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Accurate, rapid and sensitive detection of specific immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in human samples is crucial for preventing and assessing pandemics, especially in the case of recent COVID-19 outbreaks. However, simultaneous and efficient detection of IgG and IgM in a single system remains challenging. Herein, we developed a multicolor nanosystem capable of quantitatively analyzing anti-SARS-CoV-2 IgG and IgM with high sensitivity within 20 ​min. The detection system consists of core-shell upconversion nanoparticles (csUCNPs), secondary antibodies labeled with fluorescent dyes (sab), and magnetic nanocrystals (PMF). By leveraging the Förster resonance energy transfer (FRET) effect, the photoluminescence (PL) intensity of blue and green regions is restored for IgG and IgM detection, respectively. Inspiringly, owing to the introducing of PMF, the limits of detection (LODs) of IgG and IgM tested are improved to 89 ​fmol ​L−1 and 19.4 ​fmol ​L−1, representing about 416-folds and 487-folds improvement over only-dye dependent system, respectively. Mechanistic investigations reveal that the high collective effect and surface energy transfer efficiency from csUCNPs to PMF contribute to the enhanced detection sensitivity. The assay enables us to quantify clinical vaccinated samples with high specificity and precision, suggesting our multicolor platform can be a promising alternative for clinical point-of-care serological assay.

Abstract Hepatic ischemia‐reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA‐approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane‐camouflaged liposomes. These hybrid nanovesicles (NVs), leveraging MSC‐derived proteins, demonstrate efficient inflammatory chemotaxis, transendothelial migration, and drug‐loading capacity. In a HIRI mouse model, the biomimetic NVs accumulated at liver injury sites entered hepatocytes, and significantly reduced liver damage and restore function using only one‐tenth of the CsA dose typically required. Proteomic analysis verifies the protection mechanism, which includes reactive oxygen species inhibition, preservation of mitochondrial integrity, and reduced cellular apoptosis, suggesting potential for this biomimetic strategy in HIRI intervention.

At present, energy storage in industrial and commercial scenarios has problems such as poor protection levels, flexible deployment, and poor battery performance. Aiming at the pain points and storage application scenarios of industrial and commercial energy, this paper proposes liquid cooling solutions. In this paper, the box structure was first studied to optimize the structure, and based on the liquid cooling technology route, the realization of an industrial and commercial energy storage thermal management scheme for the integrated cabinet was studied to ensure that the temperature between the cabinets was consistent and reduce the system capacity loss caused by the liquid-cooled battery module was inconsistent. The industrial and commercial energy storage integrated cabinet comprehensively considers the flexible deployment of the system, enhances the protection level of the cabinet, and the structural strength of the cabinet, and improves the temperature balance characteristics of the battery module in the cabinet.

Objectives: Evidence on the link between long-term ambient particulate matter (PM) exposures and childhood sleep disorders were scarce. We examined the associations between long-term exposures to PM2.5 and PM1 (PM with an aerodynamic equivalent diameter

Based on the textual-analyzed data covering 2148 IPO firms in China’s stock market during the 2007–2018 period, the authors’ purpose is to examine the influence of anti-takeover provision (ATP) adoption on initial public offerings (IPO) underpricing and identify the reducing effect of the former. The authors examine the sample consisting of Chinese A-share listed IPO firms between 2007 and 2018 from China Stock Market Accounting Research and Chinese Research Data Services, with ATP data collected from the IPO firm chapters. Specifically, the authors use text analysis to identify whether there are ATPs in the IPO firm chapters, as well as the number of ATPs. H1: IPO underpricing is less severe for firms adopting ATPs. H2: The effect of ATP adoption on IPO underpricing is more salient for firms in worse information environments. The authors examine the influence of ATP adoption on IPO underpricing and identify the reducing effect of the former. This effect can be explained by the fact that adopting ATPs in IPO firm chapters can reduce information asymmetry to a large extent by helping external investors obtain more private information, which alleviates IPO underpricing. The authors also find that the reducing effect is more significant in the worsened information environment. Furthermore, the authors explore the influence of adopting ATPs on other IPO characteristics and find positive effects on IPO over-subscription, funds raised and trading activity and negative effects on listing fees. This study mainly contributes to the literature from the following two aspects. First, the study enriches the literature about the influencing factors of IPO underpricing. Second, the study also enriches the literature about the economic consequences of ATP adoption. This study also has important policy implications. With the coming of the era of decentralized ownership in China’s capital market, ATP adoption has become more important and attracted more attention. Also, investors focus more on pricing efficiency. The findings in this paper provide a more comprehensive understanding of the relationship between ATP adoption and IPO underpricing.

ABSTRACTPurpose Hypertensive disorder complicating pregnancy (HDCP) is a serious clinical disorder syndrome during pregnancy. This study aims at finding novel targets for HDCP therapy.Methods HDCP-related mRNAs were firstly screened out and subjected to gene enrichment analysis. We chose protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) as the research object. Thirty-nine HDCP patients at 32 to 40 weeks of gestation were selected as the HDCP group, and 39 normal controls who received cesarean section delivery at 37–42 weeks of pregnancy were enrolled in this study. Chorionic villi samples were collected within 30 min of delivery. The apoptosis of isolated placental trophoblasts was monitored to investigate the regulatory role of PRKAA2.Results PRKAA2 expression was further proven to be enhanced in the placental tissues of HDCP patients compared with that of normal puerpera. Subsequently, the results of flow cytometry analysis and western blot indicated that PRKAA2 overexpression accelerated primary placental cell apoptosis, while its knockdown attenuated cell apoptosis. Mechanistically, we determined that the level of PRKAA2 succinylation was elevated in the placental tissue of HDCP patients. Through in vitro succinylation assay and mutagenesis, we confirmed that sirtuin 5 (SIRT5) interacts with PRKAA2 at K69 and K260 to induce PRKAA2 desuccinylation. SIRT5 regulated primary HDCP cell apoptosis through PRKAA2. Finally, the animal study revealed that PRKAA2 elevates the systolic blood pressure of HDCP rat model.Conclusion Our findings indicated that SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting that PRKAA2 is a potential therapeutic target for HDCP treatment.

Abstract Outbreaks of infectious viruses offer a formidable challenge to public healthcare systems and early detection of viruses is essential for preventing virus propagation. In this work, an ultrasensitive plasmon‐enhanced fluorescence resonance energy transfer (FRET) biosensor based on core‐shell upconversion nanoparticle (csUCNP) and gold nanoparticle (AuNP) for accurate detection of SARS‐CoV‐2 viral RNA is presented. In this biodetection assay, the Tm3+/Er3+ co‐doped csUCNP NaGdF4:Yb/Tm@NaYF4:Yb/Er acts as an energy donor and AuNP serves as an energy acceptor. The upconversion emission of Tm3+ and the design of the core‐shell structure led to a simultaneous surface plasmon effect of AuNP. The localized surface plasmon resonance (LSPR) arising from collective oscillations of free electrons significantly enhanced FRET efficiency between Er3+ and AuNP. The as‐prepared biosensor obtained a limit of detection (LOD) as low as 750 am, indicating that the integration of FRET and surface plasmon into one biodetection assay significantly boosted the sensitivity of the biosensor. In addition, samples extracted from clinical samples are also utilized to validate the effectiveness of the biosensor. Therefore, this innovative plasmon‐enhanced FRET biosensor based on Tm3+/Er3+ co‐doped csUCNP may pave the way for rapid and accurate biodetection applications.

Abstract Introduction Characteristics of patients in clinical trials may differ from those of real‐world patients. Our objective was to describe biomarker testing and outcomes among patients with advanced non‐small cell lung cancer (aNSCLC) in a real‐world setting. Methods This retrospective cohort study included patients ≥18 years old, diagnosed with stage IIIB/C or IV NSCLC, and in the TEMPUS oncology dataset from January 1, 2012, to December 31, 2020. Patient characteristics associated with biomarker testing were evaluated in patients with positive biomarkers using univariate logistic regression models. Cox proportional hazard models were used to estimate median survival. Results Of 9540 patients included, 41.7% had biomarker testing, and 2158 had a positive biomarker result. Men (vs women; odds ratio [OR], 0.82; 95% CI: 0.74–0.91), Black patients (vs White; OR, 0.83; 95% CI: 0.72–0.97), patients with squamous (OR, 0.22; 95% CI: 0.19–0.25) or unknown histology (OR, 0.53; 95% CI: 0.45–0.61) (vs non‐squamous histology), and patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2+ (OR, 0.69; 95% CI: 0.57–0.84) or missing (OR, 0.56; 95% CI: 0.48–0.66) (vs ECOG PS of 0) were less likely to undergo biomarker testing. Patients with positive biomarkers who received NCCN‐recommended treatment options (55.7%) had significantly longer median overall survival (OS) (hazard ratio [HR], 0.84; 95% CI: 0.75–0.95) and real‐world progression‐free survival (rwPFS) (HR, 0.68; 95% CI: 0.62–0.75). Conclusion More than 50% of patients were untested for biomarkers. Patients who were less likely to be tested included men, Black patients, current smokers, patients with squamous aNSCLC, and patients with an ECOG PS of 2+. Patients with positive biomarkers who received NCCN‐recommended treatment options had significantly longer OS and PFS.

ABSTRACTBamboo root as by-product of bamboo shoot processing is rich in dietary fibre. The protective effects of bamboo root dietary fibre (BRDF) with different intake dose on the hyperlipidaemia mice were investigated. The mice weight in the high dose (HD) group was 31.18 g, lower than that of high fat diet (HFD) group (33.71 g, p

Abstract The vision Transformer structure performs better in salient object detection than the convolutional neural network (CNN)‐based approach. Vision Transformer predicts saliency by modelling long‐range dependencies from sequence to sequence with convolution‐free. It is challenging to distinguish the salient objects' location and obtain structural details for the influence of extracting irrelevant contextual information. A novel saliency sparse Transformer network is proposed to exploit sparse attention to guide saliency prediction. The convolution‐like with dilation in the token to token (T2T) module is replaced to achieve relationships in larger regions and to improve contextual information fusion. An adaptive position bias module is designed for the Vision Transformer to make position bias suitable for variable‐sized RGB images. A saliency sparse Transformer module is designed to improve the concentration of attention on the global context by selecting the Top‐k of the most relevant segments to improve the detection results further. Besides, cross‐modality to exploit the complementary RGB and depth modality fusion module (CMF) is used to take advantage of the complementary RGB image features and spatial depth information to enhance the feature fusion performance. Extensive experiments on multiple benchmark datasets demonstrate this method's effectiveness and superiority that it is suitable for saliency prediction comparable to state‐of‐the‐art RGB and RGB‐D saliency methods.

Abstract Introduction Nephrotic syndrome (NS) is characterized by renal sodium and water retention. The mechanisms are not fully elucidated. Methods The NS rat model was established by single intraperitoneal injection of 100 mg/kg puromycin aminonucleoside (PAN). The plasma electrolyte level and urinary sodium excretion were monitored dynamically. The changes of some sodium transporters, including epithelial Na+ channel (ENaC), Na+/H+ exchanger 3 (NHE3), Na+-K+-2Cl− cotransporter 2 (NKCC2) and Na+-Cl− cotransporter (NCC) in renal cortex at different time points and the level of peripheral circulation factors were detected. Results The urinary sodium excretion of the model group increased significantly on the first day, then decreased compared with the control group, and there was no significant difference between the model group and the control group on the 12th day. The changes of peripheral circulation factors were not obvious. Some sodium transporters in renal cortex increased in varying degrees, while NKCC2 decreased significantly compared with the control group. Conclusions The occurrence of NS edema may not be related to the angiotensin system. The decrease of urinary sodium excretion is independent of the development of albuminuria. During the 18 days of observation, it can be divided into three stages: sodium retention, sodium compensation, and simple water retention. The mechanism is related to the increased expression of α-ENaC, γ-ENaC, NHE3 and NCC in a certain period of time, the compensatory decrease of NKCC2 expression and the continuous increase of aquaporin 2 (AQP2) expression.

IntroductionMesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC). We reviewed the epidemiology and disease characteristics associated with primary and secondary METamp, as well as the testing procedures used to identify METamp, in advanced NSCLC. Economic and humanistic burdens, and the practice patterns and treatments under investigation for METamp were also examined.MethodsEmbase and Medline (via ProQuest), ClinicalTrials.gov, and Cochrane Controlled Register of Trials (2015–2022) were systematically searched. Conference abstracts were searched via Embase and conference proceedings websites (2020–2022). The review focused on evidence from the United States; global evidence was included for identified evidence gaps.ResultsThe median rate of primary METamp in NSCLC across the references was 4.8% (n=4 studies) and of secondary METamp (epidermal growth factor receptor [EGFR]-mutant NSCLC) was 15% (n=10). Next-generation sequencing (NGS; n=12) and/or fluorescence in situ hybridization (FISH; n=11) were most frequently used in real-world studies and FISH testing most frequently used in clinical trials (n=9/10). METamp definitions varied among clinical trials using ISH/FISH testing (MET to chromosome 7 centromere ratio of ≥1.8 to ≥3.0; or gene copy number [GCN] ≥5 to ≥10) and among trials using NGS (tissue testing: GCN ≥6; liquid biopsy: MET copy number ≥2.1 to >5). Limited to no data were identified on the economic and humanistic burdens, and real-world treatment of METamp NSCLC. Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines.ConclusionPrimary METamp occurs in approximately 5% of NSCLC cases, and secondary METamp in approximately 15% of cases previously treated with an EGFR inhibitor. Variability in testing methods (including ISH/FISH and NGS) and definitions were observed. Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

Abstract Liquid biopsy, a noninvasive technique to obtain tumor information from body fluids, is an emerging technology for cancer diagnosis, prognosis, and monitoring, providing crucial support for the realization of precision medicine. The main biomarkers of liquid biopsy include circulating tumor cells, circulating tumor DNA, microRNA, and circulating tumor exosomes. Traditional liquid biopsy detection methods include flow cytometry, immunoassay, polymerase chain reaction (PCR)‐based methods, and next‐generation sequencing (NGS)‐based methods, which are time‐consuming, labor‐intensive, and cannot reflect cell heterogeneity. Droplet‐based microfluidics with high throughput, low contamination, high sensitivity, and single‐cell/single‐molecule/single‐exosome analysis capabilities have shown great potential in the field of liquid biopsy. This review aims to summarize the recent development in droplet‐based microfluidics in liquid biopsy for cancer diagnosis.

Abstract Molecular interplay between host epigenetic factors and viral proteins constitutes an intriguing mechanism for sustaining hepatitis B virus (HBV) life cycle and its chronic infection. HBV encodes a regulatory protein, HBx, which activates transcription and replication of HBV genome organized as covalently closed circular (ccc) DNA minichromosome. Here we illustrate how HBx accomplishes its task by hijacking Spindlin1, an epigenetic reader comprising three consecutive Tudor domains. Our biochemical and structural studies have revealed that the highly conserved N-terminal 2–21 segment of HBx (HBx2–21) associates intimately with Tudor 3 of Spindlin1, enhancing histone H3 “K4me3-K9me3” readout by Tudors 2 and 1. Functionally, Spindlin1-HBx engagement promotes gene expression from the chromatinized cccDNA, accompanied by an epigenetic switch from an H3K9me3-enriched repressive state to an H3K4me3-marked active state, as well as a conformational switch of HBx that may occur in coordination with other HBx-binding factors, such as DDB1. Despite a proposed transrepression activity of HBx2-21, our study reveals a key role of Spindlin1 in derepressing this conserved motif, thereby promoting HBV transcription from its chromatinized genome.

In this paper, we investigate the nonlinear characteristics of the flow in a two-dimensional and a three-dimensional counterflow model with symmetrical structures. Through numerical simulations, we obtain the velocity fields of the fluid flow in these models for different Re. The numerical results are analyzed to understand the nonlinear characteristics and differences between the two-dimensional and three-dimensional models. The findings indicate that, when Re varies, both the two-dimensional and three-dimensional models exhibit solution bifurcations and nonlinear phenomena such as symmetry breaking, self-sustained oscillations, and chaos. As Re increases, the two-dimensional counterflow model displays a unique solution, an asymmetric solution, and an oscillating solution. Specifically, when Re < 4320, both the laminar and turbulent models show a unique, symmetric, and steady-state velocity distribution. For 4652 < Re < 8639, the two-dimensional model solutions are not unique, presenting a pair of antisymmetric, asymmetric solutions that nevertheless remain steady-state. When Re > 8639, the solution becomes oscillatory and unsteady. The three-dimensional counterflow model exhibits a two-dimensional solution independent of the Z-axis. At Re = 4652, both the three-dimensional and two-dimensional models produce the same unique, symmetric, and steady-state velocity distribution with no three-dimensional flow (W = 0). At Re = 8639, the three-dimensional model solutions are not unique, showing a pair of antisymmetric, asymmetric solutions, while still being steady and time-independent. At Re = 87,627, the three-dimensional model solution becomes oscillatory and unsteady. By elucidating the flow characteristics and nonlinear features of both models, this study compares the differences between the two-dimensional and three-dimensional flows, thereby laying the groundwork for simplification of the problem and further theoretical research.

Sila-substituted compounds have potential application in medicinal chemistry, but their preparation from the corresponding carbon analogues remains challenging. Here, the authors report the synthesis of sila-benzoazoles via hydrosilylation and rearrangement of benzoazoles; the reaction is enabled by a Lewis acid.

Salient object detection in optical remote sensing images (ORSI-SOD) is a very challenging task due to the complex scale, shape, details, uncertainty of the predicted location of the object, etc. In this article, we propose a novel important pick-and-pass gated refinement network model for SOD in ORSIs, named IP2GRNet, including a detail refinement stage and a feature pick-and-pass refinement stage. Specifically, the detail refinement stage, named refinement synchronization, uses the self-modality attention refinement module and the dynamic weight refinement module to accurately describe and capture approximate coordinate positions and feature information of salient objects. The feature pick-and-pass and refinement stage progressively picks and refines the prediction results in a coarse to a fine manner by combining high-level semantic information and low-level semantic information under the guidance of attention and counter-attention. In addition, the aggregation operation is used to fuse detail refinement information as well as mixture loss for supervised network training, which effectively improves the model performance from three perspectives: pixel, region, and statistics. Extensive experiments on two benchmarks datasets demonstrate that our proposed IP2GRNet, both qualitatively and quantitatively, outperforms the state-of-the-art saliency detectors.

Numerical and experimental studies were conducted to study the nonlinear phenomena of a 1000 MW ultra-supercritical four-corner tangential pulverized coal boiler. In this paper, (1) a 3D model of a furnace with a symmetrical structure was established to analyze the asymmetric flow phenomenon and multi-solution phenomenon of flow for multiple timepoints under the same boundary conditions. (2) The visual experiment verified that the flow in the furnace also behaved asymmetrically. (3) On the basis of correctly predicting the nonlinear law, the “diagonal start up” method and the “sequential start up” method are proposed. (4) An uneven coefficient of velocity distribution M, deviation coefficient of flue gas mass flow rate Eq and gas temperature deviation coefficient ET are proposed to quantitatively analyze the degree to which the actual tangent circle deviates from the ideal tangent circle. The tangent circle under the “sequential start up” method is the closest to the ideal, which can reduce the thermal deviation of the furnace outlet from 67 K under the “simultaneous start up” method to 41 K. In this paper, the initial steady-state flow field in the furnace is established by using the initial value sensitivity of the nonlinear system through different burner-opening methods, so as to reduce the thermal deviation at the furnace outlet and achieve the purpose of accurate control.

Inspired by the airway for phonation, fluid flow in an idealized model within a sudden expansion and contraction channel with a geometrically symmetric structure is investigated, and the nonlinear behaviors of the flow therein are explored via numerical simulations. Numerical simulation results show that, as the Reynolds number (Re = U0H/ν) increases, the numerical solution undergoes a pitchfork bifurcation, an inverse pitchfork bifurcation and a Hopf bifurcation. There are symmetric solutions, asymmetric solutions and oscillatory solutions for flows. When the sudden expansion ratio (Er) = 6.00, aspect ratio (Ar) = 1.78 and Re ≤ Rec1 (≈185), the numerical solution is unique, symmetric and stable. When Rec1 < Re ≤ Rec2 (≈213), two stable asymmetric solutions and one symmetric unstable solution are reached. When Rec2 < Re ≤ Rec3 (≈355), the number of numerical solution returns one, which is stable and symmetric. When Re > Rec3, the numerical solution is oscillatory. With increasing Re, the numerical solution develops from periodic and multiple periodic solutions to chaos. The critical Reynolds numbers (Rec1, Rec2 and Rec3) and the maximum return velocity, at which reflux occurs in the channel, change significantly under conditions with different geometry. In this paper, the variation rules of Rec1, Rec2 and Rec3 are investigated, as well as the maximum return velocity with the sudden expansion ratio Er and the aspect ratio Ar.

The nonlinear dynamics of the composite shaft rotor-bearing system are greatly affected by the orientation angle layer and its proportion of the ply, i.e., the ratio of the orientation angle layer in the laminate. This paper presents a nonlinear dynamic analysis of a composite rotor-bearing system with pedestal looseness that considers the nonlinear oil film force and the pedestal looseness. Nonlinear phenomena including periodic, quasi-periodic, and chaotic motions are analyzed. The analysis results indicate that the stiffness and damping coefficients of a composite shaft tube can be influenced strongly by the laminate parameters, which can in turn affect the instability speed of the rotor system. To enhance the oil film instability speed of the composite rotor system, it is essential to maximize the ratio of the small orientation angle layer or the ±45° layer. Additionally, increasing the ratio of the small orientation angle layers in the shaft tube leads to a higher rotational speed for loosening instability. The research results obtained in this paper have important theoretical value for the design of composite rotor-bearing systems.

PurposeAs glial autoantibody testing is not yet available in some areas of the world, an alternative approach is to use clinical indicators to predict which subtypes of middle-aged and elderly-onset optic neuritis (ON) have manifested.MethodThis study was a single-center hospital-based retrospective cohort study. Middle-aged and elderly-onset ON patients (age > 45 years) who had experienced the first episode of ON were included in this cohort. Single- and multi-parametric diagnostic factors for middle-aged and elderly-onset myelin oligodendrocyte glycoprotein immunoglobulin-associated ON (MOG-ON) and aquaporin-4 immunoglobulin-related ON (AQP4-ON) were calculated.ResultsFrom January 2016 to January 2020, there were 81 patients with middle-aged and elderly-onset ON, including 32 (39.5%) AQP4-ON cases, 19 (23.5%) MOG-ON cases, and 30 (37.0%) Seronegative-ON cases. Bilateral involvement (47.4%, P = 0.025) was most common in the MOG-ON group. The presence of other concomitant autoimmune antibodies (65.6%, P = 0.014) and prior neurological history (37.5%, P = 0.001) were more common in the AQP4-ON group. The MOG-ON group had the best follow-up best-corrected visual acuity (BCVA) (89.5% ≤ 1.0 LogMAR, P = 0.001). The most sensitive diagnostic factors for middle-aged and elderly-onset MOG-ON were ‘follow-up VA ≤ 0.1 logMAR’ (sensitivity 0.89), ‘bilateral involvement or follow-up VA ≤ 0.1 logMAR’ (sensitivity 0.95), ‘bilateral involvement or without neurological history’ (sensitivity 1.00), and ‘follow-up VA ≤ 0.1 logMAR or without neurological history’ (sensitivity 1.00), and the most specific factor was ‘bilateral involvement’ (specificity 0.81). The most sensitive diagnostic factors for middle-aged and elderly-onset AQP4-ON were ‘unilateral involvement’ (sensitivity 0.88), ‘unilateral involvement or neurological history’ (sensitivity 0.91), and ‘unilateral involvement or other autoimmune antibodies’ (sensitivity 1.00), and the most specific factor was neurological history (specificity 0.98).ConclusionBased on our cohort study of middle-aged and elderly-onset ON, MOG-ON is less prevalent than AQP4-ON and Seronegative-ON. Using multiple combined parameters improves the sensitivity and negative predictive value for diagnosing middle-aged and elderly-onset MOG-ON and AQP4-ON. These combined parameters can help physicians identify and treat middle-aged and elderly-onset ON early when glial autoantibody status is not available.

4D printed photo-triggered liquid crystal elastomers (LCEs) microactuators by direct laser writing via two-photon polymerization (DLW-TPP) have attracted increasing attention due to their manipulation flexibility, reversible and rapid actuation capabilities. However, their development is hampered by the lack of room-temperature printable liquid crystal (LC) photoresists. Here, we developed new light-responsive LC photoresists by incorporating novel conjugated polymers (CPs) as photothermal agents for the DLW-TPP technology. The CPs displayed a remarkable photothermal effect and effectively avoided the aggregation problems that always happened for inorganic nanoparticles in photoresists. Moreover, the CPs incorporation lowered the nematic-to-isotropic temperature of the LC photoresists which is beneficial for room-temperature DLW-TPP. The printing parameters, including laser power and scanning speed, were investigated using the developed LC photoresists. It was found the range of printing parameters decreased with the increase of the CPs loading fraction from 0.1 to 0.5 wt%, which was attributed to the high photothermal conversion efficiency (52.7%). A well-defined CPs/LCEs microactuator with CPs as low as 0.3 wt% was printed, which could achieve a large 25.0% actuation strain in 5 s upon near-infrared (NIR) light stimulation. It could be used for thriving soft micro-robotics and micro-membranes with controllable separation capabilities.

Abstract Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored. Here, we identified increased expression of a c-Mpl alternative splicing isoform, c-Mpl-del, in AMKL patients. We found that c-Mpl-del expression was associated with enhanced AMKL cell proliferation and chemoresistance, and decreased survival in xenografted mice, while c-Mpl-del knockdown attenuated proliferation and restored apoptosis. Interestingly, we observed that c-Mpl-del exhibits preferential utilization of phosphorylated c-Mpl-del C-terminus Y607 and biased activation of PI3K/AKT pathway, which culminated in upregulation of GATA1 and downregulation of DDIT3-related apoptotic responses conducive to AMKL chemoresistance and proliferation. Thus, this study elucidates the critical roles of c-Mpl alternative splicing in AMKL progression and drug resistance, which may have important diagnostic and therapeutic implications for leukemia accelerated by c-Mpl-del overexpression.

Intelligent robots are leading a new round of technological revolution and industrial transformation. Promoting the intelligent robot core chip technology and industry is strategically significant for industrial upgrading and productivity improvement in China. In this study, we illustrate the strategic significance of the intelligent robot core chip technology in China in promoting technological independence, realizing high-quality economic development, satisfying residents’ need for a better life, and promoting a nation’s core competitiveness. Additionally, we review the development status of chips for intelligent robots in terms of policy, technology, and industry, and analyze the advantages and problems of developing intelligent robot chips in China. On this basis, the development route of intelligent robot chips is analyzed, and the development strategic goals of intelligent robot chip technology for 2025, 2030, and 2035 are proposed. Moreover, we propose the key tasks and strategic goals of intelligent robot core chips in China. We suggest that the independent and controllable development of intelligent robot chips should be elevated to a national strategy; major scientific and technological projects should be established for intelligent robot chips; policies should be introduced to encourage intelligent robot chip technology research and industrial applications; and high-level talent training should be implemented.

Abstract The ongoing outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) pandemic has posed significant challenges in early viral diagnosis. Hence, it is urgently desirable to develop a rapid, inexpensive, and sensitive method to aid point‐of‐care SARS‐CoV‐2 detection. In this work, we report a highly sequence‐specific biosensor based on nanocomposites with aggregation‐induced emission luminogens (AIEgen)‐labeled oligonucleotide probes on graphene oxide nanosheets (AIEgen@GO) for one step‐detection of SARS‐CoV‐2‐specific nucleic acid sequences (Orf1ab or N genes). A dual “turn‐on” mechanism based on AIEgen@GO was established for viral nucleic acids detection. Here, the first‐stage fluorescence recovery was due to dissociation of the AIEgen from GO surface in the presence of target viral nucleic acid, and the second‐stage enhancement of AIE‐based fluorescent signal was due to the formation of a nucleic acid duplex to restrict the intramolecular rotation of the AIEgen. Furthermore, the feasibility of our platform for diagnostic application was demonstrated by detecting SARS‐CoV‐2 virus plasmids containing both Orf1ab and N genes with rapid detection around 1 h and good sensitivity at pM level without amplification. Our platform shows great promise in assisting the initial rapid detection of the SARS‐CoV‐2 nucleic acid sequence before utilizing quantitative reverse transcription‐polymerase chain reaction for second confirmation.

BackgroundGastric cancer (GC) is a serious threat to human health. The clinical GC characteristics in China may be impacted by changes in people’s lifestyles and the promotion of early GC (EGC) screening. The present study aims to evaluate the recent trends of GC characteristics in South China and search for hazardous factors limiting the survival time of GC patients.MethodsData on GC patients that were hospitalized in the Department of Digestive Center, the First Affiliated Hospital, Sun Yat-sen University, from 1994 to 2019 were collected and divided into two categories according to the time when the EGC screening began in China: the PRE group (previous 13 years, 1994–2006) and the PAS group (past 13 years, 2007–2019).ResultsWe found that, although the 5-year survival rate increased in the PAS group compared with the PRE group (P < 0.0001), patients with age ≥60 years or Borrmann type IV still had a worse prognosis. In the PAS group, the larger percentages of elderly patients and patients with Borrmann type IV in the lymphatic metastases (N1) group (41.0% vs. 51.1%, P = 0.0014) and stage IV subgroup (20.7% vs. 32.2%, P = 0.016), respectively, when compared with the PRE group, may have contributed to the poor outcome of GC. By comparing the odds ratio (OR) of 5-year overall survival (OS) in the two 13-year periods, female sex and T2 turned into risk factors because of a greater proportion of Borrmann type IV or elderly patients in the PAS group (OR = 0.983, 95% CI = 0.723–1.336 vs. OR = 1.277, 95% CI = 1.028–1.586 and OR = 1.545, 95% CI = 0.499–4.775 vs. OR = 2.227, 95% CI = 1.124–4.271, respectively).ConclusionsDespite the GC epidemiology changes, the overall prognosis of GC patients has improved in South China. However, old age and Borrmann type IV are still the major restrictions affecting the survival of GC patients, a situation which calls for additional attention.

Tumor cells progressively remodel cytoskeletal structures and reduce cellular stiffness during tumor progression, implicating the correlation between cell mechanics and malignancy. However, the roles of tumor cell cytoskeleton and the mechanics in tumor progression remain incompletely understood. We report that softening/stiffening tumor cells by targeting actomyosin promotes/suppresses self-renewal in vitro and tumorigenic potential in vivo. Weakening/strengthening actin cytoskeleton impairs/reinforces the interaction between adenomatous polyposis coli (APC) and β-catenin, which facilitates β-catenin nuclear/cytoplasmic localization. Nuclear β-catenin binds to the promoter of Oct4, which enhances its transcription that is crucial in sustaining self-renewal and malignancy. These results demonstrate that the mechanics of tumor cells dictate self-renewal through cytoskeleton–APC–Wnt/β-catenin–Oct4 signaling, which are correlated with tumor differentiation and patient survival. This study unveils an uncovered regulatory role of cell mechanics in self-renewal and malignancy, and identifies tumor cell mechanics as a hallmark not only for cancer diagnosis but also for mechanotargeting.

Objective: To investigate whether genomic instability (GI)-derived long non-coding RNAs (lncRNAs) have a prognostic impact on the patients with endometrial cancer. Material and methods: Patients with Uterine Corpus Endometrial Carcinoma (UCEC) were selected from The Cancer Genome Atlas (TCGA) database. Systematic bioinformatics analyses were performed, including Pearson correlations, GO and KEGG enrichment analysis, bivariate and multiple logistic regression analysis, and Kaplan–Meier (KM) method. Results: A total of 552 UCEC samples were included in the study. The differentially expressed lncRNAs (DELs) were identified, including 79 down-regulated lncRNAs and 31 up-regulated lncRNAs. Bivariate logistic regression analysis showed that 19 GI-derived lncRNAs were prognostic factors. By further multivariate logistic regression analysis, AC005256.1 (estimated coefficient = −0.474), AC026336.3 (estimated coefficient = −0.030), AL161618.1 (estimated coefficient = −1.661), and BX322234.1 (estimated coefficient = 1.511) were used to construct a prognostic risk model. In the train set and test set, the risk model was shown to have both a high prognostic and a diagnostic value. Conclusion: We developed a novel GI-derived 4-lncRNA signature for the diagnosis and prognosis of patients with endometrial cancer. These findings offered a novel perspective in the clinical management of endometrial cancer.

Epidemiological and toxicological evidence show that PM1 is a key driver of PM2.5. However, the particle sizes that play the major damaging role in PM1 is unclear. Our aims were to (1) explore the concentration and chemical composition of ultrafine particles in PM1; (2) evaluate and compare the differences in toxicity of PM1-0.2 and PM0.2 to different airway cell models. We collected PM1-0.2 and PM0.2 in Guangzhou in December 2017, monitored and detected their concentrations, size, and components. A549, THP-1 mono-cultures and A549/THP-1 co-cultured cells were exposed to PM1-0.2 and PM0.2, and evaluated for toxicological responses. PM0.2 contributed to15% PM1 mass and 87.67% to particle number (PN). Most of PM0.2 was PM0.1 (exceed 75%). Structure of particles in PM0.2 were mostly spherical, whereas in PM1-0.2 they were more diverse. Within the same mass unit, PM0.2 contained more chemical components than PM1-0.2; within the same volume, a higher mass of components was found in PM1-0.2. IL-6 and IL-8 were secreted by co-cultured cells in higher manner compared to mono cell cultures. PM0.2-induced higher toxicological responses compared to PM1-0.2. Our findings suggest that high PN concentration and toxicity of ultrafine or PM1 cannot be ignored. Mono-cell culture may underestimate the true PM toxicity.

BackgroundNicotinamide Adenine Dinucleotide (NAD) depletion is reported to be a potential treatment for B-cell Acute Lymphoblastic Leukemia (B-ALL), but the mechanism of NAD metabolism-related genes (NMRGs) in B-ALL relapse remains unclear.MethodsTranscriptome data (GSE3912), and single-cell sequencing data (GSE130116) of B-ALL patients were downloaded from Gene Expression Omnibus (GEO) database. NMRGs were sourced from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Further, the differentially expressed NMRGs (DE-NMRGs) were selected from the analysis between initial diagnosis and relapse B-ALL samples, which further performed functional enrichment analyses. The biomarkers were obtained through random forest (RF) algorithm and repeated cross validation. Additionally, cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was used to evaluate the immune cell differences between the initial diagnosis and relapse samples, and the correlations between biomarkers and gene markers of differential immune cells were analyzed. Furthermore, single cell RNA sequencing was conducted in the GSE130116 dataset to find key cell clusters. In addition, according to biomarkers expressions, cell clusters were categorized into high and low biomarker expression groups, and Gene Set Enrichment Analysis (GSEA) analysis was performed on them. Finally, the cell clusters with the highest expression of biomarkers were selected to explore the roles of biomarkers in different cell clusters and identify transcription factors (TFs) influencing biological markers.Results23 DE-NMRGs were screened out, which were mainly enriched in nucleoside phosphate metabolic process, nucleotide metabolic process, and Nicotinate and nicotinamide metabolism. Moreover, 3 biomarkers (NADSYN1, SIRT3, and PARP6) were identified from the machine learning. CIBERSORT results demonstrated that four types of immune cells (B Cells naive, Monocyte, Neutrophils, and T cells CD4 memory Activated) were significantly different between the initial diagnosis and the relapse B-ALL samples, and there were strong correlations between biomarkers and differential immune cells such as positive correlation between NADSYN1 and B Cells naive. The single cell analyses showed that the biomarkers were highly expressed in common myeloid progenitors (CMP), granulocyte-macrophage progenitor (GMP), and megakaryocyte-erythroid progenitor (MEP) cell clusters. Gene set enrichment analysis (GSEA) results indicated that 55 GO terms and 3 KEGG pathways were enriched by the genes in high and low biomarker expression groups. It was found that TF CREB3L2(+) was significantly reduced in the high expression group, which may be the TF affecting biomarkers in the high expression group.ConclusionThis study identified NADSYN1, SIRT3, and PARP6 as the biomarkers of B-ALL, explored biological significance of NMRGs in the initial diagnosis and relapse of B-ALL, and revealed mechanism of biomarkers at the level of the single cell.

ObjectiveTo elucidate the clinical, radiologic characteristics of Leber’s hereditary optic neuropathy (LHON) associated with the other diseases.Materials and methodsClinical data were retrospectively collected from hospitalized patients with LHON associated with the other diseases at the Neuro-Ophthalmology Department at the Chinese People’s Liberation Army General Hospital (PLAGH) from December 2014 to October 2018.ResultsA total of 13 patients, 24 eyes (10 men and 3 women; mean age, 30.69 ± 12.76 years) with LHON mitochondrial DNA (mtDNA) mutations, were included in the cohort. 14502(5)11778(4)11778 &11696(1)12811(1)11696(1)3460(1). One patient was positive for aquaporin-4 antibody (AQP4-Ab), and two were positive for myelin oligodendrocyte glycoprotein antibody (MOG-Ab). Three patients were associated with idiopathic optic neuritis (ON). Two patients were with compression optic neuropathy. Three patients were with the central nervous system (CNS) diseases. One patient was with proliferative diabetic retinopathy (PDR) and one with idiopathic orbital inflammatory syndrome (IOIS). At the onset, visual acuity (VA) in eighteen eyes was below 0.1, one eye was 0.5, five eyes were above 0.5, while VA in sixteen eyes was below a 0.1 outcome, three eyes experienced moderate vision loss. MRI images showed T2 lesions and enhancement in nine patients who received corticosteroids treatment; additional immune modulators treatment was performed on two patients. None of the patients had relapse during the follow-up time.ConclusionLeber’s hereditary optic neuropathy can be accompanied with multiple-related diseases, especially different subtypes of ON, which were also exhibited with IOIS and compression optic neuropathy for the first time in this cohort. This condition may be a distinct entity with an unusual clinical and therapeutic profile.

Here, we firstly introduce a detection system consisting of upconversion nanoparticles (UCNPs) and Au nanorods (AuNRs) for an ultrasensitive, rapid, quantitative and on-site detection of SARS-CoV-2 spike (S) protein based on Förster resonance energy transfer (FRET) effect. Briefly, the UCNPs capture the S protein of lysed SARS-CoV-2 in the swabs and subsequently they are bound with the anti-S antibodies modified AuNRs, resulting in significant nonradiative transitions from UCNPs (donors) to AuNRs (acceptors) at 480 nm and 800 nm, respectively. Notably, the specific recognition and quantitation of S protein can be realized in minutes at 800 nm because of the low autofluorescence and high Yb-Tm energy transfer in upconversion process. Inspiringly, the limit of detection (LOD) of the S protein can reach down to 1.06 fg mL−1, while the recognition of nucleocapsid protein is also comparable with a commercial test kit in a shorter time (only 5 min). The established strategy is technically superior to those reported point-of-care biosensors in terms of detection time, cost, and sensitivity, which paves a new avenue for future on-site rapid viral screening and point-of-care diagnostics.

Background: Monoclonal antibodies such as rituximab (RTX), eculizumab, inebilizumab, satralizumab, and tocilizumab have been found to be effective therapies for neuromyelitis optica spectrum disease ​(NMOSD) in several clinical randomized controlled trials. Objective: The purpose of this meta-analysis of randomized controlled trials was to assess the efficacy and safety of monoclonal antibodies in the treatment of NMOSD. Methods: We searched the following databases for relevant English language literature from the establishment of the database to June 2021: PubMed, Embase, Cohorane Library, the Central Register of Controlled Trials (CENTRAL), and Web of Science. Randomized controlled trials of monoclonal antibodies were the targets of the review. Results: We included seven trials containing 775 patients (485 in the monoclonal antibody group and 290 in the control group). Patients in the monoclonal group (HR 0.24, 95% CI: 0.14 to 0.40, P ​

Qi-Yu-San-Long decoction (QYSLD), a traditional Chinese medicine (TCM) prescription, consisting of ten types of herbal medicine which has significant clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). However, the bioactive ingredients of QYSLD remain unclear, due to their “multi-ingredients” and “multi-targets” features. This study aimed to construct a spectrum-effect correlation analysis model and screen the potential active components of QYSLD. A fingerprint method based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was developed and validated to obtain seventy common peaks of ten batches of QYSLD. The results of methodological evaluation, including precision, repeatability and stability, were less than 8.19%. In terms of linearity, eleven common components did not reach the linear standard (R2 < 0.99), they were removed before spectrum-effect relationship analysis. After treated with ten batches of QYSLD, the results of DPPH and FRAP assays ranged from 1.59 to 5.50 mg mL−1 and 143.83–873.83 μmol L−1, respectively. Meanwhile, the cell viabilities of A549 cells treated with QYSLD samples ranged from 21.73% to 85.71%. The relative healing rates ranged from 21.50% to 44.46%. The number of migrated and invaded cells ranged from 12.00 to 68.67 and 7.67 to 27.00, respectively. Then, the potential active components of QYSLD were screened through spectrum-effect relationship constructed by grey correlation analysis (GRA), partial least squares regression (PLSR) and backpropagation neural network (BP-ANN). The results were as follow: 1) eight ingredients of QYSLD were relevant to DPPH free radical scavenging ability; 2) nine ingredients were relevant to FRAP; 3) six ingredients were relevant to inhibit the proliferation ability of A549 cells; 4) twenty-two ingredients were relevant to inhibit the horizontal migration ability; 5) five ingredients were relevant to inhibit the vertical migration ability; 6) twelve ingredients were relevant to inhibit the invasion ability. Confirmatory experiments showed that compared with the unscreened ingredients, the potential active ingredients screened by the spectrum-effect relationship had better antioxidant and anti-NSCLC effects. In general, this study found the potential active ingredients in QYSLD. Meanwhile, the established method provided a valuable reference model for the potential active ingredients of TCM.

Abstract Background Though the combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) appears to be very attractive in cancer treatment, hypoxia and overproduced glutathione (GSH) in the tumor microenvironment (TME) limit their efficacy for further application. Results In this work, a smart hypoxia-irrelevant free radical nanogenerator (AIPH/PDA@CuS/ZIF-8, denoted as APCZ) was synthesized in situ via coating copper sulphide (CuS)-embedded zeolitic imidazolate framework-8 (ZIF-8) on the free radical initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH)-loaded polydopamine (PDA). APCZ showed promising GSH-depleting ability and near-infrared (NIR)-II photothermal performance for combined cancer therapy. Once internalized by 4T1 cells, the outer ZIF-8 was rapidly degraded to trigger the release of CuS nanoparticles (NPs), which could react with local GSH and sequentially hydrogen peroxide (H2O2) to form hydroxyl radical (·OH) for CDT. More importantly, the hyperthermia generated by APCZ upon 1064 nm laser excitation not only permitted NIR-II photothermal therapy (PTT) and promoted CDT, but also triggered the decomposition of AIPH to give toxic alkyl radical (·R) for oxygen-independent PDT. Besides, the PDA together with CuS greatly decreased the GSH level and resulted in significantly enhanced PDT/CDT in both normoxic and hypoxic conditions. The tumors could be completely eradicated after 14 days of treatment due to the prominent therapeutic effects of PTT/PDT/CDT. Additionally, the feasibility of APCZ as a photoacoustic (PA) imaging contrast agent was also demonstrated. Conclusions The novel APCZ could realize the cooperative amplification effect of free radicals-based therapies by NIR-II light excitation and GSH consumption, and act as a contrast agent to improve PA imaging, holding tremendous potential for efficient diagnosis and treatment of deep-seated and hypoxic tumors. Graphic abstract

Background: Nephrotic syndrome (NS) is a common glomerular disease, and podocyte injury is the character of primary NS, usually caused by minimal change disease and membranous nephropathy. Podocytopathy is primarily associated with glomerular proteinuria. Losartan, an angiotensin receptor blocker (ARB), is commonly used in the treatment of NS, and the AngiotensinⅡ (AngⅡ)–transient receptor potential ion channel 6 (TRPC6) axis has been reported to act on podocytes to regulate proteinuria in NS. Therefore, the purpose of this study was to explore the relationship in between AngⅡ–TRPC6, podocyte injury, and proteinuria based on the adriamycin (ADR) NS rat model.Method: All male rats were divided into three groups: control group, model group, and ARB group. The rats in the model group were induced by ADR, and the rats in the ARB group received losartan after induction of renal injury for 4 weeks. The changes in parameters related to renal dysfunction, and glomerular and podocyte structural damage, such as AngⅡ, AngⅡ type I receptor (AT1R), TRPC6, CaN, Caspase-3, Nephrin, and Podocin, were analyzed. Furthermore, the kidneys were isolated for study via transmission electron microscopy (TEM), immunohistochemistry, and western blot (WB) after the rats were sacrificed. In vitro, immortalized mouse MPC5 podocytes were used to investigate the regulatory effect of flufenamic acid (Flu) and SAR7334 (SAR) on the AngⅡ-TRPC6 signaling axis. Flow cytometry and WB were conducted to determine the relationship between podocyte injury and AngⅡ-TRPC6.Results:In vivo results showed that NS rats developed massive albuminuria and abnormal renal function, accompanied by abnormally increased levels of AngⅡ, TRPC6, AT1R, and CaN and a decreased expression of actin molecules in podocytes, extensive fusion of foot processes (FP), loss of glomerular structural integrity, collapse of podocyte structure, and skeletal reorganization. In vitro experiments indicated that both AngⅡ and Flu (the specific agonist of TRPC6) stimulated the expressions of TRPC6, AT1R, and Caspase-3 in podocytes. The AngⅡ receptor–blocker losartan and TRPC6-specific inhibitor SAR blocked the overexpression of the aforementioned proteins. In addition, SAR also attenuated the degradation of podocyte structural proteins and inhibited the fluorescence intensity of intracellular calcium (Ca2+) and cell apoptosis.Conclusion: The involvement of AngⅡ in the occurrence of NS proteinuria may be related to podocyte injury induced by activated TRPC6.

Legionnaires’ disease (LD), caused by Legionella, including the most prevalent Legionella pneumophila, has been treated primarily with antibiotics. Environmental water and soil are the reservoirs for L. pneumophila. Studying antimicrobial susceptibility using a large number of isolates from various environmental sources and regions could provide an unbiased result. In the present study, antimicrobial susceptibility of 1464 environmental L. pneumophila isolates that were derived from various environmental water and soil sources of 12 cities in China to rifampin (RIF), erythromycin (ERY), clarithromycin (CLA), azithromycin (AZI), ciprofloxacin (CIP), moxifloxacin (MOX), levofloxacin (LEV), and doxycycline (DOX) was investigated, and minimum inhibitory concentration (MIC) data were obtained. We show that regarding macrolides, ERY was least active (MIC90 = 0.5 mg/L), while CLA was most active (MIC90 = 0.063 mg/L). A total of three fluoroquinolones have similar MICs on L. pneumophila. Among these antimicrobials, RIF was the most active agent, while DOX was the most inactive one. We observed different susceptibility profiles between serogroup 1 (sg1) and sg2-15 or between water and soil isolates from different regions. The ECOFFs were ERY and AZI (0.5 mg/L), RIF (0.002 mg/L), CIP, CLA and MOX (0.125 mg/L), LEV (0.063 mg/), and DOX (32 mg/L). Overall, two fluoroquinolone-resistant environmental isolates (0.14%) were first documented based on the wild-type MIC distribution. Not all azithromycin-resistant isolates (44/46, 95.65%) harbored the lpeAB efflux pump. The MICs of the ERY and CLA on the lpeAB + isolates were not elevated. These results suggested that the lpeAB efflux pump might be only responsible for AZI resistance, and undiscovered AZI-specific resistant mechanisms exist in L. pneumophila. Based on the big MIC data obtained in the present study, the same defense strategies, particularly against both CLA and RIF, may exist in L. pneumophila. The results determined in our study will guide further research on antimicrobial resistance mechanisms of L. pneumophila and could be used as a reference for setting clinical breakpoints and discovering antimicrobial-resistant isolates in the clinic, contributing to the antibiotic choice in the treatment of LD.

Chronic kidney disease (CKD) is a common and progressive disease that has become a major public health problem on a global scale. Renal fibrosis is a common feature in the pathogenesis of CKD, which is mainly related to the excessive accumulation and deposition of extracellular matrix caused by various inflammatory factors. No ideal treatment has yet been established. In recent years, based on the traditional Chinese medicine (TCM) theory of CKD and its molecular mechanism, clinical evidence or experimental studies have confirmed that a variety of Chinese materia medica (CMM) and their effective components can delay the progress of CKD. TCM believes that the pathogenesis of CKD is the deficiency in the root and excess in the branch, and the deficiency and excess are always accompanied by the disease. The strategies of TCM in treating CKD are mainly based on invigorating Qi, tonifying the kidneys, promoting blood circulation, removing stasis, eliminating heat and dampness, removing turbidity, and eliminating edema, and these effects are multitargeted and multifunctional. This review attempts to summarize the theories and treatment strategies of TCM in the treatment of CKD and presents the efficacy and mechanisms of several CMMs supported by clinical evidence or experimental studies. In addition, the relationship between the macroscopic of TCM and the microscopic of modern medicine and the problems faced in further research were also discussed.

Although tumor immunotherapy has emerged as a promising therapeutic method for oncology, it encounters several limitations, especially concerning low response rates and potential off-targets that elicit side effects. Furthermore, tumor immunogenicity is the critical factor that predicts the success rate of immunotherapy, which can be boosted by the application of nanotechnology. Herein, we introduce the current approach of cancer immunotherapy and its challenges and the general methods to enhance tumor immunogenicity. Importantly, this review highlights the integration of anticancer chemo/immuno-based drugs with multifunctional nanomedicines that possess imaging modality to determine tumor location and can respond to stimuli, such as light, pH, magnetic field, or metabolic changes, to trigger chemotherapy, phototherapy, radiotherapy, or catalytic therapy to upregulate tumor immunogenicity. This promotion rouses immunological memory, such as enhanced immunogenic cell death, promoted maturation of dendritic cells, and activation of tumor-specific T cells against cancer. Finally, we express the related challenges and personal perspectives of bioengineered nanomaterials for future cancer immunotherapy.

In the published publication [...]

Abstract Infectious virus outbreaks pose a significant challenge to public healthcare systems. Early and accurate virus diagnosis is critical to prevent the spread of the virus, especially when no specific vaccine or effective medicine is available. In clinics, the most commonly used viral detection methods are molecular techniques that involve the measurement of nucleic acids or proteins biomarkers. However, most clinic‐based methods require complex infrastructure and expensive equipment, which are not suitable for low‐resource settings. Over the past years, smartphone‐based point‐of‐care testing (POCT) has rapidly emerged as a potential alternative to laboratory‐based clinical diagnosis. This review summarizes the latest development of virus detection. First, laboratory‐based and POCT‐based viral diagnostic techniques are compared, both of which rely on immunosensing and nucleic acid detection. Then, various smartphone‐based POCT diagnostic techniques, including optical biosensors, electrochemical biosensors, and other types of biosensors are discussed. Moreover, this review covers the development of smartphone‐based POCT diagnostics for various viruses including COVID‐19, Ebola, influenza, Zika, HIV, et al. Finally, the prospects and challenges of smartphone‐based POCT diagnostics are discussed. It is believed that this review will aid researchers better understand the current challenges and prospects for achieving the ultimate goal of containing disease‐causing viruses worldwide.

Background and ObjectiveIt is urgent to find out an alternative therapy for Kawasaki disease (KD) since around 20% patients are resistant to intravenous immunoglobulin (IVIG) or aspirin. Tanshinone IIA is the active component of the traditional Chinese medicine Danshen (Salvia miltiorrhiza), which has anti-inflammatory and anti-platelet properties; however, whether or not tanshinone IIA has a therapeutic effect on KD remains unclear. Therefore, the present study aimed to examine the effect of tanshinone IIA on KD patients and rabbits with immune vasculitis, and to identify the potential mechanisms with special emphasis on megakaryopoiesis and megakaryocytic apoptosis.MethodsKawasaki disease patients were recruited and prescribed with tanshinone IIA in the absence or presence of aspirin and IVIG, and the inflammatory responses and platelet functions were determined. Megakaryocytes (MKs) isolated from rabbits with immune vasculitis and human megakaryocytic CHRF-288-11 cells were treated with tanshinone IIA to examine the colony forming unit (CFU) and apoptosis, respectively. Microarray assay was conducted to identify potential targets of tanshinone IIA-induced apoptosis.ResultsTanshinone IIA reduced the serum levels of C-reactive protein (CRP), interleukin (IL)-1β, IL-6, and P-selectin in KD patients; such inhibitory effect was more significant compared to aspirin and IVIG. It also dose-dependently lowered the levels of tumor necrosis factor (TNF)-α and IL-8 in peripheral blood mononuclear cells isolated from KD patients. In rabbits with immune vasculitis, tanshinone IIA significantly reduced the serum levels of proinflammatory cytokines and platelet functions. In addition, tanshinone IIA significantly decreased the number of bone marrow MKs and inhibited the Colony Forming Unit-Megakaryocyte (CFU-MK) formation. In human megakaryocytic CHRF-288-11 cells, tanshinone IIA induced caspase-dependent apoptosis, probably through up-regulating TNF receptor superfamily member 9 (TNFRSF9) and the receptor (TNFRSF)-interacting serine/threonine-protein kinase 1 (RIPK1), which may contribute to its anti-platelet and anti-inflammatory properties.ConclusionTanshinone IIA exerts better anti-inflammatory and anti-platelet effects in treating KD patients than aspirin and IVIG. It attenuates immune vasculitis likely by inhibiting IL-mediated megakaryopoiesis and inducing TNFRSF9/RIPK1/caspase-dependent megakaryocytic apoptosis. The findings therefore suggest that tanshinone IIA may be a promising alternative therapy for the treatment of KD.

Aniline is a toxic organic pollutant and raw material in industries. In this study, the start-up of sequencing batch reactor for treating aniline wastewater was assessed and functional microbial clusters were analyzed after enrichment of denitrifying phosphate-accumulating organisms (DNPAOs). The aniline degradation and subsequent removal of NH4+-N mainly happened in aerobic condition, and denitrification was conducted in both anaerobic and anoxic conditions. Besides aerobic phosphorus uptake, phosphorus accumulation also occurred via DNPAOs in anoxic condition utilizing nitrate as electron acceptor. The removal efficiencies of COD, NH4+-N, TN, and TP was over 91.6, 67.1, 65.0, and 79.9% respectively. Proteobacteria, Bacteroidetes, and Firmicutes were found to be predominant at phylum level treating aniline wastewater. Blastocatella, Ferruginibacter and Clostridium were predominant strains involved in aniline degradation and Pseudomonas was enriched in the presence of aniline. Aeromonas, Acinetobacter, and Comamonas may play key roles in nitrogen removal and phosphorus accumulation with tolerance of aniline.

Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in ATAAD tissues by scRNA-seq. Ascending aortic wall tissue from six ATAAD patients and three heart transplant donors was assessed by scRNA-seq and then analyzed and validated by various bioinformatic algorithms and histopathology experiments. The results revealed that the proportion of macrophages in ATAAD tissues (24.51%) was significantly higher than that in normal tissues (13.69%). Among the six macrophage subclusters, pro-inflammatory macrophages accounted for 14.96% of macrophages in the AD group and 0.18% in the normal group. Chemokine- and inflammation-related genes (CCL2, CCL20, S100A8, and S100A9) were expressed more intensively in macrophages in ATAAD tissue than in those in normal tissue. Additionally, intercellular communication analysis and transcription factor analysis indicated the activation of inflammation and degradation of the extracellular matrix in ATAAD tissue. Finally, immunohistochemistry, immunofluorescence, and Western blot experiments confirmed the overexpression of macrophage marker genes (CD68 and CD163) and matrix metalloproteinases (MMP9 and MMP2) in ATAAD tissue. Collectively, our study provides a preliminary evaluation of the role of macrophages in ATAAD, and the results could aid in the development of therapeutic options in the future.

Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating disease, the pathogenesis of which involves autoantibodies targeting the extracellular epitopes of aquaporin-4 on astrocytes. We neutralized the AQP4-IgG from NMOSD patient sera using synthesized AQP4 extracellular epitope peptides and found that the severe cytotoxicity produced by aquaporin-4 immunoglobin (AQP4-IgG) could be blocked by AQP4 extracellular mimotope peptides of Loop A and Loop C in astrocyte protection and animal models. ACT001, a natural compound derivative, has shown anti-tumor activity in various cancers. In our study, the central nervous system anti-inflammatory effect of ACT001 was investigated. The results demonstrated the superior astrocyte protection activity of ACT001 at 10 µM. Furthermore, ACT001 decreases the behavioral score in the mouse NMOSD model, which was not inferior to Methylprednisolone Sodium Succinate, the first-line therapy of NMOSD in clinical practice. In summary, our study showed that astrocytes are protected by specific peptides, or small molecular drugs, which is a new strategy for the treatment of NMOSD. It is possible for ACT001 to be a promising therapy for NMOSD.

Abstract Chitinase and chitin-oligosaccaride can be used in multiple field, so it is important to develop a high-yield chitinase producing strain. Here, a recombinant Pichia pastoris with 4 copies of ChiA gene from Bacillus licheniformis and co-expression of molecular chaperon HAC1 was constructed. The amount of recombinant ChiA in the supernatant of high-cell-density fermentation reaches a maximum of 12.7 mg/mL, which is 24-fold higher than that reported in the previous study. The recombinant ChiA can hydrolyze 30% collodidal chitin with 74% conversion ratio, and GlcNAc is the most abundant hydrolysis product, followed by N, N′-diacetylchitobiose. Combined with BsNagZ, the hydrolysate of ChiA can be further transformed into GlcNAc with 88% conversion ratio. Additionally, the hydrolysate of ChiA can obviously accelerate the germination growth of rice and wheat, increasing the seedling height and root length by at least 1.6 folds within 10 days.

Abstract Exosomes are secreted by cells and are widely present in body fluids. Exosomes contain various molecular constituents of their cells of origin such as proteins, mRNA, miRNAs, DNA, lipid and glycans which are very similar as the content in tumor cells. These contents play an important role in various stages of tumor development, and make the tumor-derived exosome as a hot and emerging biomarker for various cancers diagnosis and management in non-invasive manner. The present problems of exosome isolation and detection hinder the application of exosomes. With the development of exosome isolation and detection technology, the contents of exosomes can be exploited for early cancer diagnosis. This review summarizes the recent progress on exosome-associated tumor biomarkers and some new technologies for exosome isolation and detection. Furthermore, we have also discussed the future development direction in exosome analysis methods.