Search

Abstract Objective To explore the effects of tube voltage, radiation dose and adaptive statistical iterative reconstruction (ASiR-V) strength level on the detection and characterization of pulmonary nodules by an artificial intelligence (AI) software in ultra-low-dose chest CT (ULDCT). Materials and methods An anthropomorphic thorax phantom containing 12 spherical simulated nodules (Diameter: 12 mm, 10 mm, 8 mm, 5 mm; CT value: -800HU, -630HU, 100HU) was scanned with three ULDCT protocols: Dose-1 (70kVp:0.11mSv, 100kVp:0.10mSv), Dose-2 (70kVp:0.34mSv, 100kVp:0.32mSv), Dose-3 (70kVp:0.53mSv, 100kVp:0.51mSv). All scanning protocols were repeated five times. CT images were reconstructed using four different strength levels of ASiR-V (0%=FBP, 30%, 50%, 70%ASiR-V) with a slice thickness of 1.25 mm. The characteristics of the physical nodules were used as reference standards. All images were analyzed using a commercially available AI software to identify nodules for calculating nodule detection rate (DR) and to obtain their long diameter and short diameter, which were used to calculate the deformation coefficient (DC) and size measurement deviation percentage (SP) of nodules. DR, DC and SP of different imaging groups were statistically compared. Results Image noise decreased with the increase of ASiR-V strength level, and the 70 kV images had lower noise under the same strength level (mean-value 70 kV: 40.14 ± 7.05 (dose 1), 27.55 ± 7.38 (dose 2), 23.88 ± 6.98 (dose 3); 100 kV: 42.36 ± 7.62 (dose 1); 30.78 ± 6.87 (dose 2); 26.49 ± 6.61 (dose 3)). Under the same dose level, there were no differences in DR between 70 kV and 100 kV (dose 1: 58.76% vs. 58.33%; dose 2: 73.33% vs. 70.83%; dose 3: 75.42% vs. 75.42%, all p > 0.05). The DR of GGNs increased significantly at dose 2 and higher (70 kV: 38.12% (dose 1), 60.63% (dose 2), 64.38% (dose 3); 100 kV: 37.50% (dose 1), 59.38% (dose 2), 66.25% (dose 3)). In general, the use of ASiR-V at higher strength levels (> 50%) and 100 kV provided better (lower) DC and SP. Conclusion Detection rates are similar between 70 kV and 100 kV scans. The 70 kV images have better noise performance under the same ASiR-V level, while images of 100 kV and higher ASiR-V levels are better in preserving the nodule morphology (lower DC and SP); the dose levels above 0.33mSv provide high sensitivity for nodules detection, especially the simulated ground glass nodules.

Cutaneous pseudolymphoma is a type of reactive lymphoid hyperplasia that pathologically and/or clinically mimics cutaneous lymphoma. It has a variety of pathogenic factors. However, in many cases, no etiology can be identified. The histopathological findings of cutaneous pseudolymphoma can only be used as the basis for suspected diagnosis. Clinical data, further diagnostic tests and follow-up are needed to confirm the diagnosis. This article reports three cases of cutaneous pseudolymphoma, with different etiology, clinical manifestations and treatment methods. The purpose of this article is to emphasize that the etiology and clinical manifestations of cutaneous pseudolymphoma are diverse, and targeted treatment strategies and long-term follow-up are needed.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates known as Lewy bodies. MicroRNA-7 (miR-7) targets the gene SNCA, which encodes α-synuclein, reducing its expression and alleviating neuronal damage in PD. Regulating the post-transcriptional levels of α-synuclein through miR-7 effectively inhibits its production. Herein, we use nanodiamonds as carriers to deliver miR-7 (N-7), which can effectively protect dopaminergic neurons. Dopaminergic neurons efficiently take up N-7 and express miR-7. N-7 inhibits the expression of α-synuclein, reduces oxidative stress and restores dopamine levels effectively. These findings suggest that nanocomposites have significant potential in treating PD.

The emergence and spread of Acinetobacter baumannii pose a severe threat to public health, highlighting the urgent need for the next generation of therapeutics due to its increasing resistance to existing antibiotics. BfmR, a response regulator modulating virulence and antimicrobial resistance, shows a promising potential as a novel antimicrobial target. Developing BfmR inhibitors may propel a new therapeutic direction for intractable infection of resistant strains. In this study, we conducted a structure-based hierarchical virtual screening pipeline combining molecular docking, molecular dynamic simulation, and MM/GBSA calculation to sift the Specs chemical library and finally discover three novel potential BfmR inhibitors. The three hits can reduce the MIC of meropenem for the carbapenem-resistant Acinetobacter baumannii (CRAB) strain ZJ06. Similar to the BfmR knockout strain, Cmp-98 was demonstrated to downregulate the expression of K locus genes, indicating it as a BfmR inhibitor. Bacteria underwent harmful morphological changes after treatment with these inhibitors. Molecular dynamic simulations found that all the hits tend to dynamically bind to different positions of the phosphorylation site of BfmR. Wherein we identified a potential inhibitory-binding cleft, beside a possible activated binding cleft at the edge of the phosphorylation site. Restraining the ligand binding poses may help exert inhibitory effects. This study reports a group of new scaffold BfmR inhibitors, offering new insights for novel antibiotic therapeutics against CRAB.

Abstract Background Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. Methods In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. Results We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48–72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. Conclusions In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.

Abstract A pressing challenge in spatially resolved transcriptomics (SRT) is to benchmark the computational methods. A widely-used approach involves utilizing simulated data. However, biases exist in terms of the currently available simulated SRT data, which seriously affects the accuracy of method evaluation and validation. Herein, we present scCube ( https://github.com/ZJUFanLab/scCube ), a Python package for independent, reproducible, and technology-diverse simulation of SRT data. scCube not only enables the preservation of spatial expression patterns of genes in reference-based simulations, but also generates simulated data with different spatial variability (covering the spatial pattern type, the resolution, the spot arrangement, the targeted gene type, and the tissue slice dimension, etc.) in reference-free simulations. We comprehensively benchmark scCube with existing single-cell or SRT simulators, and demonstrate the utility of scCube in benchmarking spot deconvolution, gene imputation, and resolution enhancement methods in detail through three applications.

Sodium-glucose cotransporter 2 inhibitors are a class of glucose-lowering drugs known for robust cardiovascular protective properties. However, the side effects induced by Sodium-glucose cotransporter 2 inhibition limit application in cardiovascular medicine. Our prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, we showed that the glyceraldehyde derivative, JX22, developed by scaffold hopping from empagliflozin, exhibits a superior cardiomyocyte protective effect, albeit with increased cytotoxicity compared to empagliflozin. In the current study systematic structural modifications of JX22 were performed to enhance anti-heart failure efficacy and safety, while reducing glucose-lowering activity. Twenty glyceraldehyde-based derivatives were synthesized and compound 12 emerged as an optimal candidate by exhibiting an improved cytoprotective effect compared to JX22. Compound 12 significantly inhibited the activity of NHE1 on the myocardial membrane, thereby maintaining intracellular ion homeostasis. In vivo efficacy results demonstrated that compound 12 at 10 mg/kg significantly ameliorated cardiac dysfunction, myocardial fibrosis, and exercise tolerance in isoproterenol-induced heart failure mice without a glucose-lowering effect. Furthermore, compound 12 exhibited favorable safety profiles in single-dose toxicity and hERG inhibition tests, along with promising pharmacokinetic properties in mice. The current study not only underscores the potential of compound 12 for further investigation but also highlights the effectiveness of the scaffold hopping strategy.

Abstract Background Small extracellular vesicles (sEVs) mediate intercellular communication that contributes to hepatocellular carcinoma (HCC) progression via multifaceted pathways. The success of cell entry determines the effect of sEV on recipient cells. Here, we aimed to delineate the mechanisms underlying the uptake of sEV in HCC. Methods Macropinocytosis was examined by the ability of cells to internalize dextran and sEV. Macropinocytosis was analyzed in Na(+)/H(+) exchanger 7 (NHE7)‐knockdown and ‐overexpressing cells. The properties of cells were studied using functional assays. pH biosensor was used to evaluate the intracellular and endosomal pH. The expression of NHE7 in patients’ liver tissues was examined by immunofluorescent staining. Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7. Results The data revealed that macropinocytosis controlled the internalization of sEVs and their oncogenic effect on recipient cells. It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non‐metastatic HCC cells. Attenuation of macropinocytic activity by 5‐(N‐ethyl‐N‐isopropyl)‐amiloride (EIPA) limited the entry of sEVs and compromised cell aggressiveness. Mechanistically, we delineated that high level of NHE7, a sodium‐hydrogen exchanger, alkalized intracellular pH and acidized endosomal pH, leading to the maturation of macropinosomes. Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis. Clinically, NHE7 expression was upregulated and linked to dismal prognosis of HCC. Conclusions This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells. Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC.

Background: A. baumannii is an important and common clinical pathogen, especially in the intensive care unit (ICU). This study aimed to characterize one hypervirulent A. baumannii strain in a patient with community-acquired pneumonia and herpes simplex type 1 virus infection. Methods: Minimum inhibitory concentrations (MICs) were determined using the Kirby-Bauer (K-B) and broth microdilution methods. Galleria mellonella infection model experiment was conducted. Whole-genome sequencing (WGS) was performed using the Illumina and Nanopore platforms. The resistance and virulence determinants were identified using the ABRicate program with ResFinder and the VFDB database. The capsular polysaccharide locus (K locus) and lipooligosaccharide outer core locus (OC locus) were identified using Kleborate with Kaptive. Phylogenetic analyses were conducted using the BacWGSTdb server. Results: A. baumannii XH2146 strain belongs to ST10Pas and ST447Oxf. The strain was resistant to cefazolin, ciprofloxacin, and trimethoprim/sulfamethoxazole (TMP-SMX). Bautype and Kaptive analyses showed that XH2146 contains OCL2 and KL49. WGS analysis revealed that the strain harbored blaADC-76, blaOXA-68, ant(3′’)-IIa, tet(B), and sul2. Notably, tet(B) and sul2, both were located within a 114,700-bp plasmid (designated pXH2146–1). Virulence assay revealed A. baumannii XH2146 possessed higher virulence than A. baumannii AB5075 at 12 h. Comparative genomic analysis showed that A. baumannii ST447 strains were mainly isolated from the USA and exhibited a relatively close genetic relationship. Importantly, 11 strains were observed to carry blaOXA-58; blaOXA-23 was identified in 11 isolates and three ST447 A. baumannii strains harbored blaNDM-1. Conclusions: Early detection of community-acquired hypervirulent Acinetobacter baumannii strains is recommended to prevent their extensive spread in hospitals.

With the development of intelligent protective wearable equipment, flexible materials with impact resistance have become a focus of attention. Shear stiffening gel (SSG) is a flexible smart material that can perceive external force loads and generate mechanical responses, boasting exceptional properties like fast response, adaptability, and self-healing. Since the SSG can absorb a large amount of energy during dynamic impact, it shows remarkable advantages for safety protection applications. During the past decade, there has been strong interests in the research community on the SSG composites and their various applications in cutting-edge fields. In this review, we summarize the recent research achievements of SSG composite, by focusing on the improved properties, enhanced functions, and manifold structures. Meanwhile, we also discuss the practical applications of SSG composite in battery protection, vibration control, intelligent sensing, wearable safety protection, and triboelectric nanogenerator (TENG). Finally, we propose the prospects and challenges for the further development and application of SSG composite in the future.

NH2-MIL-125(Ti) is a Ti-MOFs (MOFs: metal-organic frameworks) with high adsorption properties and is therefore widely used for wastewater purification. However, the powdered MOF material suffers from the disadvantages of being difficult to separate and being potentially wasted due to easy agglomeration, which limits its application in practical applications. Here, a mesoporous Ti-MOF/polymer (PEG, PVA, and PAM) monolithic material was prepared by freeze casting in liquid nitrogen (−196 °C) as an adsorbent for wastewater remediation. The composites could be easily picked up with tweezers and used for recovery tests. Characterization results such as XRD, BET, FT-IR, and SEM proved the successful synthesis of Ti-MOF/polymer. Adsorption tests using 100 mg/L methylene blue (MB) simulated wastewater showed that the Ti-MOF/PEG monolithic material had the best adsorption capacity. The order of adsorption was Ti-MOF@PEG10 (747.4 mg/g) > Ti-MOF@PVA10 (687.4 mg/g) > Ti-MOF@PAM10 (633.7 mg/g) > NH2-MIL-125(Ti) (571.4 mg/g). The effects of polymer dosage, different pollutants (methylene blue, methyl orange, indigo, actual textile wastewater), pH, anions, and cations on the adsorption effect of Ti-MOF/polymer were also investigated. It was demonstrated that all the above pollutants were well adsorbed by this Ti-MOF/polymer in the pH range 3–9. The adsorption isotherms and kinetic data are fully consistent with the Langmuir and pseudo-secondary models. This suggests that the adsorption between the pollutant and the adsorbent is a chemical interaction. Thermodynamic studies indicate that the adsorption process is exothermic and spontaneous. This work provides the potential methods to fabricate Ti-MOF/polymer monolith to avoid the pollution from powdery adsorbents that could be practical applications.

Abstract In histopathology, doctors identify diseases by characterizing abnormal cells and their spatial organization within tissues. Polarization microscopy and supervised learning have been proved as an effective tool for extracting polarization parameters to highlight pathological features. Here, we present an alternative approach based on unsupervised learning to group polarization-pixels into clusters, which correspond to distinct pathological structures. For pathological samples from different patients, it is confirmed that such unsupervised learning technique can decompose the histological structures into a stable basis of characteristic microstructural clusters, some of which correspond to distinctive pathological features for clinical diagnosis. Using hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) samples, we demonstrate how the proposed framework can be utilized for segmentation of histological image, visualization of microstructure composition associated with lesion, and identification of polarization-based microstructure markers that correlates with specific pathology variation. This technique is capable of unraveling invisible microstructures in non-polarization images, and turn them into visible polarization features to pathologists and researchers.

Dongting Lake is the second largest freshwater lake in China, located in the middle reaches of the Yangtze River. Since the 21st century, it has faced intensified human activities, particularly the Three Gorges Dam impoundment and sand mining. The water quality of Dongting Lake has significantly changed due to human activities and climate change. Currently, quantitative studies on the spatial–temporal variations of total suspended matter (TSM) during Dongting Lake’s dry season and the human impacts on its concentration are lacking. This study utilizes Landsat-5 TM and Landsat-8 OLI data to estimate the changes in TSM concentration during the dry season from 1986 to 2021, analyzing their spatial–temporal variations and driving mechanisms. By evaluating the atmospheric calibration accuracy and model precision metrics, we select a model based on the ratio of red to green band, achieving an R2 of 0.84, RMSE of 18.94 mg/L, and MRE of 27.32%. Applying this model to the images, we map the distribution of the TSM concentration during the dry season from 1986 to 2021, analyzing its spatial pattern and inter-annual variation, and further investigate the impacts of natural factors and human activities on the TSM concentration. Our results show the following: (1) From 1986 to 2021, the TSM concentration during the dry season ranges from 0 to 200 mg/L of Dongting Lake, with an area-wide average value between 41.61 and 75.44 mg/L. (2) The TSM concentration from 1986 to 2021 is significantly correlated with the water level. Before 2006, it correlates positively, but no significant correlation exists from 2006 onward. (3) From 2006 onward, the mean TSM concentration is notably decreased compared to that before 2006, likely due to the Three Gorges Dam, while our analysis indicates a significant positive correlation between the TSM concentration and sand mining intensity during this period. This study highlights the influence of the Three Gorges Dam and sand mining on the TSM concentration in Dongting Lake during the dry season, providing valuable insights for related research on similar lakes.

Cigarette combustion has the potential to generate over 7000 chemicals, the majority of which are reactive free radicals that are known to trigger pro-inflammatory and carcinogenic responses. Numerous contemporary investigations have proposed that the pathophysiological and cellular mechanisms underlying the release of extracellular vesicles (EVs) in response to cigarette smoke (CS) may serve as potential pathways for CS-induced pathogenesis, while also reflecting the physiological state of the originating cells. This review provides a concise overview of the pathophysiological mechanisms linked to CS-induced EVs in various lung diseases, including chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, and pulmonary hypertension. Additionally, it explores the potential and prospects of EVs as diagnostic biomarkers for CS-related lung diseases.

Motion artifacts are a major challenge in the in vivo application of catheter-based cardiac imaging modalities. Gating is a critical tool for suppressing motion artifacts. Electrocardiogram (ECG) gating requires a trigger device or synchronous ECG recordings for retrospective analysis. Existing retrospective software gating methods extract gating signals through separate steps based on changes in vessel morphology or image features, which require a high computational cost and are prone to error accumulation. In this paper, we report on an end-to-end unsupervised learning framework for retrospective image-based gating (IBG) of catheter-based intracoronary images, named IBG Network. It establishes a direct mapping from a continuously acquired image sequence to a gated subsequence. The network was trained on clinical data sets in an unsupervised manner, addressing the difficulty of obtaining the gold standard in deep learning-based motion suppression techniques. Experimental results of in vivo intravascular ultrasound and optical coherence tomography sequences show that the proposed method has better performance in terms of motion artifact suppression and processing efficiency compared with the state-of-the-art nonlearning signal-based and IBG methods.

Abstract The purpose of this study was to evaluate the feasibility of opportunistic screening for osteoporosis in postmenopausal females using the dual-energy CT(DECT)-derived hydroxyapatite (HAP) concentration and CT value of L1-vertebra. 239 consecutive postmenopausal female patients were enrolled and underwent both chest DECT and Dual energy X-ray absorptiometry (DXA). According to the T-score of the 1st lumbar vertebra on DXA, patients were divided into the osteoporosis group (T $$\le$$ ≤ − 2.5, n = 112) and non-osteoporosis group (T $$>$$ > − 2.5, n = 127). The HAP values of the 1st lumbar vertebra were measured from the coronal-view HAP(Fat)-based material decomposition(MD) images, and CT values were measured on the 75 keV monochromatic image. The cutoff values of using HAP and CT value for diagnosing osteoporosis were obtained by drawing receiver operating characteristic (ROC) curves. Both HAP and CT value of the 1st lumbar vertebra had moderate-high correlation with bone-mineral-density measurement on DXA (HAP, r = 0.614; CT value, r = 0.625; all p

Acinetobacter baumannii is an important nosocomial pathogen. Upon colonizing a host, A. baumannii are subjected to selective pressure by immune defenses as they adapt to the host environment. However, the mechanism of this pathoadaptation is unknown. Here, we established an in vitro system to evolve A. baumannii driven by the continuous selective pressure exerted by epithelial cells, and we used a combination of experimental evolution, phenotypic characterization and multi-omics analysis to address the underlying mechanism. When continuously exposed to selective pressure by pulmonary epithelial cells, A. baumannii showed ptk mutation-mediated mucoid conversion (reduced adhesion and increased anti-phagocytic ability) by enhancement of capsular exopolysaccharide chain length; rsmG mutation-mediated deficiency of 7-methylguanosine modification in the 524th nucleotide of 16S rRNA, which increased ribosome translation efficiency; and rnaseI mutation-mediated changes in outer membrane permeability and efflux pump expression. Together, these mutations altered susceptibility to a variety of antimicrobial agents, including the novel antibiotic cefiderocol, by regulating siderophore and siderophore-receptor biosynthesis. In conclusion, pulmonary epithelial cells modulate A. baumannii pathoadaptation, implicating the host–microbe interaction in the survival and persistence of A. baumannii.

Abstract Background Posttranscriptional processing of precursor mRNAs contributes to transcriptome and protein diversity and gene regulatory mechanisms in eukaryotes. However, this posttranscriptional mechanism has not been studied in the marine macroalgae Gracilariopsis lemaneiformis, which is the most cultivated red seaweed species in China. Results In the present study, third-generation sequencing (Pacific Biosciences single-molecule real-time long-read sequencing, SMRT-Seq) was used to sequence the full-length transcriptome of G. lemaneiformis to identify alternatively spliced transcripts and alternative polyadenylation (APA) sites in this species. RNAs were isolated from G. lemaneiformis under various treatments including abiotic stresses and exogenous phytohormones, and then equally pooled for SMRT-Seq. In summary, 346,544 full-length nonchimeric reads were generated, from which 13,630 unique full-length transcripts were obtained in G. lemaneiformis. Compared with the known splicing events in the gene models, more than 3000 new alternative splicing (AS) events were identified in the SMRT-Seq reads. Additionally, 810 genes were found to have poly (A) sites and 91 microRNAs (miRNAs), 961 long noncoding RNAs and 1721 novel genes were identified in G. lemaneiformis. Moreover, validation experiments showed that abiotic stresses and phytohormones could induce some specific AS events, especially intron retain isoforms, cause some alterations to the relative ratios of transcripts annotated to the same gene, and generate novel 3′ ends because of differential APA. The growth of G. lemaneiformis was inhibited by Cu stress, while this inhibition was alleviated by ACC treatment. RNA-Seq analysis further revealed that 211 differential alternative splicing (DAS) events and 142 DAS events was obtained in CK vs Cu and Cu vs Cu + ACC, respectively, suggesting that AS of functional genes could be regulated by Cu stress and ACC. Compared with Cu stress, the expression of transcripts with DAS events mainly involved in the carbon fixation in photosynthetic organisms and oxidative phosphorylation pathway was upregulated in Cu + ACC treatment, revealing that ACC alleviated the growth inhibition by Cu stress by increasing carbon fixation and oxidative phosphorylation. Conclusions Our results provide the first comprehensive picture of the full-length transcriptome and posttranscriptional mechanism in red macroalgae, including transcripts that appeared in the presence of common abiotic stresses and phytohormones, which will improve the gene annotations of Gracilariopsis and contribute to the study of gene regulation in this important cultivated seaweed.

Cognitive impairment frequently coexists with diabetes. Trelagliptin is a once-weekly taking selective dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-term effective hypoglycemic medicine; nonetheless, its effects for the treatment of diabetes-related cognitive impairment have only sometimes been explored. In this study, a DM model was built using streptozotocin (STZ) and a high-fat diet (HFD). The morris water maze test on DM rats revealed a considerably reduced capacity for spatial learning and memory, but trelagliptin was able to restore function. Trelagliptin could lower the mRNA expression of inflammatory factors such IL-1β, TNF-α, and IL-6 in DM rats. It could also reduce the ratio of p-IKKα/IKKα, and the immunofluorescence result of NF-κB also demonstrated a drop. Trelagliptin partially restored dendritic spines and prevented the loss or shrinkage of neurons, respectively, according to the results of Nissl's staining and golgi staining. Furthermore, PI3K/Akt/GSK-3β has been activated, and synaptic plasticity has been modified during this process. In conclusion, trelagliptin improved the cognitive lesion in DM rats by suppressing the activation of the inflammatory route and by activating the PI3K/Akt/GSK-3β pathway at the same time, as well as interacting with the pathways that protect neurons, which still need further research.

Ovarian cancer is one of the most aggressive and heterogeneous female tumors in the world, and serous ovarian cancer (SOC) is of particular concern for being the leading cause of ovarian cancer death. Due to its clinical and biological complexities, ovarian cancer is still considered one of the most difficult tumors to diagnose and manage. In this study, three datasets were assembled, including 30 cases of serous cystadenoma (SCA), 30 cases of serous borderline tumor (SBT), and 45 cases of serous adenocarcinoma (SAC). Mueller matrix microscopy is used to obtain the polarimetry basis parameters (PBPs) of each case, combined with a machine learning (ML) model to derive the polarimetry feature parameters (PFPs) for distinguishing serous ovarian tumor (SOT). The correlation between the mean values of PBPs and the clinicopathological features of serous ovarian cancer was analyzed. The accuracies of PFPs obtained from three types of SOT for identifying dichotomous groups (SCA versus SAC, SCA versus SBT, and SBT versus SAC) were 0.91, 0.92, and 0.8, respectively. The accuracy of PFP for identifying triadic groups (SCA versus SBT versus SAC) was 0.75. Correlation analysis between PBPs and the clinicopathological features of SOC was performed. There were correlations between some PBPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], rqcross, [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]) and clinicopathological features, including the International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grading, preoperative ascites, malignant ascites, and peritoneal implantation. The research showed that PFPs extracted from polarization images have potential applications in quantitatively differentiating the SOTs. These polarimetry basis parameters related to the clinicopathological features of SOC can be used as prognostic factors.

Mueller matrix imaging is emerging for the quantitative characterization of pathological microstructures and is especially sensitive to fibrous structures. Liver fibrosis is a characteristic of many types of chronic liver diseases. The clinical diagnosis of liver fibrosis requires time-consuming multiple staining processes that specifically target on fibrous structures. The staining proficiency of technicians and the subjective visualization of pathologists may bring inconsistency to clinical diagnosis. Mueller matrix imaging can reduce the multiple staining processes and provide quantitative diagnostic indicators to characterize liver fibrosis tissues. In this study, a fiber-sensitive polarization feature parameter (PFP) was derived through the forward sequential feature selection (SFS) and linear discriminant analysis (LDA) to target on the identification of fibrous structures. Then, the Pearson correlation coefficients and the statistical T-tests between the fiber-sensitive PFP image textures and the liver fibrosis tissues were calculated. The results show the gray level run length matrix (GLRLM)-based run entropy that measures the heterogeneity of the PFP image was most correlated to the changes of liver fibrosis tissues at four stages with a Pearson correlation of 0.6919. The results also indicate the highest Pearson correlation of 0.9996 was achieved through the linear regression predictions of the combination of the PFP image textures. This study demonstrates the potential of deriving a fiber-sensitive PFP to reduce the multiple staining process and provide textures-based quantitative diagnostic indicators for the staging of liver fibrosis.

Abstract Whole tumor cells expressing a wide array of tumor antigens are considered as a highly promising source of antigens for cancer vaccines. However, simultaneously preserving the antigen diversity, improving immunogenicity, and eliminating the potential tumorigenic risk of whole tumor cells are highly challenging. Inspired by the recent progress in sulfate radical‐based environmental technology, herein, an advanced oxidation nanoprocessing (AONP) strategy is developed for boosting the immunogenicity of whole tumor cells. The AONP is based on the activation of peroxymonosulfate by ZIF‐67 nanocatalysts to produce SO4−∙ radicals continuously, leading to sustained oxidative damage to tumor cells and consequently extensive cell death. Importantly, AONP causes immunogenic apoptosis as evidenced by the release of a series of characteristic damage associated molecular patterns and at the same time maintains the integrity of cancer cells, which is critical to preserve the cellular components and thus maximize the diversity of antigens. Finally, the immunogenicity of AONP‐treated whole tumor cells is evaluated in a prophylactic vaccination model, demonstrating significantly delayed tumor growth and increased survival rate of live tumor‐cell‐challenged mice. It is expected that the developed AONP strategy would pave the way to develop effective personalized whole tumor cell vaccines in future.

Abstract Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV‐clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme‐linked immunosorbent assay (ELISA). The functions of sEV‐CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV‐CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans‐endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV‐CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP‐8356, was tested in a mouse model of patient‐derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV‐CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP‐8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV‐CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.

Cladophora qinghaiensis, an endemic species of Cladophora in saltwater lakes, was scientifically named in 2021 (hereafter referred to as Cladophora). Cladophora exists in different morphologies, including attached submerged Cladophora (AC), grown floating Cladophora (GFC), and death floating Cladophora (DFC). Previous satellite remote sensing has mainly focused on identifying floating algae. In this study, Qinghai Lake served as a case study, and a classification decision tree model (CDTM) was proposed. The model employed the chlorophyll spectral index (CSI) and the normalized difference vegetation index (NDVI) to differentiate AC, Floating Cladophora (FC), and water. Additionally, the floating Cladophora index (FCI) was introduced to further distinguish GFC and DFC within FC. The method was applicable to Sentinel-2 images from 2016–2023. Visual interpretation methods were used for Landsat series images from the summer months (July to September) to obtain the AC and FC. The results demonstrate that over the past 30 years, the areas inhabited by AC and FC have increased gradually. The three morphologies of Cladophora also exhibited seasonal variations, with growth observed annually in May–June, reaching peaks in August–September, and gradually declining in October. In addition, by combining factors such as water surface area and climatic factors, we analyzed the driving forces influencing the changes in Cladophora. In this research, AC and FC showed significant correlations with the water surface area, with correlation coefficients (r) of approximately 0.9 and 0.7, respectively. These new findings provide valuable insights regarding the spatiotemporal changes and underlying causes for different morphologies of Cladophora in global saline lakes.

Aquatic vegetation is an important component of aquatic ecosystems; therefore, the classification and mapping of aquatic vegetation is an important aspect of lake management. Currently, the decision tree (DT) classification method based on spectral indices has been widely used in the extraction of aquatic vegetation data, but the disadvantage of this method is that it is difficult to fix the threshold value, which, in turn, affects the automatic classification effect. In this study, Sentinel-2 MSI data were used to produce a sample set (about 930 samples) of aquatic vegetation in four inland lakes (Lake Taihu, Lake Caohai, Lake Honghu, and Lake Dongtinghu) using the visual interpretation method, including emergent, floating-leaved, and submerged vegetation. Based on this sample set, a DL model (Res-U-Net) was used to train an automatic aquatic vegetation extraction model. The DL model achieved a higher overall accuracy, relevant error, and kappa coefficient (90%, 8.18%, and 0.86, respectively) compared to the DT method (79%, 23.07%, and 0.77) and random forest (78%,10.62% and 0.77) when utilizing visual interpretation results as the ground truth. When utilizing measured point data as the ground truth, the DL model exhibited accuracies of 59%, 78%, and 91% for submerged, floating-leaved, and emergent vegetation, respectively. In addition, the model still maintains good recognition in the presence of clouds with the influence of water bloom. When applying the model to Lake Honghu from January 2017 to October 2023, the obtained temporal variation patterns in the aquatic vegetation were consistent with other studies. The study in this paper shows that the proposed DL model has good application potential for extracting aquatic vegetation data.

ABSTRACT The treatment of extensively drug-resistant (XDR) A. baumannii has emerged as a major problem. Tigecycline (TGC) and sulbactam (SUL) are both effective antibiotics against XDR A. baumannii. Here, we investigated the in-host evolution and mechanism of collateral sensitivity (CS) phenomenon in development of tigecycline resistance accompanied by a concomitant increase of sulbactam susceptibility. A total of four XDR A. baumannii strains were sequentially isolated from the same patient suffering from bacteremia. Core-genome multilocus sequence typing separated all the strains into two clusters. Comparative analysis of isolate pair 1 revealed that multiplication of blaOXA-23 within Tn2006 on the chromosome contributed to the change in the antimicrobial susceptibility phenotype of isolate pair 1. Additionally, we observed the emergence of CS to sulbactam in isolate pair 2, as demonstrated by an 8-fold increase in the TGC MIC with a simultaneous 4-fold decrease in the SUL MIC. Compared to the parental strain Ab-3557, YZM-0406 showed partial deletion in the two-component system sensor adeS. Reconstruction of the adeS mutant in Ab-3557 in situ suggested that TGC resistance and CS to SUL were mainly caused by the mutation of adeS. Overall, our study reported a novel CS combination of TGC and SUL in A. baumannii and further revealed a mechanism of CS attributed to the mutation of adeS. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii. IMPORTANCE Collateral sensitivity (CS) has become an increasingly common evolutionary trade-off during adaptive bacterial evolution. Here, we report a novel combination of tigecycline (TGC) resistance and CS to sulbactam (SUL) in A. baumannii. TGC and SUL are both effective antibiotics against XDR A. baumannii, and it is essential to reveal the mechanism of CS between TGC and SUL. In our study, the partial deletion of adeS, a two-component system sensor, was confirmed to be the key factor contributing to this CS phenomenon. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii.

Objective No consensus exists regarding the association between pemphigus and thyroid disease. To explore the relationship between the two conditions by synthesizing the existing data. Methods We performed this review based on PubMed, Embase and Web of Science (from inception to 2022) and used the Newcastle-Ottawa scale for assessing the quality of studies. The outcome was represented by pooled odds ratios (ORs) with 95% confidence intervals (CI). And the publication bias and sensitivity analyses were developed. Results Our analyze finally included six studies containing 17,567 pemphigus patients. Overall, we revealed that pemphigus is significantly associated with hypothyroidism (OR 1.70, 95% CI 1.54–1.87), while not with thyroid cancer (OR 0.93, 95% CI 0.41–2.11) and autoimmune thyroid disease (AITD) (OR 1.64, 95% CI 0.91–2.95). In subgroup analyses, pemphigus was also not associated with Graves’ disease (OR 0.97, 95% CI 0.63–1.49) and Hashimoto’s thyroiditis (OR 1.32, 95% CI 0.88–1.97). Conclusion Our results reveal a significant association between pemphigus and hypothyroidism. Considering other relevant studies, we also speculate that the prevalence of AITD is higher in pemphigus patients than in the general population.

Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of Cynoscion microlepidotus and Gadus morhua. The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc4S-β1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA2S-α1,3-GalNAc4S-β1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-β1,3-GalNAc4S6S-β1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC50 of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.

The European Space Agency (ESA) developed the Sentinel-2 Multispectral Imager (MSI), which offers a higher spatial resolution and shorter repeat coverage, making it an important source for the remote-sensing monitoring of water bodies. Atmospheric correction is crucial for the monitoring of water quality. To compare the applicability of seven publicly available atmospheric correction processors (ACOLITE, C2RCC, C2XC, iCOR, POLYMER, SeaDAS, and Sen2Cor), we chose complex and diverse lakes in Qinghai Province, China, as the research area. The lakes were divided into three types based on the waveform characteristics of Rrs: turbid water bodies (class I lakes) represented by the Dabusun Lake (DBX), clean water bodies (class II lakes) represented by the Qinghai Lake (QHH), and relatively clean water bodies (class III lakes) represented by the Longyangxia Reservoir (LYX). Compared with the in situ Rrs, it was found that for the DBX, the Sen2Cor processor performed best. The POLYMER processor exhibited a good performance in the QHH. The C2XC processor performed well with the LYX. Using the Sen2Cor, POLYMER, and C2XC processors for classes I, II, and III, respectively, compared with the Sentinel-3 OLCI Level-2 Water Full Resolution (L2-WFR) products, it was found that the estimated Rrs from the POLYMER had the highest consistency. Slight deviations were observed in the estimation results for both the Sen2Cor and C2XC.

With the increasing connectivity between multiple smart devices in the Internet of Vehicles, privacy and security have become stringent threats due to unauthorized access. To overcome this issue, designing continuous authentication systems has become an important research topic because of the advantages of continuous monitoring of users after the initial access to the smart devices. Unfortunately, the existing systems are based on a third-party centralized structure, and most of them suffer storage pressure on equipment, thus resulting in significant security hazards and limited performance. In this paper, we propose a multistage continuous authentication system based on blockchain technology and the IPFS, which achieves decentralization and reduces storage pressure. In the first stage of authentication, we adopt Hyperledger Fabric to implement the underlying technical architecture of the blockchain to enhance the security and reliability of identity parameters. The preoutputs of the first-stage authentication are compared against behavioral biometric characteristics stored in the IPFS that aim to accomplish the final authentication. In particular, we use fuzzy extractors to deal with behavioral biometric feature templates, thus solving the privacy problem caused by user information leakage. To evaluate the security of our system, we prove the correctness of the communication protocol and two-way authentication of the scheme using BAN Logic. Furthermore, we use Hyperledger Caliper to analyze the impact of the sending rate of authentication requests on various performance parameters such as throughput, memory, and CPU utilization of the authentication system. Security and experimental results show that: (i) We solve the problem of centralized authentication and can resist replay attacks. (ii) Our scheme can maintain high throughput and effectively reach consensus. Compared to related works, the throughput is improved by 8.6%.

AbstractIn Saccharomyces cerevisiaecdc13-2MEC1cdc13-2cdc13-2

Abstract Background Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. Methods Follicular fluid, granulosa cells and peripheral venous blood were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. Results Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). Conclusions Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that elevation of SAA1 in the ovary promotes the development of IR in granulosa cells of PCOS patients.

Land subsidence is an environmental geological phenomenon with slowly decreasing ground elevation, The North China Plain is one of the areas with the most serious land subsidence in China, and Guangrao County is one of the subsidence centers. This paper is based on the hydrogeological and engineering geological data of Guangrao County, the groundwater monitoring data for many years and the land subsidence monitoring data, systematically analyzes the dynamic characteristics of groundwater, the distribution and evolution of land subsidence, and the correlation between groundwater exploitation and land subsidence development in different layers of this area. Based on Biot porous medium consolidation theory, establishes a three-dimensional fluid solid coupling numerical model of land subsidence in Guangrao County, restores the development process of land subsidence, predicts and analyzes the subsidence evolution law under different groundwater exploitation schemes, and proposes targeted prevention and control measures. The research results show that: the shallow groundwater forms a cone of depression with Guangbei Salt Field as the center, and the deep groundwater forms an elliptical regional cone of depression with the urban area as the center. The ground is gradually formed two small settlement areas with the urban area of Guangrao County and Guangbei Salt Field as the settlement center, and there is a trend of interrelated expansion. The three-dimensional fluid solid coupling model of land subsidence accurately restored the development process of land subsidence in the study area, predicted that under the current groundwater exploitation conditions, by 2040, the settlement of Guangrao urban settlement center will increase to 1,350 mm, forming a large regional funnel centered around the urban area, and gradually developing and expanding around. Prohibition of groundwater exploitation in the main funnel area is a more reasonable and effective exploitation plan to prevent the development of land subsidence.

To improve communication stability, more wireless devices transmit multi-modal signals while operating. The term ‘modal’ refers to signal waveforms or signal types. This poses challenges to traditional specific emitter identification (SEI) systems, e.g., unknown modal signals require extra open-set mode identification; different modes require different radio frequency fingerprint (RFF) extractors and SEI classifiers; and it is hard to collect and label all signals. To address these issues, we propose an enhanced SEI system consisting of a universal RFF extractor, denoted as multiple synchrosqueezed wavelet transformation of energy unified (MSWTEu), and a new generative adversarial network for feature transferring (FTGAN). MSWTEu extracts uniform RFF features for different modal signals, FTGAN transfers different modal features to a recognized distribution in an unsupervised manner, and a novel training strategy is proposed to achieve emitter identification across multi-modal signals using a single clustering method. To evaluate the system, we built a hybrid dataset, which consists of multi-modal signals transmitted by various emitters, and built a complete civil air traffic control radar beacon system (ATCRBS) dataset for airplanes. The experiments show that our enhanced SEI system can resolve the SEI problems associated with crossing signal modes. It directly achieves 86% accuracy in cross-modal emitter identification using an unsupervised classifier, and simultaneously obtains 99% accuracy in open-set recognition of signal mode.

Although chimeric antigen receptor T (CAR-T) cell therapy has been indicated to be effective in treating relapsed or refractory multiple myeloma (R/R MM), severe hematological toxicity (HT) remains an intractable issue. This study enrolled 54 patients with R/R MM following combined infusion of anti-CD19 and anti-BCMA CAR-T cells. The results showed that the rates of severe cytopenia were high, including severe neutropenia (28/54, 52%), severe anemia (15/54, 28%), and severe thrombocytopenia (18/54, 33%). Moreover, the incidence of prolonged HT (PHT) on Day 28 post-infusion was 52% (28/54), including 46% for severe neutropenia, 30% for severe anemia, and 31% for severe thrombocytopenia. Patients with PHT had a poorer median progression-free survival (PFS) and overall survival (OS) than patients without PHT (P=0.011; P=0.007). Furthermore, Cox regression analyses showed that PHT was an independent risk factor for PFS and OS. Univariate analyses showed that IFNγ (OR: 1.046; 95% CI: 1.002-1.093, P=0.042) and severe HT after lymphodepletion chemotherapy (OR: 0.082; 95% CI: 0.017-0.404; P=0.002) were independent risk factors for PHT. In conclusion, these results indicated that PHT was associated with poor outcomes following CAR-T-cell therapy in MM patients. Early detection and management of PHT would be beneficial for the prevention of life-threatening complications and improvement in the survival of patients after CAR-T-cell therapy.Clinical trial registrationThis trial was registered on 1 May 2017 at http://www.chictr.org.cn as ChiCTR-OIC-17011272.

Alopecia areata (AA) is a common inflammatory, non-cicatricial hair loss. At present, it is considered that its pathogenesis is an autoimmune disease specific to hair follicle organs mediated by T cells under the combined action of genetic and environmental factors. Treatment is challenging for children with severe AA who are resistant or intolerant to conventional treatment.Here, we treated a 3-year-old child with severe AA with microneedling combined with compound betamethasone. After 6 months of treatment, the patient’s condition was significantly improved, and most of the primary hair loss areas had hair regeneration.

Extracellular vesicles (EVs)-mediated epithelium-macrophage crosstalk has been proved to maintain lung homeostasis in cigarette smoke-induced lung diseases such as chronic obstructive pulmonary disease (COPD). In our previous study, we found that EVs derived from cigarette smoke extract (CSE) treated BEAS-2B promoted M1 macrophage polarization, which probably accelerated the development of inflammatory responses. Naringenin has been proved to suppress M1 macrophage polarization, but whether naringenin regulates macrophage polarization mediated by EVs has not been reported. In this study, we firstly found that EVs derived from naringenin and CSE co-treated BEAS-2B significantly inhibited the expression of CD86 and CD80 and the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and IL-12 in macrophage induced by EVs derived from CSE-treated BEAS-2B. Further research revealed that naringenin downregulated BEAS-2B-derived EVs miR-21-3p which targeted phosphatase and tensin homolog deleted on chromosome ten/protein kinase B (PTEN/AKT) cascade in macrophages and then suppressed M1 macrophage polarization. Subsequent proteomics suggested that naringenin decreased BEAS-2B-derived EVs poly ADP-ribose polymerase (PARP)1 expression thereby suppressing M1 macrophage polarization probably. Our study provides novel pharmacological references for the mechanism of naringenin in the treatment of cigarette smoke-induced lung inflammatory diseases.

Pulmonary epithelial barrier dysfunction is a critical pathophysiological process in pneumonia and associated invasive infections, such as those caused by Acinetobacter baumannii. However, the mechanisms underlying A. baumannii-induced pulmonary epithelial barrier dysfunction and bacterial translocation remain unclear. In this study, lungs of mice and A549 human epithelial cell monolayers were challenged with the A. baumannii wild-type strain and an outer membrane protein A (ompA) deletion strain. In addition, epithelial cells in culture were treated with purified OmpA protein or transfected with a eukaryotic expression vector encoding ompA (pCMV-ompA). Bacterial translocation across cell monolayers and intrapulmonary burden were measured, barrier function was evaluated in vivo and in vitro; cell migration ability was determined. The specific inhibitors C29 and JSH-23 were used to suppress the activity of Toll-like receptor 2 (TLR2) and of NF-κB, respectively. IQ-GTPase-activating protein 1 (IQGAP1) small interfering RNA was used to knock down endogenous IQGAP1 expression. In this work, we show that OmpA from A. baumannii increased the production of pro-inflammatory cytokines, remodeled the cytoskeleton, and internalized intercellular adherens junctions (AJs); these changes eventually induced pulmonary epithelial barrier dysfunction to promote bacterial translocation. IQGAP1-targeting small interfering RNA and chemical inhibition of TLR2 or NF-κB prevented high permeability of the pulmonary epithelial barrier. TLR2/NF-κB signaling was involved in OmpA-induced inflammation, IQGAP1-mediated OmpA-induced opening of the pulmonary epithelial barrier via cytoskeleton dynamic remodeling, and cellular redistribution of the major AJ protein, E-cadherin. These observations indicate that A. baumannii uses OmpA to overcome epithelial defences and cross the pulmonary epithelial barrier.

BackgroundSepsis-associated encephalopathy (SAE) has been identified as a frequent complication of sepsis, featured by an aberrant level of cognitive and affective functions. The present study is designed to explore the changes in functional connectivity (FC) of the hippocampus in rats with SAE utilizing resting-state functional magnetic resonance imaging (rs-fMRI).MethodsSprague-Dawley rats were randomly assigned to the SAE and control groups. We acquired rs-fMRI data using a 7T MRI to evaluate hippocampal network functional differences between the two groups with a seed-based approach. Behavioral performance was assessed using the open field test and forced swimming test. Statistical analysis was undertaken to evaluate the correlation between the hippocampal FC and behavioral findings.ResultsCompared with the control group, the SAE group showed increased FC between the bilateral hippocampus and thalamus, septum, bed nuclei stria terminalis (BNST), left primary forelimb somatosensory cortex (S1FL), primary motor cortex (M1), and inferior colliculus. Increased FC between the left hippocampus and thalamus, septum, BNST, left S1FL, and inferior colliculus was observed. While with the right hippocampus, FC in thalamus, septum, left S1FL and inferior colliculus was enhanced. Additionally, positive correlations were found between the hippocampal FC and the immobility time in the forced swimming test.ConclusionHippocampus-related brain networks have significant alterations in rats with SAE, and the elevated hippocampal resting-state FC was positively related to affective deficits. Changes in FC between the hippocampus and other brain regions could be a potential neuroimaging biomarker of cognitive or mental disorders triggered by SAE.

Patients with colonic adenocarcinoma (COAD) are at relatively high risk of SARS-CoV-2 infection. However, there is a lack of medical strategies to treat COVID-19/COAD comorbidity. Puerarin, a natural product, is a known antiviral, antitumor, and immunomodulatory effect. Therefore, we hypothesised that puerarin could be used to treat COVID-19/COAD patients. Based on network pharmacology and bioinformatics analysis, the potential targets and pharmacological mechanisms of puerarin in COVID-19/COAD were identified. By intersecting therapeutic target genes for puerarin, COVID-19-related genes and COAD-related genes, 42 target genes of puerarin that could potentially treat COVID-19/COAD comorbidity were obtained. By using the 42 potential target genes to construct the protein-protein interaction (PPI) network, we obtained five core target genes, namely RELA, BCL2, JUN, FOS, and MAPK1. The results of bioinformatics analysis revealed that puerarin could be able to treat COVID-19/COAD comorbidity through apoptosis, antiviral, antioxidant, NF-κB signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway etc. This study found that puerarin has the potential to treat COVID-19/COAD patients and that the therapeutic target genes obtained in the study may provide clues for the treatment of COVID19/COAD comorbidity.

Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.

Although chimeric antigen receptor T (CAR-T) cell therapy has proven to be effective in treating relapsed or refractory multiple myeloma (R/R MM), the severity of cytokine release syndrome (CRS) can affect patient survival and the risk factors for CRS remain an intractable issue. We enrolled 54 patients with R/R MM following combined infusion of anti-CD19 and anti-B-cell maturation antigen (BCMA) CAR-T cells. The results showed the overall response rate was 94% (51/54) after CAR-T cell infusion, with a 100% incidence of CRS, including 47 patients with grade 1-2 (mild) CRS and 7 patients with grade 3-5 (severe) CRS. In the mild CRS group, the median progression-free survival (PFS) was 18.2 months (95% CI, 6.5 to 30.1) and the median overall survival (OS) was not reached yet. In the severe CRS group, median PFS and median OS were 1.9 months (95% CI, 0.2 to 3.8). Further analysis demonstrated that severe CRS had a shorter median PFS and OS than mild CRS (p=0.029, p=0.020). Bone marrow tumor burden was found to be independently associated with CRS. The grade of CRS was positively correlated with six serum cytokines levels including G-CSF, IL-6, IL-8, IP-10, MIP-1a and RANTES. In conclusion, early detection and management of CRS are imperative for the prevention of life-threatening complications and improvement in the survival of patients of CAR-T cell therapy.Clinical Trial Registrationwww.chictr.org.cn, identifier ChiCTR-OIC-17011272.

A 24-year-old male presented with asymptomatic penile papules for 1 month. Dermatology examination showed pink, soft papules on the ventral side of the penis, with a clear boundary and rough surface, and papillary hyperplasia could be seen. Dermoscopy revealed multiple finger-like projections without vessels in the center of the lesion under polarized light, and linear and crown-like vessels could be seen at the edge of the lesion. Histopathological examination revealed endophytic infundibular hyperplasia with keratinocytes containing Henderson–Patterson bodies. A diagnosis of molluscum contagiosum was made. Molluscum contagiosum can present with several atypical presentations including giant, cystic, ulcerated, or condyloma acuminatum-like, especially in immunosuppressed patients. Here, we report a case of atypical genital molluscum contagiosum with novel dermoscopic findings in an otherwise-healthy adult.

The North Pacific subtropical gyre (NPSTG) redistributes heat and moisture between low and high latitudes and plays a key role in modulating the global climate change and ecosystem. Recent evidence suggests intensification and poleward shift of the subtropical gyres over the last decades due to global warming, but insufficient observations have hampered insight into the integrated effects of ocean-atmosphere interactions at longer timescales. Here we present the first high-resolution (∼12 years) grain-size record from Core CF1 in the Okinawa Trough, western subtropical North Pacific, to reconstruct the evolution of the western boundary Kuroshio Current (KC) of NPSTG during the Late Holocene. Our results indicate the KC slow-down during 4.6–2.0 ka, followed by quick enhancement after 2.0 ka, with centennial-scale variabilities (500–700 years) superimposed on the long-term trend. Over millennial timescales, gradually increased pole-to-equator thermal gradient, due to orbital forcing mechanisms, resulted in long-term enhanced KC, whereas solar activity triggered phase changes in the tropical Pacific mean state and controlled KC anomalies on centennial timescales. We suggest that both forcing mechanisms resulted in ocean-atmosphere feedback provoking concurrent changes in mid-latitude westerly and subtropical easterly winds over the North Pacific, alternating their dominance as source regions causing the dynamic changes of KC at different timescales. Our findings offer insight into the role of external forcing mechanisms in the NPSTG changes before the Anthropocene, which have profound implications for the deeper understanding of changes in ocean gyres under global warming scenarios.

AimsLiuzijue Qigong (LQG) exercise is a traditional Chinese exercise method in which breathing and pronunciation are combined with movement guidance. Breathing is closely related to balance, and LQG, as a special breathing exercise, can be applied to balance dysfunction after stroke. The purpose of this study was to observe the clinical effects of short-term LQG exercise on balance function in patients recovering from stroke.MethodsStroke patients were randomly divided into an Intervention Group (IG) (n = 80) and a Control Group (CG) (n = 80). The IG received conventional rehabilitation training plus LQG and the CG received conventional rehabilitation training plus Core Stability Training (CST). All patients received treatment once a day, 5 times a week for 2 weeks. The primary outcome was Berg Balance Scale (BBS). Secondary outcome measures were static standing and sitting balance with eyes open and closed, Fugl-Meyer Assessment (FMA), Maximum Phonation Time (MPT), Modified Barthel Index (MBI) and diaphragm thickness and mobility during quiet breath (QB) and deep breath (DB).ResultsCompared with the CG, the IG showed significant improvement in the BBS (10.55 ± 3.78 vs. 9.06 ± 4.50, P = 0.039), MPT (5.41 ± 4.70 vs. 5.89 ± 5.24, P = 0.001), MBI (12.88 ± 6.45 vs. 10.00 ± 4.84, P = 0.003), diaphragmatic mobility during QB (0.54 ± 0.73 vs. 0.33 ± 0.40, P = 0.01) and diaphragmatic mobility during DB (0.99 ± 1.32 vs. 0.52 ± 0.77, P = 0.003), Cop trajectory in the standing position with eyes open (−108.34 ± 108.60 vs. −89.00 ± 140.11, P = 0.034) and Cop area in the standing positions with eyes open (−143.79 ± 431.55 vs. −93.29 ± 223.15, P = 0.015), Cop trajectory in the seating position with eyes open (−19.95 ± 23.35 vs. −12.83 ± 26.64, P = 0.001) and Cop area in the seating position with eyes open (−15.83 ± 9.61 vs. −11.29 ± 9.17, P = 0.002).ConclusionsThe short-term LQG combined with conventional rehabilitation training significantly improved the balance functions of stroke patients. It also improved static standing and sitting balance with the eyes open, diaphragm functions, maximum phonation time and the quality of daily life for stroke patients.Clinical Trial Registrationhttp://www.chictr.org.cn/edit.aspx?pid=25313&htm=4, Identifier: ChiCTR1800014864.

Remote sensing reflectance (Rrs), which is currently measured mainly using the above-water approach, is the most crucial parameter in the remote sensing inversion of plateau inland water colors. It is very difficult to measure the Rrs of plateau inland unmanned areas; thus, we provide a measurement solution using a micro-spectrometer. Currently, commercial micro-spectrometers are not factory calibrated for radiation, and thus, a radiometric calibration of the micro-spectrometer is an essential step. This article uses an Ocean Optics micro-spectrometer (STS-VIS) and a traditional water spectrometer (Trios) to simultaneously measure the irradiance and radiance of diffuse reflectance plates with different reflectance values for field calibration. The results show the following: (1) different fiber types have different calibration coefficients, and the integration time is determined according to the diameter of the fiber and the type of fiber, and (2) by comparing the simultaneous measurement results of STS-VIS with Trios, the mean absolute percentage difference (MAPD) of both reached 18.64% and 5.11% for Qinghai Lake and Golmud River, respectively, which are accurate Rrs measurements of water bodies. The Rrs of the Hoh Xil and Qarhan Salt Lake water bodies in unmanned areas of China was measured, and this was the first collection of in situ spectral information with a micro-spectrometer. This article shows that the micro-spectrometer can perform the in situ measurement of water Rrs in unmanned inland areas. With this breakthrough in the radiometric performance of the micro-spectrometer, we are able to obtain more accurate remote sensing reflectance results of unmanned water bodies.

Echinoderms have been attracting increasing attention for their polysaccharides, with unique chemical structure and enormous potential for preparing drugs to treat diseases. In this study, a glucan (TPG) was obtained from the brittle star Trichaster palmiferus. Its structure was elucidated by physicochemical analysis and by analyzing its low-molecular-weight products as degraded by mild acid hydrolysis. The TPG sulfate (TPGS) was prepared, and its anticoagulant activity was investigated for potential development of anticoagulants. Results showed that TPG consisted of a consecutive α1,4–linked D-glucopyranose (D-Glcp) backbone together with a α1,4–linked D-Glcp disaccharide side chain linked through C-1 to C-6 of the main chain. The TPGS was successfully prepared with a degree of sulfation of 1.57. Anticoagulant activity results showed that TPGS significantly prolonged activated partial thromboplastin time, thrombin time, and prothrombin time. Furthermore, TPGS obviously inhibited intrinsic tenase, with an EC50 value of 77.15 ng/mL, which was comparable with that of low-molecular-weight heparin (LMWH) (69.82 ng/mL). TPGS showed no AT-dependent anti-FIIa and anti-FXa activities. These results suggest that the sulfate group and sulfated disaccharide side chains play a crucial role in the anticoagulant activity of TPGS. These findings may provide some information for the development and utilization of brittle star resources.

During the laser application process, laser energy is usually converted into heat energy, causing high temperature, which affects the (high-speed) aircraft in routine flight. A completely novel photochemical method was investigated to potentially minimize the energy effect of the laser beam. Ag nanoparticles/C3N4 were synthesized by an ultra-low temperature reduced deposit method with Ag mean diameters of 5–25 nm for photofixation of N2. The absorption performance of laser can be improved by using appropriate charge density and small size Ag metal particles. The energy absorption rate was 7.1% over Ag/C3N4 (−40) at 5 mJ/cm2 of laser energy.