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Abstract Adamantinomatous craniopharyngioma (ACP) is a clinically aggressive tumor without effective treatment method. Previous studies proposed a paracrine tumorigenesis model, in which oncogenic β-catenin induces senescence in pituitary stem cells and the senescent cells lead the formation of paracrine tumors through secretion of pro-tumorigenic factors. However, there lacks characterization on senescent cells in ACPs. Here, we profiled 12 ACPs with single-cell RNA and TCR-sequencing to elucidate the cellular atlas in ACPs and 3 of them were also subject to spatial sequencing to localize different subpopulations of the tumor cells. In total, we obtained the transcriptome profiles of 70,682 cells. Tumor cells, which were unambiguously identified through the cellular mutation status of the driver CTNNB1 mutations, were clustered into 6 subsets. The whorl-like cluster (WC) cells show distinct molecular features from the other tumor cells and the palisading epithelium (PE) cells consists of a proliferating subset. Other than typical PE and WC, we identified two novel subpopulations of the tumor cells. In one subpopulation, the cells express a high level of cytokines, e.g., FDCSP and S100A8/A9, and are enriched with the senescence-associated secretory phenotype (SASP) factors. Hematoxylin and eosin staining reveals that these SASP cells lack an ordered structures and their nuclei are elongated. In the other subpopulation, the cell sizes are small and they are tightly packed together with an unusual high density expressing a high level of mitochondrial genes (median 10.9%). These cells are the origin of the tumor developmental trajectories revealed by RNA velocity and pseudo-time analysis. Single-cell RNA and TCR analysis reveals that some ACPs are infiltrated with clonally expanded cytotoxic T cells. We propose a hypothesis that WC and PE are formed via different negative regulation mechanisms of the overactivated WNT/β-catenin signaling which provides a new understanding on the tumorigenesis of ACPs. The study lays a foundation for future studies on targeting senescent cells in ACPs with senolytic compounds or other therapeutic agents.

Abstract The goal of the next‐generation COVID‐19 vaccine is to provide rapid respiratory tract protection with a single dose. Circulating antibodies do not protect the olfactory mucosa from viral infection, necessitating localized mucosal immunization. Live attenuated vesicular stomatitis virus (VSVMT)‐based COVID‐19 vaccines effectively stimulate mucosal immunity in animals, though safety concerns remain, particularly in immunocompromised populations. A viral vector capable of single‐cycle replication may face less stringent regulatory requirements. A replication‐defective VSVMT is developed with its G protein replaced by a SARS‐CoV‐2 spike protein (S) mutant, where residues K986 and V987 are substituted by prolines (S2P). This studies show that single‐cycle VSVMT encoding Omicron subvariant S2P (VSVMT‐S2P) is safe in both healthy and immunocompromised animals treated with cyclophosphamide (CP). Significant antibody and T‐cell responses against the spike protein are observed in VSVMT‐S2P vaccinated healthy animals. Intramuscular VSVMT‐S2P administration induces neutralizing antibody responses comparable to those from replication‐competent VSVMT‐S. In immunocompromised animals, lower and delayed immune responses are observed. Thus, single‐cycle M‐protein mutated VSV offers a safe and effective platform for SARS‐CoV‐2 immunogen delivery. Remarkably, replication‐competent VSVMT‐S caused no pathogenicity and elicited potent mucosal immunity via intranasal administration, highlighting its potential as a mucosal COVID‐19 vaccine.

Abstract. Background:. Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. Methods:. Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. Results:. Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial–mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P

Abstract Accurately identification of the seizure onset zone (SOZ) is pivotal for successful surgery in patients with medically refractory epilepsy. The purpose of this study is to improve the performance of model predicting the epilepsy surgery outcomes using genetic neural network (GNN) model based on a hybrid intracranial electroencephalography (iEEG) marker. We extracted 21 SOZ related markers based on iEEG data from 79 epilepsy patients. The least absolute shrinkage and selection operator (LASSO) regression was employed to integrated seven markers, selected after testing in pairs with all 21 biomarkers and 7 machine learning models, into a hybrid marker. Based on the hybrid marker, we devised a GNN model and compared its predictive performance for surgical outcomes with six other mainstream machine-learning models. Compared to the mainstream models, underpinning the GNN with the hybrid iEEG marker resulted in a better prediction of surgical outcomes, showing a significant increase of the prediction accuracy from approximately 87% to 94.3% (P = 0.0412). This study suggests that the hybrid iEEG marker can improve the performance of model predicting the epilepsy surgical outcomes, and validates the effectiveness of the GNN in characterizing and analyzing complex relationships between clinical data variables.

PurposeInsulin-like growth factor-1 (IGF-1) has a variety of neurotrophic effects, including neurogenesis, remyelination and synaptogenesis, and is an effective regulator of neuronal plasticity. Although multiple studies have investigated IGF-1 in depression-related disorders, few studies have focused on patients with a first episode of clearly diagnosed depression who had never used antidepressants before. Therefore, this study investigated first-episode and drug-naïve patients with depression to supplement the current evidence around IGF-1 levels in depressive disorders.Patients and methodsThis study consisted of two parts. In the first part, 60 patients with first-episode and drug-naïve depression and 60 controls matched for age, sex, and BMI were recruited from the outpatient department of the Fourth Hospital of Wuhu City, and the community. The case-control method was used to compare differences in serum IGF-1 levels between the two groups. In the second part, 13 case-control studies were screened through the database for meta-analysis to verify the reliability of the results.ResultsResults of the case-control study demonstrated that serum IGF-1 levels are significantly higher in patients with first-episode and drug-naïve depression compared to healthy controls (p

COVID-19 is caused by coronavirus SARS-CoV-2. Current systemic vaccines generally provide limited protection against viral replication and shedding within the airway. Recombinant VSV (rVSV) is an effective vector which inducing potent and comprehensive immunities. Currently, there are two clinical trials investigating COVID-19 vaccines based on VSV vectors. These vaccines were developed with spike protein of WA1 which administrated intramuscularly. Although intranasal route is ideal for activating mucosal immunity with VSV vector, safety is of concern. Thus, a highly attenuated rVSV with three amino acids mutations in matrix protein (VSVMT) was developed to construct safe mucosal vaccines against multiple SARS-CoV-2 variants of concern. It demonstrated that spike protein mutant lacking 21 amino acids in its cytoplasmic domain could rescue rVSV efficiently. VSVMT indicated improved safeness compared with wild-type VSV as the vector encoding SARS-CoV-2 spike protein. With a single-dosed intranasal inoculation of rVSVΔGMT-SΔ21, potent SARS-CoV-2 specific neutralization antibodies could be stimulated in animals, particularly in term of mucosal and cellular immunity. Strikingly, the chimeric VSV encoding SΔ21 of Delta-variant can induce more potent immune responses compared with those encoding SΔ21 of Omicron- or WA1-strain. VSVMT is a promising platform to develop a mucosal vaccine for countering COVID-19.

Abstract Background The clinical applications of dispensing granules (DG) have increased dramatically. However, it is controversial whether the DG has the same quality and efficacy compared with traditional decoction (TD). In this study, the contents of main compounds, hypoglycemic effects, and potential mechanism of Coptidis Rhizoma (CR) and Scutellaria–coptis (SC), constituted of a 1:1 mixture of CR and Scutellariae Radix (SR), in the forms of TD and DG were compared. Methods The quantitative analysis was performed on an UPLC-PDA method. The 6-weeks-old male db/db mice were used as Type 2 Diabetes Mellitus (T2DM) mouse modle to investigate the antidiabetic effects of CR and SC in TD form (CR TD and SC TD), as well as CR and SC in DG form (CR DG and SC DG). Results The total content of five alkaloids in CR TD ranged from 71.00 to 78.62 mg, whereas in CR DG it ranged from 38.77 to 53.68 mg in CR DG per 1 g of decoction pieces. Compared to CR TD, CR DG exhibited a 36% reduction on average. For SC samples, the precipitation occurred in the processing of TD but not in the DG, and the relative ratio of alkaloids to flavonoids was determined to be 1:1 in TD and 1:2 in DG. Furthermore, the animal experiments showed that the CR DG (equivalent to 3 g decoction pieces/kg) had almost the same hypoglycemic effect as CR TD when they were administered for 6 weeks. Compared with SC DG (equivalent to 6 g decoction pieces/kg), SC TD showed a better trend in ameliorating T2DM via ameliorating pancreatic structure and function, and activating Akt/AMPK/GLUT4 signaling pathways. Conclusion This study indicated that the contents of main compounds were generally higher in CR TD than CR DG originated from the same raw materials. Additionally, changes in the contents of the primary components validated that the compound interactions are exclusive to SC TD during co-decoction, rather than SC DG. The disparate prossing of SC DG and SC TD caused differences both in chemical composition and hypoglycemic effect, suggesting that the substitutability of DG and TD requires further research.

Soil salinization has become a major challenge that severely threatens crop growth and influences the productivity of agriculture. It is urgent to develop effective management measures to improve saline–alkali soil. Thus, in this study, soil properties, microbial communities, and function under desulfurization gypsum (DE), soil amendment (SA), farm manure (FA), and co-application of desulfurization gypsum, soil amendment, and farm manure (TA) in a field experiment were examined by high-throughput sequencing. The results showed that the application of modified materials is an effective approach in improving saline–alkali soil, especially TA treatment significantly increased the content of available phosphorus (AP), available potassium (AK), soil organic matter (SOM), and alkaline hydrolysis nitrogen (AHN) and decreased pH, bulk density (BD), and electrical conductivity (EC). The application of modified materials resulted in notable enhancement in fungal diversity and altered the composition and structure of the fungal community. Conversely, the effect on the bacterial community was comparatively minor, with changes limited to the structure of the community. Regarding the fungal community composition, Ascomycota, Mortierellomycota, and Basidiomycota emerged as the dominant phyla across all treatments. At each taxonomic level, the community composition exhibited significant variations in response to different modified materials, resulting in divergent soil quality. The TA treatment led to a decrease in Mortierellomycota and an increase in Ascomycota, potentially enhancing the ability to decompose organic matter and facilitate soil nutrient cycling. Additionally, the sensitivity of fungal biomarkers to modified materials surpassed that of the bacterial community. The impact of modified materials on soil microbial communities primarily stemmed from alterations in soil EC, AP, AK, and SOM. FUNGuild analysis indicated that the saprotroph trophic mode group was the dominant component, and the application of modified materials notably increased the symbiotroph group. PICRUSt analysis revealed that metabolism was the most prevalent functional module observed at pathway level 1. Overall, the application of modified materials led to a decrease in soil EC and an increase in nutrient levels, resulting in more significant alterations in the soil fungal community, but it did not dramatically change the soil bacterial community. Our study provides new insights into the application of modified materials in increasing soil nutrients and altering soil microbial communities and functions and provides a better approach for improving saline–alkali soil of Hetao Plain.

ObjectivesThe high incidence of abdominal aortic calcification (AAC) is well-documented in individuals with severe renal function decline. However, there is limited research on the historical relationship between estimated glomerular filtration rate (eGFR) and the risk of AAC occurrence in the general population undergoing routine medical examinations. The main objective of this study was to investigate the historical relationship between eGFR and AAC in the general population of the United States.MethodsWe performed a cross-sectional study using the National Health and Nutrition Examination Survey 2013–2014 database. Weighted multivariate linear regression models were used to estimate the associations of eGFR with AAC score. Smooth curve fitting and two-piecewise linear regression were employed to explore the potential non-linear relationship.ResultsA total of 2,978 participant (48.22% were male) aged 40–80 years were included in this study. The fully-adjusted model demonstrated a negative correlation between eGFR and AAC score (β = −0.015, 95% CI: −0.023 to −0.006). However, when applying the smooth curve fitting method, a U-shaped relationship was identified, and the inflection point was calculated at 76.43 ml/min/1.73 m2 using the two-piecewise linear regression model.ConclusionsThere was a U-shaped association between eGFR and AAC score in general US adults, with an inflection point at about 76.43 ml/min/1.73 m2.

Abstract Background There is little evidence on whether PM2.5 and ground surface ozone have consistent effects on increased individual medical costs, and there is a lack of evidence on causality in developing countries. Methods This study utilized balanced panel data from 2014, 2016, and 2018 waves of the Chinese Family Panel Study. The Tobit model was developed within a counterfactual causal inference framework, combined with a correlated random effects and control function approach (Tobit-CRE-CF), to explore the causal relationship between long-term exposure to air pollution and medical costs. We also explored whether different air pollutants exhibit comparable effects. Results This study encompassed 8928 participants and assessed various benchmark models, highlighting the potential biases from failing to account for air pollution endogeneity or overlooking respondents without medical costs. Using the Tobit-CRE-CF model, significant effects of air pollutants on increased individual medical costs were identified. Specifically, margin effects for PM2.5 and ground-level ozone signifying that a unit increase in PM2.5 and ground-level ozone results in increased total medical costs of 199.144 and 75.145 RMB for individuals who incurred fees in the previous year, respectively. Conclusions The results imply that long-term exposure to air pollutants contributes to increased medical costs for individuals, offering valuable insights for policymakers aiming to mitigate air pollution’s consequences.

The quality of underwater images is often marred by noticeable color casts and blurring, resulting from complex phenomena such as differential light attenuation based on wavelength, veiling light scattering, and light scattering by plankton and suspended particles in water. In this paper, we propose an effective underwater image enhancement method called Optimal Contrast and Attenuation Difference (OCAD) to tackle these issues. The OCAD method employs a two-step approach. First, it estimates a coarse transmission map by optimizing contrast and minimizing information loss during image mapping. This transmission map is then refined using a combination of dark channel prior and guided filter refining techniques to improve its accuracy. Second, OCAD estimates the veiling light by considering the differential attenuation of red, green, and blue light underwater. This estimated veiling light is utilized to partially mitigate the color cast caused by the attenuation effect, while also addressing the blurring based on an imaging model. To further enhance the image quality, we introduce the Gray World approach to correct the color and obtain a deblurred and color-corrected underwater image. To evaluate the performance of our proposed method, extensive experiments are conducted on well-established underwater image datasets, including the EUVP, UIEB, and RUIE datasets. Comparative analysis against state-of-the-art and classical underwater image enhancement methods reveals that our OCAD algorithm significantly enhances underwater images and outperforms other methods in terms of image quality improvement.

ObjectiveTo date, the current diagnosis of major depressive disorder (MDD) still depends on clinical symptomatologic criteria, misdiagnosis and ineffective treatment are common. The study aimed to explore circulating biomarkers for MDD diagnosis.MethodsA high-throughput antibody array technology was utilized to detect 440 circulating cytokines in eight MDD patients and eight age–and gender-matched healthy controls. LASSO regression was conducted for MDD-related characteristic proteins selection. Enzyme-linked immunosorbent assay (ELISA) was used to validate the characteristic proteins in 40 MDD patients and 40 healthy controls. Receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic values of characteristic proteins for discriminating MDD patients from healthy controls. Correlations between the levels of characteristic proteins and depression severity (HAMD-17 scores) were evaluated using linear regression.ResultsThe levels of 59 proteins were found aberrant in MDD patients compared with healthy controls. LASSO regression found six MDD-related characteristic proteins including insulin, CD40L, CD155, Lipocalin-2, HGF and LIGHT. ROC curve analysis showed that the area under curve (AUC) values of six characteristic proteins were more than 0.85 in discriminating patients with MDD from healthy controls. Furthermore, significant relationship was found between the levels of insulin, CD155, Lipocalin-2, HGF, LIGHT and HAMD-17 scores in MDD group.ConclusionThese results suggested that six characteristic proteins screened from 59 proteins differential in MDD may hold promise as diagnostic biomarkers in discriminating patients with MDD. Among six characteristic proteins, insulin, CD155, Lipocalin-2, HGF and LIGHT might be useful to estimate the severity of depressive symptoms.

A fast, simple, and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established for the quantification of safinamide in rat plasma. Plasma samples were treated with acetonitrile for protein precipitation, and diazepam was used as an internal standard (IS). The analytes were separated on an Acquity UPLC C18 (2.1 mm × 50 mm, 1.7 μm) chromatographic column with gradient elution using a mobile phase (0.1% formic acid-acetonitrile). Then, the eluates were detected by electrospray ionization (ESI) in positive ion mode. The analytes were quantified by multiple reaction monitoring (MRM) using the transition m/z 303.3→215.0 of safinamide and m/z 285.0→154.0 of IS. Safinamide had good linearity in the concentration range of 1.0–2000 ng/mL, and the lower limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precision and accuracy of safinamide were less than 7.63%, while the average recovery rate was 92.98%–100.29%. The method was validated to be stable and had low noise, short chromatographic run time, wide linear range, small sample volumes, low sample injection volumes, and high sensitivity. Therefore, it can be used in pharmacokinetics and preclinical and clinical studies.

This paper addresses the pressing scientific problem of accurately predicting the equivalent stiffness of local resonance metamaterial concrete unit cells. Existing theoretical models often fail to capture the nuanced dynamics of these complex systems, resulting in suboptimal predictions and hindering advancements in engineering applications. To address this deficit, this paper proposes a novel two-dimensional theoretical vibration model that incorporates shear stiffness, a crucial yet often overlooked parameter in previous formulations. Motivated by the need for improved predictive accuracy, this paper rigorously validates a new theoretical model through numerical simulations, considering variations in material parameters and geometric dimensions. The analysis reveals several key findings: firstly, the equivalent stiffness increases with elastic modulus while the error rate decreases, holding geometric parameters and Poisson’s ratio constant. Secondly, under fixed geometric parameters and coating elastic modulus, the equivalent stiffness rises with an increasing Poisson’s ratio, accompanied by a decrease in error rate. Importantly, this paper demonstrates that the proposed model exhibits the lowest error rate across all parameter conditions, facilitating superior prediction of equivalent stiffness. This advancement holds significant implications for the design and optimization of metamaterial structures in various engineering applications for vibration isolation, with promising enhancements of performance and efficiency.

Technological progress has led to significant advancements in Earth observation and satellite systems. However, some services associated with remote sensing face issues related to timeliness and relevance, which affect the application of remote sensing resources in various fields and disciplines. The challenge now is to help end-users make precise decisions and recommendations for relevant resources that meet the demands of their specific domains from the vast array of remote sensing resources available. In this study, we propose a remote sensing resource service recommendation model that incorporates a time-aware dual LSTM neural network with similarity graph learning. We further use the stream push technology to enhance the model. We first construct interaction history behavior sequences based on users’ resource search history. Then, we establish a category similarity relationship graph structure based on the cosine similarity matrix between remote sensing resource categories. Next, we use LSTM to represent historical sequences and Graph Convolutional Networks (GCN) to represent graph structures. We construct similarity relationship sequences by combining historical sequences to explore exact similarity relationships using LSTM. We embed user IDs to model users’ unique characteristics. By implementing three modeling approaches, we can achieve precise recommendations for remote sensing services. Finally, we conduct experiments to evaluate our methods using three datasets, and the experimental results show that our method outperforms the state-of-the-art algorithms.

The lifting construction process of high-rise structure is very difficult, and the unloading and demolition of lifting equipment and temporary support pose a greater challenge to the construction safety of high-rise structure. With the Beijiang Pearl Tower Project as the background, the unloading process of the revolving restaurant after hoisting was studied by combining Abaqus life and death element technology with unloading process monitoring. Five unloading schemes were formulated to analyze and compare the influence of different unloading sequence on the internal force of the structure. The finite element simulation results are basically consistent with the monitoring data, indicating that the technology is effective and feasible, and the combination of the two can effectively ensure the safety of the construction unloading process. The analysis results show that: for the overall lifting construction of multi-layer frame convex structure of similar high-rise structure, when unloading the temporary support, it is appropriate to first remove the secondary components outside the floor where the lifting steel strand lifting point is located, then gradually remove the steel strand load, and remove the steel strand and equipment, and finally remove the main support components near the upper and lower lifting points of steel strand.

Porcine epidemic diarrhea virus (PEDV) mainly infects the intestinal epithelial cells of pigs, causing porcine epidemic diarrhea (PED). In particular, the virus causes severe diarrhea, dehydration, and death in neonatal piglets. Maternal immunity effectively protects neonatal piglets from PEDV infection; however, maternal antibodies can only prevent PEDV attachment and entry into target cells, but have no effects on intracellular viruses. Intracellular antibodies targeting virus-encoded proteins are effective in preventing viral infection. We previously identified four single chain variable fragments (scFvs), ZW1-16, ZW3-21, ZW1-41, and ZW4-16, which specifically targeted the PEDV N protein and significantly inhibited PEDV replication and up-regulated interferon-λ1 (IFN-λ1) expression in host cells. In our current study, the four scFvs were subcloned into replication-defective adenovirus vectors to generate recombinant adenoviruses rAdV-ZW1-16, rAdV-ZW3-21, rAdV-ZW1-41, and rAdV-ZW4-16. ScFvs were successfully expressed in Human Embryonic Kidney 293 (HEK293) cells and intestinal porcine epithelial cell line J2 (IPEC-J2) and were biosafe for piglets as indicated by body temperature and weight, scFv excretion in feces, IFN-γ and interleukin-4 (IL-4) expression in jejunum, and pathological changes in porcine tissue after oral administration. Western blotting, immunofluorescence, and immunohistochemical analyses showed that scFvs were expressed in porcine jejunum. The prophylactic effects of rAdV-ZW, a cocktail of the four rAdV-scFvs, on piglet diarrhea caused by PEDV was investigated. Clinical symptoms in piglets orally challenged with PEDV, following a two-time treatment with rAdV-ZW, were significantly reduced when compared with PEDV-infected piglets treated with phosphate buffered saline (PBS) or rAdV-wild-type. Also, no death and jejunal lesions were observed. ScFv co-localization with the PEDV N protein in vivo was also observed. Next, the expression of pro-inflammatory serum cytokines such as tumor necrosis factor-α (TNF-α), IL-6, IL-8, IL-12, and IFN-λ was assessed by enzyme-linked immunosorbent assay (ELISA), which showed that scFvs significantly suppressed PEDV-induced pro-inflammatory cytokine expression and restored PEDV-inhibited IFN-λ expression. Therefore, our study supported a promising role for intracellular scFvs targeting the PEDV N protein to prevent and treat diarrhea in PEDV-infected piglets.

Oprozomib, as a second-generation orally bioavailable protease inhibitor (PI), is undergoing clinical evaluation for the treatment of haematological malignancies. In relapsed refractory multiple myeloma (RRMM) patients, oprozomib has shown good efficacy as a single agent or combination therapy. In this experiment, our purpose was to validate a sensitive and rapid method for the determination of oprozomib concentration in rat plasma by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The samples were treated with acetonitrile as the precipitant and separated by gradient elution using a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm). Using the selective reaction monitoring (SRM) method, the measurement was finished with the ion transitions of m/z 533.18 ⟶ 199.01 for oprozomib and m/z 493.03 ⟶ 112.03 for tepotinib (internal standard, IS), respectively. Meanwhile, acetonitrile and 0.1% formic acid aqueous solution were used as the mobile phase, and the flow rate was 0.3 mL/min. The lower limit of quantification (LLOQ) of the method was 1.0 ng/mL, and the linear relationship was good in the range of 1.0–100 ng/mL. In addition, the precision of four concentration levels was determined with the values of 3.1–7.3% and the accuracy was from −14.9% to 12.9%. Moreover, the recovery was determined to be from 85.1% to 96.1%, and the values of matrix effect were no more than 110.4%. The optimized UPLC-MS/MS method was also suitable for the pharmacokinetic study of rats after a single oral administration of 21 mg/kg oprozomib.

ABSTRACT The thick mucus layer covering of the intestinal epithelium has received increasing attention, owing to its protective role in intestinal infection. However, the exact mechanisms by which the mucus increases intestinal resistance against viral infection remain largely unclear. Here, we identify prominent antiviral activity of the small intestinal mucus and extracted total mucus proteins, as evidenced by their inhibitory effects against porcine epidemic diarrhea virus (PEDV) infection. Of all the extracted mucus proteins, mucin 2 and fraction III (~70 kDa) exhibited potent antiviral activity. We further evaluated the antiviral effects of three candidate factors in fraction III and found that calpain-1 contributed substantially to its antiviral activity. In vivo studies demonstrated that oral administration of calpain-1 provided effective protection against intestinal PEDV infection. As a calcium-activated cysteine protease, calpain-1 inhibited viral invasion by binding to and hydrolyzing the S1 domain of the viral spike protein. The region between amino acids 297 and 337 in the b domain of PEDV S1 protein was critical for calpain-1-mediated hydrolysis. Further investigation indicated that calpain-1 could be produced by goblet cells between intestinal epithelia. Taken together, the results of our study revealed calpain-1 to be a novel antiviral protein in porcine small intestinal mucus, suggesting that calpain-1 has potential for defending against intestinal infections. IMPORTANCE Although the antiviral activity of the intestinal mucus was recognized 20 years ago, the antiviral active ingredients in the mucus are poorly understood. Currently, most research on antiviral molecules in the intestinal mucus remains limited to members of the mucin family. This study identified the cysteine protease calpain-1 as a novel antiviral protein in porcine small intestinal mucus and revealed its underlying protective mechanism for the first time. This mechanism involves inhibiting porcine epidemic diarrhea virus (PEDV) invasion by binding and hydrolyzing the S1 domain of the viral spike protein. Furthermore, the results of our PEDV-challenge experiment in piglets indicated that calpain-1 provides effective protection against intestinal PEDV infection. Our findings provide new insights into the protective function of the small intestinal mucus. In addition to potential therapeutic implications for the swine industry, our analysis of antiviral proteins in the small intestinal mucus may have implications for the prevention and control of coronavirus infection in humans.

The environmental change in the wetlands in the southern Mongolian Plateau has important impacts on the environment of North China and even the entire Northeast Asia, from which the global climate change can be understood on a large scale, especially the climate change in the Mongolian Plateau. This study extracted the information on the wetlands from three stages of remote sensing images (also referred to as RS images) of the study area, including Enhanced Thematic Mapper Plus (ETM+) images of 2000, TM images of 2010, and Landsat 8 Operational Land Imager (OLI) images of 2018. As indicated by the extraction results, the area of wetlands decreased from 796.90 km2 of 2000 to 666.24 km2 of 2018 at a rate of 7.26 km2/a. The reduced area is 130.66 km2, which is about 16.4% reduction. And the patch number of wetlands decreased from 731 of 2000 to 316 of 2018 in the study area, approximately 56.8% reduction (415 patches), and the decrease in the area of the wetlands mainly occurred in the northwest endorheic region. In terms of wetland types, the change of the wetlands was dominated by the decrease of lacustrine wetlands, of which the area and patch number decreased by 106.2 km2 and 242, respectively. Furthermore, the area of the lacustrine wetlands decreased at the highest rate of 8.70 km2/a in 2010–2018. From the perspective of spatial distribution, the wetlands in the western part shrunk more notably than those in the eastern part as a whole in the study area. According to local meteorological data, the precipitation gently decreased and the temperature increased (about 1.7°C) from 1975–2018. Overall, the decrease in the area of the wetlands and the temperature rises in the study area were mainly driven by the Mongolian monsoon climate, reduction in precipitation, and human activities.

Abstract Porcine epidemic diarrhea virus (PEDV) primarily infects neonatal piglets causing catastrophic effects on the global pig farming industry. PEDV infects piglets through the nasal cavity, a process in which dendritic cells (DCs) play an important role. However, neonatal piglets have fewer nasal DCs. This study found that subepithelial CD3+ T cells mediated PEDV invasion through the nasal cavity in neonatal piglets. PEDV could replicate in the nasal epithelial cells (NECs) isolated from the nasal cavity of neonatal piglets. Infection of NECs with PEDV could induce antiviral and inflammatory cytokines at the late stage. The infected NECs mediated transfer of virus to CD3+ T cells distributed in the subepithelial of the nasal cavity via cell-to-cell contact. The infected CD3+ T cells could migrate to the intestine via blood circulation, causing intestinal infection in neonatal piglets. Thus, the findings of this study indicate the importance of CD3+T cells in the dissemination of PEDV from the nasal cavity to the intestinal mucosa in neonatal piglets.

Cartilage dysfunctions caused by congenital disease, trauma and osteoarthritis are still a serious threat to joint activity and quality of life, potentially leading to disability. The relatively well-established tissue engineering technology based on hydrogel is a promising strategy for cartilage defect repairing. However, several unmet challenges remain to be resolved before its wide application and clinical translation, such as weak mechanical property and compromised bioactivity. The development of nanomedicine has brought a new dawn to cartilage tissue engineering, and composite hydrogel containing nanoparticles can substantially mimic natural cartilage components with good histocompatibility, demonstrating unique biological effects. In this review, we summarize the different advanced nanoparticle hydrogels currently adopted in cartilage tissue engineering. In addition, we also discuss the various application scenarios including injection and fabrication strategies of nanocomposite hydrogel in the field of cartilage repair. Finally, the future application prospects and challenges of nanocomposite hydrogel are also highlighted.

Threshold private set intersection (TPSI) allows a receiver to obtain the intersection when the cardinality of the intersection is greater or equal to the threshold, which has a wide range of applications such as fingerprint matching, online dating and ridesharing. Existing TPSI protocols are inefficient because almost all of them rely on lots of expensive public-key techniques or require an exponential number of possible combinations among the shares. In this work, we design an efficient TPSI protocol, which achieves computational security in semi-honest model. To improve the efficiency of the TPSI protocol, we design a new TPSI protocol based on garbled Bloom filter (GBF) and threshold secret sharing, which uses a small amount of public-key operations. Moreover, our protocol combines with the Reed-Solomon decoding algorithm to reconstruct the secret which is a feasible method to avoid calculating all possible combinations among the shares. The performance analysis shows that our protocol is more efficient than the previous TPSI protocols. To the best of our knowledge, the optimal TPSI protocol implemented by Zhao and Chow (WPES'18) has an online time of 78 seconds to compute the intersection of two datasets of 100 elements each with threshold t = 50. In contrast, our protocol has a total time of 2.988 seconds.

Abstract Background Porcine circovirus type 2 (PCV2) is the causative agent of postweaning multisystemic wasting syndrome, and is associated with a number of other diseases. PCV2 is widely distributed in most developed swine industries, and is a severe economic burden. With an eye to developing an effective, safe, and convenient vaccine against PCV2-associated diseases, we have constructed a recombinant Bacillus subtilis strain (B. subtilis-Cap) that expresses the PCV2 capsid protein (Cap). Methods Electroporation of a plasmid shuttle vector encoding the PCV2 Cap sequence was use to transform Bacillus subtilis. Flow cytometry was used to evaluate in vitro bone marrow derived dendritic cell (BM-DC) maturation and T cell proliferation induced by B. subtilis-Cap. Orally inoculated piglets were used for in vivo experiments; ELISA and western blotting were used to evaluate B. subtilis-Cap induced PCV2-specific IgA and IgG levels, as well as the secretion of cytokines and the expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 9 (TLR9). Results We evaluated the immune response to B. subtilis-Cap in vitro using mouse BM-DCs and in vivo using neonatal piglets orally inoculated with B. subtilis-Cap. Our results showed that the recombinant B. subtilis-Cap activated BM-DCs, significantly increased co-stimulatory molecules (CD40 and CD80) and major histocompatibility complex II, and induced allogenic T cells proliferation. Piglets immunized with B. subtilis-Cap had elevated levels of PCV2-specific IgA in the mucosal tissues of the digestive and respiratory tract, and PCV2-specific IgG in serum (P

Colorimetric sensors have been widely used to detect numerous analytes due to their cost-effectiveness, high sensitivity and specificity, and clear visibility, even with the naked eye. In recent years, the emergence of advanced nanomaterials has greatly improved the development of colorimetric sensors. This review focuses on the recent (from the years 2015 to 2022) advances in the design, fabrication, and applications of colorimetric sensors. First, the classification and sensing mechanisms of colorimetric sensors are briefly described, and the design of colorimetric sensors based on several typical nanomaterials, including graphene and its derivatives, metal and metal oxide nanoparticles, DNA nanomaterials, quantum dots, and some other materials are discussed. Then the applications, especially for the detection of metallic and non-metallic ions, proteins, small molecules, gas, virus and bacteria, and DNA/RNA are summarized. Finally, the remaining challenges and future trends in the development of colorimetric sensors are also discussed.

Objective: Accumulated evidence has implicated that brain-derived neurotrophic factor (BDNF) gene polymorphisms play a role in the etiology of obsessive-compulsive disorder (OCD). A single nucleotide polymorphism in the coding exon of the BDNF gene at position 66, Val66Met (rs6265), is found to be associated with OCD in different populations, but results linking Val66Met with OCD have been inconsistent and inconclusive. In our study we performed a meta-analysis to further examine whether rs6265 genetic variants are involved in the etiology of OCD.Methods: By searching databases, relevant case-control studies were retrieved; using established inclusion criteria, we selected eligible studies for analysis.Results: Thirteen studies were identified that examined the association between the rs6265 polymorphism and OCD. After statistical analyses, no significant association was found between the rs6265 polymorphism and OCD (OR = 1.07, 95% CI = 1.00–1.15, P = 0.06 for genotype; OR = 1.06, 95% CI = 0.98–1.15, P = 0.15 for allele). However, in gender-specific analysis, female Val carriers might be a risk factor for OCD (OR = 1.36, 95% CI = 1.03–1.80, P = 0.03 for genotype; OR = 1.15, 95% CI = 1.01–1.32, P = 0.04 for allele).Conclusion: Our updated meta-analysis suggests that female carriers of the Val66Met BDNF polymorphism might be more suspectable to develop OCD.

Numerous studies have investigated concentrations of lead (Pb) and cadmium (Cd) in rice in China, but have come to divergent conclusions. Therefore we systematically reviewed and meta-analyzed the available evidence on levels of Pb and Cd in rice in different regions of China in order to assess the potential risk to human health. The meta-analysis included 24 studies of Pb levels and 29 studies of Cd levels, published in 2011–2021. The pooled Pb concentration in rice was 0.10 mg per kg dry weight (95% CI 0.08−0.11), while the pooled Cd concentration was 0.16 mg per kg dry weight (95% CI 0.14−0.18). These levels are within the limits specified by national food safety standards. However, the total target hazard quotient for both metals exceeded 1.0 for adults and children, suggesting that rice consumption poses a health risk.

Abstract Background Pseudorabies caused by pseudorabies virus (PRV) mainly infects the swine and seriously threatens the biosafety of the other animals, including humans. Since 2011, the outbreaks of PRV mutants have caused enormous economic losses in the swine industry, and traditional vaccines cannot offer enough protection. PRV can transmit by direct contact, aerosol transmission and pollutants. PRV mainly transmit through the nasal mucosa. After infecting the nasal epithelial cells, PRV can quickly infect the olfactory nerve and establish a potential infection of sensory neurons. Therefore, nasal immunity can effectively prevent viral colonization infection. Recombinant Bacillus subtilis has been widely used to deliver antigen and achieve adequate protective immune responses. Results The present study successfully constructed recombinant Bacillus subtilis (B. subtilis) expressing the dominant antigen regions of PRV gC and gD proteins (named B. subtilis-gCa and B. subtilis-gDa). Furtherly, we evaluated the immunogenicity of the two recombinant B. subtilis in mice. The mice intranasal administration with B. subtilis-gCa and B. subtilis-gDa effectively stimulated IgA and IgG immune responses, further regulated specific T lymphocytes proliferative response by IFN-γ and IL-10, and ultimately produced high titers of neutralizing antibodies against PRV infection. In particular, B. subtilis-gDa possessed more excellent immune effect than B. subtilis-gCa in mice. Conclusions These results suggested that B. subtilis-gCa and B. subtilis-gDa could trigger high levels of mucosal and systemic immune responses and would be potential candidates for developing PRV vaccines.

Introduction: Physiologically based pharmacokinetic (PBPK) models for the absorption, disposition, metabolism and excretion (ADME) of nicotine and its major metabolite cotinine in pregnant women (p-PBPK) are rare. The aim of this short research report is to present a p-PBPK model and its simulations for nicotine and cotinine clearance.Methods: The maternal-placental-fetal compartments of the p-PBPK model contain a total of 16 compartments representing major maternal and fetal organs and tissue groups. Qualitative and quantitative data of nicotine and cotinine disposition and clearance have been incorporated into pharmacokinetic parameters.Results: The p-PBPK model reproduced the higher clearance rates of nicotine and cotinine in pregnant women than non-pregnant women. Temporal profiles for their disposition in organs such as the brain were also simulated. Nicotine concentration reaches its maximum value within 2 min after an intravenous injection.Conclusion: The proposed p-PBPK model produces results consistent with available data sources. Further pharmacokinetic experiments are required to calibrate clearance parameters for individual organs, and for the fetus.

Traditional steganography methods often hide secret data by establishing a mapping relationship between secret data and a cover image or directly in a noisy area, but has a low embedding capacity. Based on the thought of deep learning, in this paper, we propose a new image steganography scheme based on a U-Net structure. First, in the form of paired training, the trained deep neural network includes a hiding network and an extraction network; then, the sender uses the hiding network to embed the secret image into another full-size image without any modification and sends it to the receiver. Finally, the receiver uses the extraction network to reconstruct the secret image and original cover image correctly. The experimental results show that the proposed scheme compresses and distributes the information of the embedded secret image into all available bits in the cover image, which not only solves the obvious visual cues problem, but also increases the embedding capacity.

To solve LWE-based proxy re-encryption schemes cannot achieve fine-grained access and low efficiency problem,a ciphertext-policy attribute-based proxy re-encryption scheme was proposed.The scheme based on linear secret sharing scheme,RLWE and attribute encryption could shorten the key size,reduce the ciphertext space and improve the efficiency of encryption and decryption.At the same time,the linear secret sharing matrix was used as an access matrix to meet the requirements of authorized person fine-grained commissioning control and to resist the collusion between the agent and the authorized person.In addition,the proposed scheme is shown to be secure under the ring learning with errors assumption in the standard model.

Abstract Background Peyer’s patches (PPs) can be considered as the immune site of the intestine. Within PPs, Dendritic cells (DCs) can uptake antigens from the gut lumen by extending dendrites into epithelium, and process it and then present to lymphocytes, which effectively antigen produces an immune response. Porcine epidemic diarrhea virus (PEDV) is the causative agent of porcine epidemic diarrhea (PED), an acute and highly contagious enteric viral disease. The interaction between inactivated porcine epidemic diarrhea virus and porcine monocyte-derived dendritic cells (Mo-DCs) has been reported. However, little is known about the interaction between inactivated PEDV and DCs in porcine PPs. Results In this study, for the first time we investigated the role of DCs in porcine PPs after oral administration inactivated PEDV. Firstly, a method to isolate DCs from porcine PPs was established, in which the purity of SWC3a+/MHC-II+ DCs was more than 90%. Our findings clearly indicate that DCs in porcine PPs after oral administration of inactivated PEDV not only stimulated the proliferation of allogeneic lymphocytes, but also secreted cytokines (IL-1, IL-4). Furthermore, the number of DCs and IgA+ cells in porcine intestinal mucosal significantly increased and the levels of anti-PEDV specific IgG antibody in the serum and SIgA antibody in the feces increased after oral administration inactivated PEDV. Conclusions Our findings indicate that oral administration of inactivated PEDV activate DCs in porcine Peyer’s patches and inactivated PEDV may be a useful and safe vaccine to trigger adaptive immunity.

Data hiding is the technique of embedding data into video or audio media. With the development of deep neural networks (DNN), the quality of images generated by novel data hiding methods based on DNN is getting better. However, there is still room for the similarity between the original images and the images generated by the DNN models which were trained based on the existing hiding frameworks to improve, and it is hard for the receiver to distinguish whether the container image is from the real sender. We propose a framework by introducing a key_img for using the over-fitting characteristic of DNN and combined with difference image grafting symmetrically, named difference image grafting deep hiding (DIGDH). The key_img can be used to identify whether the container image is from the real sender easily. The experimental results show that without changing the structures of networks, the models trained based on the proposed framework can generate images with higher similarity to original cover and secret images. According to the analysis results of the steganalysis tool named StegExpose, the container images generated by the hiding model trained based on the proposed framework is closer to the random distribution.

The value ranges of the number of output variables were determined respectively under the existence of multi-output rotation symmetric balanced functions and resilient functions with 2rinput variables.Based on the equivalence between the resilient functions and large sets of orthogonal arrays,some results on the construction and count of multi-output rotation symmetric balanced functions with 8 input variables were presented according to the different dimensions of output vectors,and construction and count of multi-output rotation symmetric 1-resilient functions with 8 input variables were also studied.Besides,constructions of multi-output rotation symmetric resilient functions are transformed into the problem of solving a system of equations.

In order to make computationally weak cloud tenants can reconstruct a secret with efficiency and fairness,a cloud outsourcing secret sharing scheme was proposed,which combined cloud outsourcing computation with secret sharing scheme.In the process of outsourcing secret sharing,cloud tenants just need a small amount of decryption and validation operations,while outsource expensive cryptographic operations to cloud service provider (CSP).The scheme,without complex interactive augment or zero-knowledge proof,could detect malicious behaviors of cloud tenants or cloud service providers.And the scheme was secure against covert adversaries.Finally,every cloud tenant was able to obtain the secret fairly and correctly.Security analysis and performance comparison show that scheme is safe and effective.

Porcine epidemic diarrhea virus (PEDV) can cause intestinal infection in neonatal piglets through the nasal cavity. A process in which CD3+ T cells carry PEDV plays a key role. However, the modes through which PEDV bridles CD3+ T cells as a vehicle for migration to the intestinal epithelium have not been clarified. In this study, we first demonstrated that PEDV could survive in blood-derived CD3+ T cells for several hours, depending on the multiplicity of infection. In addition, PEDV preferentially survived in CD4+ T cells over CD8+ T cells. Moreover, viral transmission was mediated by cell-to-cell contact between mesenteric lymph-node-derived CD3+ T cells, but did not occur in blood-derived CD3+ T cells. Following an increase in gut-homing integrin α4β7, blood-derived CD3+ T cells carrying PEDV migrated to the intestines via blood circulation and transferred the virus to intestinal epithelial cells through cell-to-cell contact in neonatal piglets. Our findings have significant implications for understanding PEDV pathogenesis in neonatal piglets, which is essential for developing innovative therapies to prevent PEDV infection.

The gut is one of the body’s major immune structures, and the gut mucosa, which contains intestinal epithelium and subepithelial immune cells, is the primary site for eliciting local immune responses to foreign antigens. Intestinal immune system development in pigs is a transitional period during birth and weaning. This study compares the morphological and immunological differences in the small intestine of neonatal and weaned piglets to potentially prevent intestinal infectious diseases in neonatal piglets. Histological analyses of weaned piglet intestines showed increased crypt depth, higher IEL count, and larger ileal Peyer’s patches compared with those of neonates. Additionally, the ileal villi of weaned piglets were longer than those of neonatal piglets, and claudin-3 protein expression was significantly higher in weaned than in neonatal piglets. The numbers of CD3+ T, goblet, and secretory cells were also higher in the small intestines of weaned piglets than in those of neonates. No significant differences were observed in the secretory IgA-positive cell number in the jejunum of weaned and neonatal piglets. The mRNA expression of most pattern recognition receptors genes in the duodenum and jejunum was higher in the weaned than neonatal piglets; however, the opposite was true in the ileum. The mRNA levels of IL-1β and TNF-α in the jejunal and ileal mucosa were higher in weaned piglets than in neonatal piglets. There were significantly fewer CD3+, CD4+, and CD8+ T cells from peripheral blood-mononuclear cells in neonatal piglets. Our study provides insights regarding the different immune mechanisms within the small intestines of 0- and 21-day-old piglets. Studies on the additional developmental stages and how differences in the small intestines affect the response of pigs to pathogens remain warranted.

Efficient large-scale and feasible industrial synthesis of the 1-oxacephem core structure from 6-aminopenicillanic acid (6-APA) has been reported for several decades. Via the industrial synthesis route, a byproduct (compound 9) containing a butenolide unit was purified and characterized by NMR and HRMS in this work. It is worth noting that compound 9 is an entirely new compound. Additionally, a plausible mechanism and effects on the formation of 9 by different Lewis acids were proposed. The discovery of compound 9 could improve the purity of this feasible industrial synthesis and provide considerable cost savings.

The performance of mobile opportunistic networks mainly relies on collaboration among nodes. Thus far, researchers have ignored the influence of node sociality on the incentive process, leading to poor network performance. Considering the fact that followers always imitate the behavior of superstars, this paper proposes FollowMe, which integrates the social importance of nodes with evolutionary game theory to improve the collaborative behavior of nodes. First, we use the prisoner’s dilemma model to establish the matrix of game gains between nodes. Second, we introduce the signal reference as a game rule between nodes. The number of nodes choosing different strategies in a game round is used to calculate the cumulative income of the node in combination with the probability formula. Finally, the Fermi function is used to determine whether the node updates the strategy. The simulation results show that, compared with the random update rule, the proposed strategy is more capable of promoting cooperative behavior between nodes to improve the delivery rate of data packets.

The original article [1] contained an error whereby the leftmost graph in Fig. 1A mistakenly had its x-axis labelled as ‘CFST’; this has now been corrected to ‘CFSE’.