: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology. Interpretation: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea. Keywords: Urea, Depression, LTP, Carbamylation, mTOR

Abstract Background Noninvasive prenatal testing (NIPT) for fetal aneuploidies by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a first-tier aneuploidy screening test in clinical practices. With the development of whole-genome sequencing technology, small subchromosomal deletions and duplications that could not be detected by conventional karyotyping are now able to be detected with NIPT technology. Methods In the present study, we examined 8141 single pregnancies with NIPT to calculate the positive predictive values of each of the chromosome aneuploidies and the subchromosomal microdeletions and microduplications. Results We confirmed that the positive predictive values (PPV) for trisomy 13, trisomy 18, trisomy 21, and sex chromosome aneuploidy were 14.28%, 60%, 80%, and 45.83%, respectively. At the same time, we also found 51 (0.63%) positive cases for chromosomal microdeletions or microduplications but only 13 (36.11%) true-positive cases. These results indicate that NIPT for trisomy 21 detection had the highest accuracy, while accuracy was low for chromosomal microdeletion and microduplications. Conclusions Therefore, it is very important to improve the specificity, accuracy, and sensitivity of NIPT technology for the detection of subchromosomal microdeletions and microduplications.

ObjectiveTo study the feasibility of use of radiomic features extracted from axillary lymph nodes for diagnosis of their metastatic status in patients with breast cancer.Materials and methodsA total of 176 axillary lymph nodes of patients with breast cancer, consisting of 87 metastatic axillary lymph nodes (ALNM) and 89 negative axillary lymph nodes proven by surgery, were retrospectively reviewed from the database of our cancer center. For each selected axillary lymph node, 106 radiomic features based on preoperative pharmacokinetic modeling dynamic contrast enhanced magnetic resonance imaging (PK-DCE-MRI) and 5 conventional image features were obtained. The least absolute shrinkage and selection operator (LASSO) regression was used to select useful radiomic features. Logistic regression was used to develop diagnostic models for ALNM. Delong test was used to compare the diagnostic performance of different models.ResultsThe 106 radiomic features were reduced to 4 ALNM diagnosis-related features by LASSO. Four diagnostic models including conventional model, pharmacokinetic model, radiomic model, and a combined model (integrating the Rad-score in the radiomic model with the conventional image features) were developed and validated. Delong test showed that the combined model had the best diagnostic performance: area under the curve (AUC), 0.972 (95% CI [0.947-0.997]) in the training cohort and 0.979 (95% CI [0.952-1]) in the validation cohort. The diagnostic performance of the combined model and the radiomic model were better than that of pharmacokinetic model and conventional model (PConclusionRadiomic features extracted from PK-DCE-MRI images of axillary lymph nodes showed promising application for diagnosis of ALNM in patients with breast cancer.

Background: The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions. Method: APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies. Findings: APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner. Interpretation: Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication. Funding: National Science Foundation of China (81670128, 81873433).

Background: The role of neutrophil extracellular traps (NETs) in procoagulant activity (PCA) in stroke patients caused by thromboembolic occlusion of the internal carotid artery (ICA) remains unclear. Our objectives were to evaluate the critical role of NETs in the induction of hypercoagulability in stroke and to identify the functional significance of NETs during atherothrombosis. Methods: The levels of NETs, activated platelets (PLTs), and PLT-derived microparticles (PMPs) were detected in the plasma of 55 stroke patients and 35 healthy controls. NET formation and thrombi were analysed using immunofluorescence. Exposed phosphatidylserine (PS) was evaluated with flow cytometry and confocal microscopy. PCA was analysed using purified coagulation complex, thrombin, and fibrin formation assays. Findings: The plasma levels of NETs, activated PLTs, and PMP markers in the carotid lesion site (CLS) were significantly higher than those in the aortic blood. NETs were decorated with PS in thrombi and the CLS plasma of ICA occlusion patients. Notably, the complementary roles of CLS plasma and thrombin-activated PLTs were required for NET formation and subsequent PS exposure. PS-bearing NETs provided functional platforms for PMPs and coagulation factor deposition and thus increased thrombin and fibrin formation. DNase I and lactadherin markedly inhibited these effects. In addition, NETs were cytotoxic to endothelial cells, converting these cells to a procoagulant phenotype. Sivelestat, anti-MMP9 antibody, and activated protein C (APC) blocked this cytotoxicity by 25%, 39%, or 52%, respectively. Interpretation: NETs played a pivotal role in the hypercoagulability of stroke patients. Strategies that prevent NET formation may offer a potential therapeutic strategy for thromboembolism interventions. Funding: This study was supported by grants from the National Natural Science Foundation of China (61575058, 81873433 and 81670128) and Graduate Innovation Fund of Harbin Medical University (YJSKYCX2018-58HYD). Keywords: Neutrophil extracellular traps, Phosphotidylserine, Stroke, Hypercoagulable state, Thrombosis, Endothelial cells

Currently, injection sites of probes, cannula, and optic fibers in stereotactic neurosurgery are typically located manually. This step involves location estimations based on human experiences and thus introduces errors. In order to reduce localization error and improve repeatability of experiments and treatments, we investigate an automated method to locate injection sites. This paper proposes a localization framework, which integrates a region-based convolutional network and a fully convolutional network, to locate specific anatomical points on skulls of rodents. Experiment results show that the proposed localization framework is capable of identifying and locatin bregma and lambda in rodent skull anatomy images with mean errors less than 300 μm. This method is robust to different lighting conditions and mouse orientations, and has the potential to simplify the procedure of locating injection sites.

Aeromonas hydrophila is an important pathogen that causes motile Aeromonas septicemia (MAS) in the aquaculture industry. Aerolysin, hemolysin, serine protease and enterotoxins are considered to be the major virulence factors of A. hydrophila. In this study, we constructed a five-gene (aerA, hly, ahp, alt and ast) deletion mutant strain (named Aeromonas hydrophila five-gene deletion strain, AHFGDS) to observe the biological characteristics and detect its potential as a live-attenuated vaccine candidate. AHFGDS displayed highly attenuated and showed increased susceptibility to fish blood and skin mucus killing, while the wild-type strain ZYAH72 was highly virulent. In zebrafish (Danio rerio), AHFGDS showed a 240-fold higher 50% lethal dose (LD50) than that of the wild-type strain. Immunization with AHFGDS by intracelomic injection or immersion routes both provided grass carp (Ctenopharyngodon idella) significant protection against the challenge of the strain ZYAH72 or J-1 and protected the fish organs from serious injury. Further agglutinating antibody titer test supported that AHFGDS could elicit a host-adaptive immune response. These results suggested the potential of AHFGDS to serve as a live-attenuated vaccine to control A. hydrophila infection in aquaculture.

Difficulties related to storage and transport of currently available live oral rotavirus vaccines can have detrimental consequences on the efficacy of the vaccines. Thus, there is a great need for thermostable vaccines that can eliminate the necessity for cold chain storage or reconstitution before administration. In this study, we developed a dissolvable oral polymeric film comprised of a live attenuated thermostable tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) powder and antacid (CaCO3). Immunogenicity and protective efficacy of the vaccine after buccal delivery was evaluated in the gnotobiotic pig model of human rotavirus (HRV) infection and diarrhea. Two doses of the vaccine were highly immunogenic and conferred strong protection against virus shedding and diarrhea upon challenge with a high dose of a virulent G1 HRV in gnotobiotic pigs. Those pigs vaccinated with the preserved film vaccine had significantly delayed onset of diarrhea; reduced duration and area under the curve of diarrhea; delayed onset of fecal virus shedding; and reduced duration and peak of fecal virus shedding titers compared to pigs in both the placebo and the reconstituted liquid oral RRV-TV vaccine groups. Associated with the strong protection, high titers of serum virus neutralization antibodies against each of the four RRV-TV mono-reassortants and G1 HRV-specific serum IgA and IgG antibodies, as well as intestinal IgA antibodies, were induced by the preserved film vaccine. These results demonstrated the effectiveness of our thermostable buccal film rotavirus vaccine and warrant further investigation into the promise of the novel technology in addressing drawbacks of the current live oral HRV vaccines.

Background: A large proportion of the patients with papillary thyroid microcarcinoma are young women. Therefore, minimally invasive endoscopic thyroidectomy with central neck dissection (CND) emerged and showed well-accepted results with improved cosmetic outcome, accelerated healing, and comforting the patients. This study aimed to evaluate the safety and effectiveness of robotic total thyroidectomy with CND via bilateral axillo-breast approach (BABA), compared with conventional open procedure in papillary thyroid microcarcinoma. Methods: One-hundred patients with papillary thyroid microcarcinoma from March 2014 to January 2015 in Jinan Military General Hospital of People's Liberation Army (PLA) were randomly assigned to robotic group or conventional open approach group (n = 50 in each group). The total operative time, estimated intraoperative blood loss, numbers of lymph node removed, visual analog scale (VAS), postoperative hospital stay time, complications, and numerical scoring system (NSS, used to assess cosmetic effect) were analyzed. Results: The robotic total thyroidectomy with CND via BABA was successfully performed in robotic group. There were no conversion from the robotic surgeries to open or endoscopic surgery. The subclinical central lymph node metastasis rate was 35%. The mean operative time of the robotic group was longer than that of the conventional open approach group (118.8 ± 16.5 min vs. 90.7 ± 10.3 min, P < 0.05). The study showed significant differences between the two groups in terms of the VASs (2.1 ± 1.0 vs. 3.8 ± 1.2, P < 0.05) and NSS (8.9 ± 0.8 vs. 4.8 ± 1.7, P < 0.05). The differences between the two groups in the estimated intraoperative blood loss, postoperative hospital stay time, numbers of lymph node removed, postoperative thyroglobulin levels, and complications were not statistically significant (all P > 0.05). Neither iatrogenic implantation nor metastasis occurred in punctured porous channel or chest wall in both groups. Postoperative cosmetic results were very satisfactory in the robotic group. Conclusions: Robotic total thyroidectomy with CND via BABA is safe and effective for Chinese patients with papillary thyroid microcarcinoma who worry about the neck scars.

The ability to live independently plays a crucial role in the mental and psychological wellbeing of the disabled. To achieve this goal, most governments spend a substantial budget on home adaptation projects. It has been observed that schemes with different target clients (residents versus landlords) are different in efficiency and effectiveness. To understand why and how these schemes differ in performance, this paper develops and applies a generic economic evaluation framework for government-funded home adaptation schemes. Based on the individual-level surveys collected in the United Kingdom, an empirical model was formulated to quantify the determinants for various performance indicators, including money costs, time costs and client satisfaction. Robust estimation procedures were applied to deal with the heteroscedasticity and outlier problems in the data. Results showed that a specialized independent living scheme dedicated to disability adaptations (e.g., the Physical Adaptations Grant, PAG) had higher efficiency and effectiveness than general-purpose schemes (e.g., the Disabled Facilities Grant, DFG), because the funds were provided to the landlords who had a stronger motivation to minimize the time cost in the short run and maximize the future rent potential in the long run. A “unified system” approach to adaptations should be a guiding principle for policy development, regardless of who actually delivers the service.

Since multi-view data are available in many real-world clustering problems, multi-view clustering has received considerable attention in recent years. Most existing multi-view clustering methods learn consensus clustering results but do not make full use of the distinct knowledge in each view so that they cannot well guarantee the complementarity across different views. In this paper, we propose a Distinction based Consensus Spectral Clustering (DCSC), which not only learns a consensus result of clustering, but also explicitly captures the distinct variance of each view. It is by using the distinct variance of each view that DCSC can learn a clearer consensus clustering result. In order to optimize the introduced optimization problem effectively, we develop a block coordinate descent algorithm which is theoretically guaranteed to converge. Experimental results on real-world data sets demonstrate the effectiveness of our method.

[This corrects the article DOI: 10.1371/journal.pone.0182866.].

Foot-and-mouth disease virus (FMDV) is a single-stranded positive RNA virus that belongs to the family Picornaviridae. FMDV infects cloven-hoofed animals, such as pigs, sheep, goats, cattle and diverse wildlife species, and remains a major threat to the livestock industry worldwide. In this study, a transcriptome analysis of whole blood from pigs infected with FMDV was performed using the paired-end Illumina sequencing technique to understand the interactions between the pathogen and its host cells. During infection with FMDV, a total of 120 differentially expressed genes (DEGs) were identified, including 110 up-regulated genes and 10 down-regulated genes. To further investigate the DEGs involved in interactions between the virus and its host, gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted. GO annotation indicated that a number of DEGs were enriched in categories involved in host-virus interactions, such as response to stimulus, immune system process and regulation of biological process. KEGG enrichment analysis indicated that the DEGs were primarily involved in the ribosome signaling pathway and immune-related signaling pathways. Ten DEGs, including the immune-related genes BTK1, C1QB, TIMD4 and CXCL10, were selected and validated using quantitative PCR, which showed that the expression patterns of these genes are consistent with the results of the in silico expression analysis. In conclusion, this study presents the first transcriptome analysis of pig whole blood cells infected with FMDV, and the results obtained in this study improve our understanding of the interactions between FMDV and host cells as well as the diagnosis and control of FMD.

Bats are important reservoirs of many viruses, which are capable of infecting the host without inducing obvious clinical diseases. Interferon and the downstream interferon regulated genes (IRGs) are known to act as the first line of defense against viral infections. Little is known about the transcriptional profile of genes being induced by interferon in bats and their role in controlling virus infection. In this study, we constructed IFNAR2 knockout bat cell lines using CRISPR technology and further characterized gene expression profiles induced by the most abundant IFN-α (IFN-α3). Firstly, we demonstrated that the CRISPR/Cas9 system is applicable for bat cells as this represents the first CRIPSR knockout cell line for bats. Our results showed the pleiotropic effect of IFN-α3 on the bat kidney cell line, PaKiT03. As expected, we confirmed that IFNAR2 is indispensable for IFN-a signaling pathway and plays an important role in antiviral immunity. Unexpectedly, we also identified novel IFNAR2-dependent IRGs which are enriched in pathways related to cancer. To our knowledge, this seems to be bat-specific as no such observation has been reported for other mammalian species. This study expands our knowledge about bat immunology and the cell line established can provide a powerful tool for future study into virus-bat interaction and cancer biology.