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Abstract Understanding the mechanical characteristics of rocks when subjected to direct tension is crucial for assessing the stability of rock formations. Within the scope of this research, a series of tests was conducted using Tage tuff to assess the deformation behavior and crack extension of rock under direct tension. The axial, lateral, and shear strain fields as well as crack propagation, localized deformation behavior, and failure mode of the rocks were analyzed using three-dimensional digital image correlation method. The results showed that the axial strain fields on the specimen surface were heterogeneous, with different locations and localization occurring in the pre-peak stage, which was similar to the evolution of shear strain, whereas the lateral strain only showed slight changes. The crack extension direction was inferred, indicating that both tensile and shear stress occurred in the tests. Furthermore, different stress–strain responses were observed for the inside and outside of the localized bands. Then, the surface patterns of specimen failure were scanned and analyzed to assess the failure mode and residual strength of the specimen under direct tensile stress. Finally, the results of direct tension, uniaxial compression, and Brazilian split tests for Tage tuff were compared, and the complete stress–strain curve of uniaxial tension (UT) was simulated using a nonlinear-variable-compliance constitutive equation. This study provides a deeper understanding into the damage behavior of rocks under direct tension.

Abstract Background Previous research has revealed a negative association between social support and procrastination. However, few studies have investigated the mechanism underlying this relationship among vocational college students. Objective Based on the social cognitive theory, this study was intended to investigate the multiple mediating effects of self-efficacy and resilience on the relationship between social support and procrastination among vocational college students. Methods This study employed a cross-sectional design involving a sample of 1,379 students from a vocational college in China. Data were collected using the General Procrastination Scale, the Multidimensional Scale of Perceived Social Support, the General Self-Efficacy Scale, and the Resilience Scale-14. The PROCESS macro for SPSS was used to examine the multiple mediation model. Results Our findings indicate significant negative correlations between social support, self-efficacy, resilience, and procrastination. The multiple mediation analysis showed that social support did not have a significant direct impact on procrastination. Instead, the relationship between social support and procrastination was fully mediated by self-efficacy (indirect effect: -0.017; 95% CI: -0.032, -0.004) and resilience (indirect effect: -0.047; 95% CI: -0.072, -0.025), and sequentially mediated by both factors (indirect effect: -0.013; 95% CI: -0.020, -0.007). Conclusions The results emphasise the importance of enhancing self-efficacy and resilience in initiatives aimed at preventing and intervening in case of procrastination among vocational college students. Additionally, strengthening social support may also be crucial to preventing or reducing procrastination among this population.

The occurrence of geological hazards and the instability of geotechnical engineering structures are closely related to the time-dependent behavior of rock. However, the idealization boundary condition for constant stress in creep or constant strain in relaxation is not usually attained in natural geological systems. Therefore, generalized relaxation tests that explore the simultaneous changes of stress and strain with time under different stress levels with constant pore-water pressure are conducted in this study. The results show that in area I, area II, and area III, the stress and strain both change synchronously with time and show similar evolutionary laws as the strain-time curve for creep or the stress-time curve for relaxation. When the applied stress level surpasses the σci or σcd threshold, the variations in stress and strain and their respective rates of change exhibit a significant increase. The radial deformation and its rate of change exhibit greater sensitivity in response to stress levels. The apparent strain deforms homogeneously at the primary stage, and subsequently, gradually localizes due to the microcrack development at the secondary stage. Ultimately, interconnection of the microcracks causes the formation of a shear-localization zone at the tertiary stage. The strain-time responses inside and outside the localization zone are characterized by local strain accumulation and inelastic unloading during the secondary and tertiary stages, respectively. The width of the shear-localization zone is found to range from 4.43 mm to 7.08 mm and increased with a longer time-to-failure. Scanning electron microscopy (SEM) reveals a dominant coalescence of intergranular cracks on the fracture surface, and the degree of physiochemical deterioration caused by water-rock interaction is more severe under a longer lifetime. The brittle sandstone's time-dependent deformation is essentially controlled by microcrack development during generalized relaxation, and its expectancy-life is determined by its initial microstructural state and the rheological path.

Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients’ cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. Methods In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. Results Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. Conclusions In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.

Abstract Background To establish a predictive model based on multisequence magnetic resonance imaging (MRI) using deep learning to identify wild-type (WT) epidermal growth factor receptor (EGFR), EGFR exon 19 deletion (19Del), and EGFR exon 21-point mutation (21L858R) simultaneously. Methods A total of 399 patients with proven brain metastases of non-small cell lung cancer (NSCLC) were retrospectively enrolled and divided into training (n = 306) and testing (n = 93) cohorts separately based on two timepoints. All patients underwent 3.0-T brain MRI including T2-weighted, T2-weighted fluid-attenuated inversion recovery, diffusion-weighted imaging, and contrast-enhanced T1-weighted sequences. Radiomics features were extracted from each lesion based on four sequences. An algorithm combining radiomics approach with graph convolutional networks architecture (Radio-GCN) was designed for the prediction of EGFR mutation status and subtype. The area under the curve (AUC) at receiver operating characteristic analysis was used to evaluate the predication capabilities of each model. Results We extracted 1,290 radiomics features from each MRI sequence. The AUCs of the Radio-GCN model for identifying EGFR 19Del, 21L858R, and WT for the lesion-wise analysis were 0.996 ± 0.004, 0.971 ± 0.013, and 1.000 ± 0.000 on the independent testing cohort separately. It also yielded AUCs of 1.000 ± 0.000, 0.991 ± 0.009, and 1.000 ± 0.000 for predicting EGFR mutations respectively for the patient-wise analysis. The κ coefficients were 0.735 and 0.812, respectively. Conclusions The constructed Radio-GCN model is a new potential tool to predict the EGFR mutation status and subtype in NSCLC patients with brain metastases. Relevance statement The study demonstrated that a deep learning approach based on multisequence MRI can help to predict the EGFR mutation status in NSCLC patients with brain metastases, which is beneficial to guide a personalized treatment. Key points • This is the first study to predict the EGFR mutation subtype simultaneously. • The Radio-GCN model holds the potential to be used as a diagnostic tool. • This study provides an imaging surrogate for identifying the EGFR mutation subtype. Graphical Abstract

Abstract Cytoskeleton is extensively recruited by flaviviruses for their infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain protein 2 (SUN2) linking cytoskeleton and nucleoskeleton in the flavivirus replication. CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, significantly reduces the replication of Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV). In contrast, SUN2 does not affect the infection of non-flaviviridae RNA viruses. All three regions of SUN2 are required for its proviral effect. Mechanistically, SUN2 facilitates rearrangement of cytoskeleton and formation of replication organelles induced by viral infection, and hence promotes viral RNA synthesis. SUN2 is required for the interaction between cytoskeleton actin and ZIKV nonstructural protein 1 (NS1). Expression of dominant negative Nesprin-1 and Nesprin-2, which connect SUN2 to cytoskeleton proteins, alleviates the interaction between actin and NS1 and reduces viral replication levels. In a neonatal mouse infection model, SUN2 knockout dramatically alleviates the in vivo ZIKV replication and development of neuropathology. This work elucidates that recruitment of cytoskeleton proteins by flavivirus is coordinated by nuclear membrane proteins SUN2 and Nesprins, providing evidence for a link between nuclear membrane proteins and flavivirus infection.

Abstract Background Breast cancer is the most common malignant tumor in the world. Intraoperative frozen section of sentinel lymph nodes is an important basis for determining whether axillary lymph node dissection is required for breast cancer surgery. We propose an RRCART model based on a deep-learning network to identify metastases in 2362 frozen sections and count the wrongly identified sections and the associated reasons. The purpose is to summarize the factors that affect the accuracy of the artificial intelligence model and propose corresponding solutions. Methods We took the pathological diagnosis of senior pathologists as the gold standard and identified errors. The pathologists and artificial intelligence engineers jointly read the images and heatmaps to determine the locations of the identified errors on sections, and the pathologists found the reasons (false reasons) for the errors. Through NVivo 12 Plus, qualitative analysis of word frequency analysis and nodal analysis was performed on the error reasons, and the top-down error reason framework of “artificial intelligence RRCART model to identify frozen sections of breast cancer lymph nodes” was constructed based on the importance of false reasons. Results There were 101 incorrectly identified sections in 2362 slides, including 42 false negatives and 59 false positives. Through NVivo 12 Plus software, the error causes were node-coded, and finally, 2 parent nodes (high-frequency error, low-frequency error) and 5 child nodes (section quality, normal lymph node structure, secondary reaction of lymph nodes, micrometastasis, and special growth pattern of tumor) were obtained; among them, the error of highest frequency was that caused by normal lymph node structure, with a total of 45 cases (44.55%), followed by micrometastasis, which occurred in 30 cases (29.70%). Conclusions The causes of identification errors in examination of sentinel lymph node frozen sections by artificial intelligence are, in descending order of influence, normal lymph node structure, micrometastases, section quality, special tumor growth patterns and secondary lymph node reactions. In this study, by constructing an artificial intelligence model to identify the error causes of frozen sections of lymph nodes in breast cancer and by analyzing the model in detail, we found that poor quality of slices was the preproblem of many identification errors, which can lead to other errors, such as unclear recognition of lymph node structure by computer. Therefore, we believe that the process of artificial intelligence pathological diagnosis should be optimized, and the quality control of the pathological sections included in the artificial intelligence reading should be carried out first to exclude the influence of poor section quality on the computer model. For cases of micrometastasis, we suggest that by differentiating slices into high- and low-confidence groups, low-confidence micrometastatic slices can be separated for manual identification. The normal lymph node structure can be improved by adding samples and training the model in a targeted manner.

Abstract Liquid nitrogen (LN2) fracturing is recognized as an innovative reservoir enhancement technique, demonstrating significant potential in establishing high permeability pathways in geothermal development. Understanding the physico-mechanical properties and microscopic mechanisms of hot dry rock post LN2 cooling treatment is pivotal for promoting the effective deployment of LN2 fracturing. This study undertook physical and mechanical testing on a quintessential hot dry rock type-granite-post various temperature and LN2 cooling treatments. Subsequently, a multi-scale investigation was conducted on the thermal fracture-pore structure's morphological features and the evolution of mineral components. The experimental findings indicated that LN2 cooling exerts a pronounced impact on the physico-mechanical properties of high-temperature granite. Temperature-induced damage to granite can be delineated into three phases: initial phase up to 200 °C where its effects are relatively imperceptible; an intermediate phase from 200 to 500 °C characterized by gradual deterioration; and a pronounced degradation phase evident at 600 °C. Correlations between the changes in the micro pore-fracture structure of granite and its physico-mechanical property degradation were subsequently established. As temperature escalated, the area of micro-defects in the CT-reconstructed spatial distribution increased progressively. The volumetric porosity damage ratio and fractal dimensions were quantitatively introduced to characterize the fractal geometric features and distribution patterns of internal thermal fractures in granite post thermal shock. Concurrently, NMR experiments indicated that with the escalation of temperature, micropore develop and interlink to form mesopore and macropore, enhancing rock porosity connectivity. These macropores significantly influence granite's physico-mechanical and permeability characteristics. A mineral stability analysis revealed that various minerals undergo physico-chemical reactions, such as dehydration, phase transitions, decomposition, and chemical bond fractures at elevated temperatures, altering mineralogical composition and mineral strength, thus impacting the rock's macroscopic properties. Ultimately, the study delved into the damage mechanisms of granite's physico-mechanical properties from both heating and cooling perspectives during various temperature phases. The insights garnered from this investigation offer novel value in comprehending the thermal damage characteristics induced by LN2 cooling.

T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. The current therapeutic regimens have relatively low efficacy rates. Clinical studies of single-target chimeric antigen receptor T cell (CAR-T cell) therapy in T lymphocytes require large and multiple infusions, increasing the risks and cost of treatment; therefore, optimizing targeted therapy is a way to improve overall prognosis. Despite significant advances in bispecific CAR-T cell therapy to avoid antigen escape in treatment of B cell lymphoma, applying this strategy to TCL requires further investigation. Here, we constructed an alpaca nanobody (Nb) phage library and generated high-affinity and -specificity Nbs targeting CD30 and CD5, respectively. Based on multiple rounds of screening, bispecific NbCD30-CD5-CAR T cells were constructed, and their superior anti-tumor effect against TCL was validated in vitro and in vivo. Our findings demonstrated that Nb-derived bispecific CAR-T cells significantly improved anti-tumor efficacy in TCL treatment compared with single-target CAR-T cells and bispecific single chain variable fragment (scFv)-derived CAR-T cells. Because Nbs are smaller and less immunogenic, the synergistic effect of Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.

Objective This study aimed to investigate the significant single nucleotide polymorphisms (SNPs) and genes associated with nine reproduction and morphological traits in three breed populations of Chinese goats. Methods The genome-wide association of nine reproduction and morphological traits (litter size, nipple number, wattle, skin color, coat color, black dorsal line, beard, beard length, and hind leg hair) were analyzed in three Chinese native goat breeds (n = 336) using an Illumina Goat SNP50 Beadchip. Results A total of 17 genome-wide or chromosome-wide significant SNPs associated with one reproduction trait (litter size) and six morphological traits (wattle, coat color, black dorsal line, beard, beard length, and hind leg hair) were identified in three Chinese native goat breeds, and the candidate genes were annotated. The significant SNPs and corresponding putative candidate genes for each trait are as follows: two SNPs located on chromosomes 6 (CSN3) and 24 (TCF4) for litter size trait; two SNPs located on chromosome 9 (KATNA1) and 1 (UBASH3A) for wattle trait; three SNPs located on chromosome 26 (SORCS3), 24 (DYM), and 20 (PDE4D) for coat color trait; two SNPs located on chromosome 18 (TCF25) and 15 (CLMP) for black dorsal line trait; four SNPs located on chromosome 8, 2 (PAX3), 5 (PIK3C2G), and 28 (PLA2G12B and OIT3) for beard trait; one SNP located on chromosome 18 (KCNG4) for beard length trait; three SNPs located on chromosome 17 (GLRB and GRIA2), 28 (PGBD5), and 4 for hind leg hair trait. In contrast, there were no SNPs identified for nipple number and skin color. Conclusion The significant SNPs or genes identified in this study provided novel insights into the genetic mechanism underlying important reproduction and morphological traits of three local goat breeds in Southern China as well as further potential applications for breeding goats.

Background: In nursing care organizations, nurses’ social networks affect their behavior and play an important role in nursing practice. This study aimed to explore the relationships among social network degree centrality, job satisfaction, work engagement and organizational citizenship behavior (OCB) among nurses. Methods: A cross-sectional survey design (one-on-one investigation) was used. The study was conducted among 254 nurses working in 10 nursing units in two hospitals in China from November 2019–February 2020. The participants completed a paper questionnaire that measured social network degree centrality, job satisfaction, work engagement and organizational citizenship behavior. A structural equation model (SEM) was used to analyze the mediating effects of job satisfaction and work engagement. SPSS 22.0 and Amos 21.0 software were used, and the significance level was set at 5% for all analyses. Results: Social network degree centrality was positively associated with job satisfaction, work engagement and organizational citizenship behavior, and job satisfaction and work engagement had significant positive relationships with organizational citizenship behavior. In addition, social network degree centrality influenced organizational citizenship behavior through the multiple mediating effects of job satisfaction and work engagement. Conclusions: Improving job satisfaction and work engagement can boost the positive effect of social network degree centrality on OCB.

BackgroundWhile previous studies have revealed a positive association between resilience and quality of life in advanced cancer survivors, the mechanisms of the relationship is still unclear. This study aimed to explore the relationships between resilience, social support, spirituality, and quality of life and determine the multiple mediation effects of social support and spirituality on the relationship between resilience and quality of life.MethodsWith 286 advanced cancer survivors, a cross-sectional, correlational survey was adopted using convenience sampling. Resilience, social support, spirituality, and quality of life were evaluated by self-report questionnaires. The PROCESS macro for SPSS was used to test the multiple mediation model.ResultsThe scores for resilience, social support, spirituality and quality of life were positively correlated with one another. Resilience was found to be directly impact quality of life. Meanwhile, the relationship between resilience and quality of life was mediated by social support (effect = 0.067, 95% CI [0.019, 0.120]) and by spirituality (effect = 0.221, 95% CI [0.134, 0.332]), respectively, and by these two serially (effect = 0.036, 95% CI [0.015, 0.067]).ConclusionSocial support and spirituality played multiple mediating roles in the relationship between resilience and quality of life. Interventions aimed at increasing resilience, and then boosting social support and spirituality may be beneficial for promoting quality of life of advanced cancer survivors.

BackgroundCancer caregivers directly affect patient health outcomes. To maintain the function and health of caregivers so that patients can receive efficient care, we must pay more attention to caregivers’ quality of life in the process of caring for patients. However, the factors influencing caregivers’ quality of life are complex.AimTo assess caregivers’ quality of life in the process of caring for cancer patients and to explore the factors associated with it.DesignThis was a descriptive correlational study. A self-report questionnaire was used to anonymously collect data from one Chinese cancer hospital. The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp-12), General Self-efficacy Scale (GSES), Positive and Negative Affect Schedule (PANAS), Connor-Davidson Resilience Scale 10 (CD-RISC-10), 24-item Caregiver Burden Inventory (CBI) and Caregiver Evaluation Questionnaire were used to measure caregivers’ spiritual well-being, self-efficacy, affective well-being, resilience, caregiver burden and quality of life. One-way analysis of variance, the Kruskal–Wallis H test and multiple regression analysis were applied to measure the factors influencing caregivers’ situations.Setting and participantsA total of 315 caregivers of cancer patients were selected by convenience sampling. All participants were invited to complete the questionnaire through a one-on-one approach.ResultsThe mean score for caregiver quality of life was 204.62 ± 36.61. After controlling for demographic factors, self-efficacy (β’ = 0.265, p

Abstract The frozen section (FS) diagnoses of pathology experts are used in China to determine whether sentinel lymph nodes of breast cancer have metastasis during operation. Direct implementation of a deep neural network (DNN) in clinical practice may be hindered by misdiagnosis of the algorithm, which affects a patient's treatment decision. In this study, we first obtained the prediction result of the commonly used patch-DNN, then we present a relative risk classification and regression tree (RRCART) to identify the misdiagnosed whole-slide images (WSIs) and recommend them to be reviewed by pathologists. Applying this framework to 2362 WSIs of breast cancer lymph node metastasis, test on frozen section results in the mean area under the curve (AUC) reached 0.9851. However, the mean misdiagnosis rate (0.0248), was significantly higher than the pathologists’ misdiagnosis rate (p 0.01). However, the other low-accuracy group included most of the misdiagnoses of DNN models. Our research shows that the misdiagnosis from deep learning model can be further enriched by our method, and that the low-accuracy WSIs must be selected for pathologists to review and the high-accuracy ones may be ready for pathologists to give diagnostic reports.

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major obstacle to cure HIV-1 infection. The characteristics of the HIV-1 latent reservoir have not been fully understood. Here, we identified 126 upregulated plasma membrane proteins in HIV-1 latently infected cells by a label-free liquid chromatography-tandem mass spectrometry analysis. The higher levels of CD98 expression in multiple HIV-1 latently infected cell lines and primary CD4+ T cells compared to uninfected cells were further confirmed by quantitative reverse transcription PCR (RT-qPCR) and flow cytometry analyses. In addition, CD98high CD4+ T cells displayed hyper-permissiveness to HIV-1 infection and possessed distinct immune phenotypic profiles associated with Th17 and peripheral follicular T helper (pTFH) characteristics. Notably, the CD98high resting memory CD4+ T cells harbored significantly higher cell-associated viral RNA and intact provirus than CD98low counterparts in HIV-1-infected individuals receiving combined antiretroviral therapy. Furthermore, CD98high CD4+ T cells exhibited a robust proliferative capacity and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. Our study demonstrates that CD98 can be used as a novel biomarker of HIV-1 latently infected cells to indicate the effect of various strategies to reduce the viral reservoir. IMPORTANCE Identification of cellular biomarkers is the crucial challenge to eradicate the HIV-1 latent reservoir. In our study, we identified CD98 as a novel plasma membrane biomarker for HIV-1 permissiveness and latent infection. Importantly, CD98high CD4+ T cells exhibited a hyper-permissiveness to HIV-1 infection and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. CD98 could be targeted to develop therapeutic strategies to reduce the HIV-1 latent reservoir in further research.

This study aimed to reveal the potential genetic basis for litter size, coat colour, black middorsal stripe and skin colour by combining genome-wide association analysis (GWAS) and selection signature analysis and ROH detection within the Youzhou dark (YZD) goat population (n = 206) using the Illumina GoatSNP54 BeadChip. In the GWAS, we identified one SNP (snp54094-scaffold824-899720) on chromosome 11 for litter size, two SNPs on chromosome 26 (snp11508-scaffold142-1990450, SORCS3) and chromosome 12 (snp55048-scaffold842-324525, LOC102187779) for coat colour and one SNP on chromosome 18 (snp56013-scaffold873-22716, TCF25) for the black middorsal stripe. In contrast, no SNPs were identified for skin colour. In selection signature analysis, 295 significant iHS genomic regions with a mean |iHS| score > 2.66, containing selection signatures encompassing 232 candidate genes were detected. In particular, 43 GO terms and one KEGG pathway were significantly enriched in the selected genes, which may contribute to the excellent environmental adaptability and characteristic trait formation during the domestication of YZD goats. In ROH detection, we identified 4446 ROH segments and 282 consensus ROH regions, among which nine common genes overlapped with those detected using the iHS method. Some known candidate genes for economic traits such as reproduction (TSHR, ANGPT4, CENPF, PIBF1, DACH1, DIS3, CHST1, COL4A1, PRKD1 and DNMT3B) and development and growth (TNPO2, IFT80, UCP2, UCP3, GHRHR, SIM1, CCM2L, CTNNA3 and CTNNA1) were revealed by iHS and ROH detection. Overall, this study is limited by the small population size, which affects the results of GWAS to a certain extent. Nevertheless, our findings could provide the first overview of the genetic mechanism underlying these important traits and provide novel insights into the future conservation and utilisation of Chinese goat germplasm resources.

Introduction: The pathological rare category of thyroid is a type of lesion with a low incidence rate and is easily misdiagnosed in clinical practice, which directly affects a patient’s treatment decision. However, it has not been adequately investigated to recognize the rare, benign, and malignant categories of thyroid using the deep learning method and recommend the rare to pathologists.Methods: We present an empirical decision tree based on the binary classification results of the patch-based UNet model to predict rare categories and recommend annotated lesion areas to be rereviewed by pathologists.Results: Applying this framework to 1,374 whole-slide images (WSIs) of frozen sections from thyroid lesions, we obtained an area under a curve of 0.946 and 0.986 for the test datasets with and without WSIs, respectively, of rare types. However, the recognition error rate for the rare categories was significantly higher than that for the benign and malignant categories (p < 0.00001). For rare WSIs, the addition of the empirical decision tree obtained a recall rate and precision of 0.882 and 0.498, respectively; the rare types (only 33.4% of all WSIs) were further recommended to be rereviewed by pathologists. Additionally, we demonstrated that the performance of our framework was comparable to that of pathologists in clinical practice for the predicted benign and malignant sections.Conclusion: Our study provides a baseline for the recommendation of the uncertain predicted rare category to pathologists, offering potential feasibility for the improvement of pathologists’ work efficiency.

BackgroundHeterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF).Methods and findingsWe conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data.ConclusionsHeterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines.Trial registrationStudy on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101.

Expression of host noncoding RNAs and coding mRNAs is significantly altered by viral infection. In the current study, we screened the transcriptional profile of human lung epithelial A549 cells infected with Zika virus (ZIKV) by microarray assay. Seventy-nine long noncoding RNAs (lncRNAs) and 140 mRNAs were differentially expressed (DE). The bioinformatics analysis revealed that the mRNAs adjacent to the DE lncRNAs were closely related to the host responses to viral infection. We selected 7 lncRNAs from the top 50 hits for validation. The quantitative real-time PCR data confirmed that expression of selected lncRNAs was induced by ZIKV infection. Moreover, the expression of 7 lncRNAs was induced by infection of dengue virus, Japanese encephalitis virus, or vesicular stomatitis virus, or by treatment of poly(I:C) and IFN-β. Furthermore, loss of innate immune adaptor IPS-1 or receptor IFNAR1 resulted in lower induction levels of several lncRNAs by ZIKV. Overexpression of 3 lncRNAs (RPL27-OT1, OASL-IT1, and REC8-OT3) reduced the virus yields of ZIKV. Knockout of OASL-IT1 significantly enhanced ZIKV replication. In OASL-IT1 knockout cells, the levels of interferons (IFNs) and the activation of 3 innate immune signaling pathways triggered by ZIKV were dramatically reduced. Collectively, our work found a positive feedback loop in the IFN system, in which IFNs and OASL-IT1 regulate each other, thereby promoting establishment of antiviral defense.

Summary: Background: Since late 2019, SARS-CoV-2 infection has resulted in COVID-19 accompanied by diverse clinical manifestations. However, the underlying mechanism of how SARS-CoV-2 interacts with host and develops multiple symptoms is largely unexplored. Methods: Bioinformatics analysis determined the sequence similarity between SARS-CoV-2 and human genomes. Diverse fragments of SARS-CoV-2 genome containing Human Identical Sequences (HIS) were cloned into the lentiviral vector. HEK293T, MRC5 and HUVEC were infected with laboratory-packaged lentivirus or transfected with plasmids or antagomirs for HIS. Quantitative RT-PCR and chromatin immunoprecipitation assay detected gene expression and H3K27ac enrichment, respectively. UV-Vis spectroscopy assessed the interaction between HIS and their target locus. Enzyme-linked immunosorbent assay evaluated the hyaluronan (HA) levels of culture supernatant and plasma of COVID-19 patients. Findings: Five short sequences (24–27 nt length) sharing identity between SARS-CoV-2 and human genome were identified. These RNA elements were highly conserved in primates. The genomic fragments containing HIS were predicted to form hairpin structures in silico similar to miRNA precursors. HIS may function through direct genomic interaction leading to activation of host enhancers, and upregulation of adjacent and distant genes, including cytokine genes and hyaluronan synthase 2 (HAS2). HIS antagomirs and Cas13d-mediated HIS degradation reduced HAS2 expression. Severe COVID-19 patients displayed decreased lymphocytes and elevated D-dimer, and C-reactive proteins, as well as increased plasma hyaluronan. Hymecromone inhibited hyaluronan production in vitro, and thus could be further investigated as a therapeutic option for preventing severe outcome in COVID-19 patients. Interpretation: HIS of SARS-CoV-2 could promote COVID-19 progression by upregulating hyaluronan, providing novel targets for treatment. Funding: The National Key R&D Program of China (2018YFC1005004), Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101), and the National Natural Science Foundation of China (31872814, 32000505).

Time-dependent behavior has been demonstrated to be an essential factor in determining the long-term stability of underground structures. Creep and relaxation experiments are commonly used to investigate time-dependent behavior by subjecting rock to constant stress and strain. However, both stress and strain of in-situ rock masses are likely to change with time, a phenomenon known as generalized relaxation that has not been thoroughly investigated. In this study, a newly proposed control method with a constant linear combination of stress and strain as a feedback signal is used in compression and tension tests to investigate generalized relaxation behaviors of rocks. The results showed that the stress and strain of generalized relaxation are dependent on values of α, which represented generalized relaxation direction. The isochronous curves are enclosed within stress–strain curves of different loading conditions. The variation of stress (∆σ) and strain (∆ε) increases with increasing stress level and decreases with increasing confining pressure. Also, ∆σ and ∆ε in region II are smaller than in regions I and III. Furthermore, by performing brittle rock tests, complete generalized relaxation curves are obtained; three stages are observed, which are similar to conventional creep and relaxation behavior. Finally, the time and generalized relaxation failure behavior of Class I and Class II rock are discussed. The study is a valuable resource for gaining a comprehensive understanding of the time-dependent behavior of rocks and improving the stability and safety of underground structures.

Abstract A highly sensitive and temperature-compensated methane sensor based on a liquid-infiltrated photonic crystal fiber (PCF) is proposed. Two bigger holes near the core area are coated with a methane-sensitive compound film, and specific cladding air holes are infiltrated into the liquid material to form new defective channels. The proposed sensor can achieve accurate measurement of methane concentration through temperature compensation. The sensitivity can reach to 20.07 nm/% with a high linearity as the methane concentration is within the range of 0%–3.5% by volume. The proposed methane sensor can not only improve the measurement accuracy, but also reduce the metrical difficulty and simplify the process.

A high-sensitive and transverse-stress compensated methane sensor based on a photonic crystal fiber long-period grating (PCF-LPG) is proposed. The outermost layer of the PCF consists of six large sideholes, five of which are coated with methane-sensitive compound film to achieve methane measurement. Such side-hole structure is helpful for gas sensitive reaction, but not conducive to avoiding external stress interference. Therefore, the last large hole is plated with silver layer to eliminate the cross-sensitivity effect through adding a Surface Plasmon Resonance (SPR) sensing channel with the consideration of photo-elastic effect and material deformation. Results show that the methane gas sensitivity can reach up to 6.39nm/% with the transverse-stress compensation. The sensor is very simple and effective, which provides a new method of gas measurement combined with different actual conditions.

The land surface albedo reflects the ability of the surface to reflect solar radiation and is a critical physical variable in the study of the Earth’s energy budget and global climate change. Algorithms for the retrieval of albedo usually require multi-angle measurements due to surface anisotropy. However, most of the satellites cannot currently provide sufficient and well-distributed observations; therefore, the accuracy of remotely sensed albedo is constrained. Based on the Moderate-Resolution Imaging Spectroradiometer (MODIS) Bidirectional Reflectance Distribution Function (BRDF) and albedo product (MCD43A1), this study proposed a method to further subdivide reflectance anisotropy and build an updated database of BRDF archetype, using both the Anisotropic Flat Index (AFX) and Perpendicular Anisotropic Flat Index (PAFX). The BRDF archetypes were used to fit the corresponding MODIS BRDF, and the optimal number of BRDF archetype categories was determined according to the tendency of fitting error. The effect of surface anisotropy and observation noise on albedo retrieval were explored based on simulated MODIS reflectance. Finally, the BRDF archetype A2P2 was taken as prior knowledge to retrieve albedo from a different number of MODIS observations, and the result was validated by the high-quality MODIS albedo product. The results show that the fitting error between BRDF archetypes and MODIS BRDF shows a rapid decline when introducing the PAFX in the classification process. A 3-by-3 matrix of BRDF archetypes, which occupy 73.44% and 70.13% of the total decline in the red and NIR band, can be used to represent the characteristics of reflectance anisotropy. The archetype A2P2 may be used as prior knowledge to improve the albedo retrieval from insufficient observations. The validation results based on MODIS observations show that the archetype A2P2-based albedo can reach root-mean-square errors (RMSEs) of no more than 0.03.

Understanding the time-dependent behavior of rocks is important for ensuring the long-term stability of underground structures. Aspects of such a time-dependent behavior include the loading-rate dependency of Young’s modulus, strength, creep, and relaxation. In particular, the loading-rate dependency of Young’s modulus of rocks has not been fully clarified. In this study, four different types of rocks were tested, and the results were used to analyze the loading-rate dependency of Young’s modulus and explain the underlying mechanism. For all four rocks, Young’s modulus increased linearly with a tenfold increase in the loading rate. The rocks showed the same loading-rate dependency of Young’s modulus. A variable-compliance constitutive equation was proposed for the loading-rate dependency of Young’s modulus, and the calculated results agreed well with measured values. Irrecoverable and recoverable strains were separated by loading-unloading-reloading tests at preset stress levels. The constitutive equations showed that the rate of increase in Young’s modulus increased with the irrecoverable strain and decreased with increasing stress. The increase in the irrecoverable strain was delayed at high loading rates, which was concluded to be the main reason for the increase in Young’s modulus with an increasing loading rate.

Infection of Zika virus (ZIKV) has become a severe threaten to global health while no specific drug is available. In this study, we explored the relationship between ZIKV and a cellular protein, ankyrin repeat and sterile motif domain containing 4b (ANKS4B). Our data revealed that the expression of ANKS4B in cultured cells and in neonatal mice was downregulated by ZIKV infection. The reduction of ANKS4B upon ZIKV infection was caused by decrease of two hepatocyte nuclear factors HNF1α and HNF4α. Through CRISPR/Cas9 gene editing system, we generated two ANKS4B knockout (KO) cell clones in A549 and Huh7 cells respectively. In the ANKS4B-KO cells, the viral replication levels including viral RNA, protein, and titer were significantly enhanced, which was reversed by trans-complementation of ANKS4B. ANKS4B did not affect the viral entry step, but impaired the autophagy induced by ZIKV infection. Furthermore, our data showed that inhibition of autophagy led to similar replication levels of ZIKV in ANKS4B-sufficient and ANKS4B-deficient cells, suggesting the antiviral effect of ANKS4B relied on its modulation on the autophagy. Therefore, our work identified ANKS4B as a new restriction factor of ZIKV.

Zika virus (ZIKV) is an emerging arthropod-borne virus and belongs to the Flaviviridae family. The infection of ZIKV has become the global health crisis because of its rapid spread and association with severe neurological disorders, including congenital microcephaly and Guillain-Barre Syndrome. To identify host factors contributing to ZIKV pathogenesis, transcriptomic landscape in ZIKV-infected cells was examined with mRNA microarray analysis and we observed that the expression of hydroxycarboxylic acid receptor 2 (HCAR2) could be significantly induced by ZIKV infection. By utilizing two IRE1 inhibitors and XBP1-specific shRNAs, we revealed that the up-regulation of HCAR2 expression induced by ZIKV was dependent on the IRE1-XBP1 pathway. Through the CRISPR/Cas9 system, we generated HCAR2-deficient cell clones in two cell types (human lung carcinoma epithelial A549 cell and human hepatoma Huh7.5 cell). We found that the depletion of HCAR2 significantly increased the replication level of ZIKV, including RNA levels, protein expression levels, and viral titers. In addition, our data demonstrated that the antiviral effect of HCAR2 was not involved in viral entry process and was not dependent on its antilipolytic effect on nicotinic acid/HCAR2-mediated signaling pathway. Taken together, our results indicated that HCAR2 could function as a restriction factor in control of ZIKV replication, potentially providing a novel molecular target for anti-ZIKV therapeutics.

A modified D-shaped photonic crystal fiber (PCF) based on Sagnac interferometer is proposed for methane concentration sensing. Two ultra-large air holes with methane-sensitive film are distributed horizontally in the PCF to shorten response time. Besides, a defect hole is introduced into the fiber core and theoretical analysis is carried out to enhance the sensing sensitivity. The dependence of gas sensitivity on the operable wavelength λ is obtained by analyzing the phase birefringence B(λ,C) and group birefringence Bg(λ,C). The average gas sensitivity is as high as 36.64 nm% in the sensing range of 0–3.5%. The modified D-Shaped and highly sensitive PCF sensor exhibits immunity to cross-sensitivity, and provides a new design idea for methane gas monitoring. Keywords: Photonic crystal fiber sensors, Methane sensing, Sagnac interferometer

Abstract Background MOV10 protein has ATP-dependent 5′–3′ RNA helicase activity and belongs to the UPF1p superfamily. It can inhibit human immunodeficiency virus type 1 (HIV-1) replication at multiple stages and interact with apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G), a member of the cytidine deaminase family that exerts potent inhibitory effects against HIV-1 infection. However, HIV-1-encoded virion infectivity factor (Vif) protein specifically mediates the degradation of A3G via the ubiquitin–proteasome system (UPS). Results We demonstrate that MOV10 counteracts Vif-mediated degradation of A3G by inhibiting the assembly of the Vif-CBF-β-Cullin 5-ElonginB-ElonginC complex. Through interference with UPS, MOV10 enhances the level of A3G in HIV-1-infected cells and virions, and synergistically inhibits the replication and infectivity of HIV-1. In addition, the DEAG-box of MOV10 is required for inhibition of Vif-mediated A3G degradation as the DEAG-box mutant significantly loses this ability. Conclusions Our results demonstrate a novel mechanism involved in the anti-HIV-1 function of MOV10. Given that both MOV10 and A3G belong to the interferon antiviral system, their synergistic inhibition of HIV-1 suggests that these proteins may play complicated roles in antiviral functions.

Circular RNAs (circRNAs) are a novel group of noncoding RNAs characterized by a covalently closed loop. An increasing evidence suggests that deregulated circRNAs exert their essential regulatory roles in oncogenesis. However, little is explored on the biological role of novel circRNAs in cervical cancer (CC) progression. In the present study, we analyzed two GSE microarrays to screen for CC-specific circRNAs and found two circRNAs both expressed in CC cells and tissues. Among them, circ_0005576 was significantly overexpressed in both CC tissues and cell lines. Furthermore, upregulated circ_0005576 was positively associated with advanced FIGO stage, lymph node metastasis, but was negatively related with overall survival of CC patients. Additionally, circ_0005576 knockdown induced a suppressed cell growth, colony formation and metastasis of HeLa and SiHa cells. Mechanistically, circ 0005576 was mainly located in the cytoplasm and served as a sponge of miR-153-3p to increase kinesin family member 20A (KIF20A) expression. Rescue assays further validated the effects of circ_0005576/miR-153-3p/KIF20A axis on CC proliferation, migration and invasion. In conclusion, our research reveals a novel circ_0005576/miR-153-3p/KIF20A axis promoting CC progression, which may suggest a new insight into the pathogenesis of CC.

Long noncoding RNAs have a wide range of physiological functions, though their role in viral infection and latency is poorly understood. Here the authors show a lncRNA NRON can induce degradation of HIV-1 protein Tat, potentially contributing to latent infection.

Background: Inadequate self-care management has been reported in patients with heart failure (HF) and their family caregivers. However, evidence on the influencing factors and corresponding action paths for self-care management within a dyadic context is limited. Objective: The aim of this study was to examine dyadic associations between benefit finding and self-care management in HF patient-caregiver dyads and the mediating role of mutuality in these associations. Methods: This cross-sectional study was conducted in China, and a convenience sample of 253 HF patient-caregiver dyads was included in the analysis. Dyadic benefit finding and mutuality, patients' self-care management, and caregivers' contributions to self-care management were measured using self-reported questionnaires. The actor-partner interdependence model and actor-partner interdependence mediation model were adopted to analyze the data. Results: Patients' benefit finding had an actor effect on their own self-care management (γ = 0.134, P < .05) and a partner effect on caregivers' contributions to self-care management (γ = 0.130, P < .05). Similarly, caregivers' benefit finding had an actor effect on their contributions to self-caremanagement (γ = 0.316, P < .01) and a partner effect on patients' self-care management (γ = 0.187, P < .01). Moreover, patients' mutuality completely mediated the actor effect of their benefit finding on self-care management (γ = 0.127; 95% confidence interval, 0.032-0.233), and caregivers' mutuality partially mediated the actor effect of their benefit finding on contributions to self-care management (γ = 0.060; 95% confidence interval, 0.012-0.124). In addition, caregivers' mutuality completely mediated the partner effect of patients' benefit finding on caregivers' contributions to self-care management (γ = 0.036; 95% confidence interval, 0.009-0.081). Conclusions: The findings revealed the importance of benefit finding and mutuality, 2 modifiable factors positively associated with dyadic HF self-care management. Dyadic interventions targeting on enhancing benefit finding and mutuality should be designed and implemented to improve HF self-care management. [ABSTRACT FROM AUTHOR]