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Residual δ-ferrite is ubiquitous in M50NiL bearing steel and seriously deteriorates impact toughness. In the present work, the formation mechanism of δ-ferrite in M50NiL steel and the influence of element segregation on its formation process were investigated. The residual δ-ferrite was proved to form directly from the final liquid phase at the end of solidification due to serious segregation of Mo and V elements. Calculation results indicate that the segregation of Mo and V elements expanded the “L + δ'' two-phase region and stabilized δ-ferrite. Due to the high concentration of Mo and V, large-sized V-rich MC and Mo-rich M2C carbides would precipitate in δ-ferrite at 900–1200 °C if the cooling rate is slow. When kept at 1200 °C for no more than 30 min, Mo and V elements derived from the decomposition of large-sized carbides are preferentially diffused into δ-ferrite, enhancing the stability of δ-ferrite. To achieve the effective elimination of δ-ferrite in M50NiL steel, it is necessary to keep the ingot at 1200 °C for at least 20 h.

Abstract Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level.

Abstract Dust records extracted from ice cores can facilitate the reconstruction of historical atmospheric dust levels and climate change. However, interpreting dust variations in ice cores is intricate because of the compounded influence of emission, transport, and deposition processes. This study investigated dust records retrieved from the Guliya ice cap drilled in 2015 on the West Tibetan Plateau using a mean trajectory transport and deposition model. Results showed that the Guliya dust concentration has exhibited a declining trend since the 1960s (−751 μg kg−1 yr−1). Applying an attribution approach, we discovered that low dust emission (80.3%) was the main cause of the drop in dust concentration, with changes related to transportation (5.2%) and deposition (14.5%) making only minor contributions. The weakening of surface wind speed in the desert and increasing precipitation in both the desert and glacier were the primary factors driving the decrease in Guliya dust concentration.

Introduction Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%–6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy.Methods and analysis This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable.Ethics and dissemination The study protocol has been approved by the ethics committees of the Sixth People’s Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences.Trial registration number ChiCTR2300073864.

Abstract. Background:. The incidence of well-differentiated gastric neuroendocrine tumors (G-NET) is increasing annually, and while they have a good prognosis and low mortality rate, their high recurrence rate makes treatment options controversial. This study aims to determine the relationship between individualized treatment plans and the recurrence of G-NET. Methods:. We performed a multicenter, retrospective study of 94 patients with highly differentiated G-NET and treated at Peking Union Medical College Hospital, Yantai Yuhuangding Hospital, and Beijing Zhong-Neng-Jian Hospital from November 2015 to September 2023. Risk factors for recurrence of G-NETs were investigated using chi-squared test and multifactorial logistic regression analysis. Results:. After a median follow-up of 49 months, the overall recurrence rate among the 94 G-NET patients was 14% (13/94). The recurrence rates of endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), somatostatin analog (SSA) therapy, and surgery were 43% (6/14), 10% (5/49), 5% (1/22), and 11% (1/9), respectively. Post-treatment recurrence rates were significantly different (P = 0.014) among four treatments (EMR, ESD, SSA, and surgery), and further subgroup comparisons revealed lower recurrence rates in the ESD and SSA groups than in the EMR group. From the second month onward, SSA therapy considerably reduced the gastrin levels from 1081.0 (571.5, 2472.8) pg/mL to 461.5 (255.3, 795.0) pg/mL (Z = –3.521, P

Hybrid power line communication (PLC)/visible light communication (VLC) networks have been demonstrated to be crucial for indoor practical communications and have attracted widespread attention. However, most current research in hybrid PLC/VLC networks focus mainly on communication reliability and resource allocation, and little has been carried on physical layer security. In this paper, we investigate the secure communication of a hybrid PLC/VLC network with two non-orthogonal multiple access legitimate users. During the two-hop PLC and VLC transmission, two eavesdroppers attempt to wiretap the confidential information from the PLC link via power line, and from the VLC link via visible light, respectively. Based on the randomness of the impulsive noise arriving at the PLC link, and the randomness of users’ positions covered by the VLC link, the channel statistical characteristics of the PLC and VLC links are derived, respectively. Furthermore, the approximate closed-form expressions of secrecy outage probability (SOP) are determined. Simulations are performed to validate the effectiveness of theoretical results, and simulation results show that to get a high-level secrecy outage performance, the parameters of both the PLC and VLC links should be jointly designed. Furthermore, with regard to SOP, it is the worst case for both the PLC and VLC links eavesdropping, as compared to only PLC link eavesdropping or only VLC link eavesdropping.

Cataract is one of the major causes of vision loss and even blindness in patients, and surgery is the only effective method to treat it. The pathogenesis and precaution of cataract remain hot issues in ophthalmological research. With the maturation of biotechnology in recent years, modeling methods and species of experimental animals have become more diverse, which are still the mainstay of cataract mechanism research. However, the ideal animal model of cataract has yet to be constructed due to the complexity of human cataract etiology. Herein, the modeling principles, in vivo or in vitro modeling methods, characteristics, and existing problems of animal models of cataract are summarized according to etiology, providing the theoretical foundation for the construction of a comprehensive animal model that more closely resembles the human cataract.

With the proposal of a ''dual carbon strategy '' and the rising share of renewable energy sources, the resulting low-inertia problem has seriously affected the frequency stability of new power systems. This paper proposes a minimum inertial demand estimation of renewable energy considering new power system frequency constraints to enhance the power system inertia situational awareness and clarify the system operation boundary. Firstly, the frequency response model with multi-source renewable energy units and the time-domain mathematical expressions are established, and the frequency constraints and inertial demand of new power systems are given. The minimum inertial demand estimation model is constructed on this basis, which can be solved by the sparrow search algorithm (SSA). Ultimately, the applicability and practicality of the suggested approach are demonstrated and verified in IEEE 39-bus system. The case study results demonstrate the process can accurately calculate the inertial demand of renewable energy side considering system frequency constraints and give guidance for the stable operation of new power systems.

Abstract Although highly automated vehicle fleets have committed a safe and efficient traffic flow, the next few years are likely the human‐driven vehicles (HDV) and intelligent vehicles (IV) mixed in large‐scale traffic network, where the interaction of HDVs with IVs will become more frequent. In this study, the authors investigate the traffic flow performance in a widespread of V2V environment deployed for all types of HDVs and IVs, levelled from L0 to L5. Based on this assumption, the vehicle movements and operations are collected and assembled into a V2X BSM dataset, and to any vehicle in fleet, the sequential movements and driving behaviours of the vehicle ahead can be predicted in the short term and considered as the input to cooperative adaptive cruise control (CACC) model of the controlled vehicle. The predicted motion of the vehicle ahead is applied to rolling optimization process of a given MPC framework, which calculates appropriate longitudinal operation for each car‐following vehicle and keeps optimal equilibrium state of the vehicle fleets in heterogeneous traffic flow. The experimental results showed that when the front vehicle generates random acceleration/deceleration in saturated and over saturated traffic state, in the car‐following case, the improved CACC controller maintains average car‐following distance at 20–40 m, the acceleration variation in the range [−0.1, 0.25], the gap error changed within [−10, 13], and controls the relative speed variation from −0.25 to 0.3 m/s, compared to an average headway of 20–140 m, acceleration variation in the range [−1.6, 0.65], gap error changed within [−21, 30], and a relative speed variation from −1.75 to 4.1 m/s by the traditional CACC controller. In the car‐in and car‐out cases, the vehicle controlled by the improved CACC controller had a travel displacement of 4050 m, a speed fluctuation interval of [18.7, 27.7], and an acceleration variation range of [−0.15, 0.2], while the vehicle controlled by the traditional MPC controller had a travel displacement of 3800 m, a speed fluctuation interval of [13.8,27.7] and an acceleration variation range of [−2.9, 0.6]. The improved CACC model can adapt more accurately and quickly to the maneouvre of vehicle ahead in V2V environment, which can effectively improve the capacity of heterogeneous traffic flow and the safety and comfort of driving.

The proliferation of blockchain technology has resulted in diverse token standards, posing challenges for compatibility, security, and performance in existing cross-chain bridges. This paper introduces a novel framework capable of concurrently facilitating fungible token exchange, as well as the processing of both individual and batch non-fungible tokens (NFTs). We deploy token bridges that meet different token standards to support cross-chain staking and unlocking of ERC20, ERC721, and ERC1155. To minimize both waiting times and handling fees, we relocate processes necessitating frequent transactions and verifications to the sidechain. Additionally, we adopt a batch-processing approach for tokens necessitating cross-chain transfers, leveraging payment channels to facilitate efficiency. The system’s reliability is upheld through the validator group. Validators acquire an initial reputation value by making deposits and enhance both their rewards and reputation by successfully completing NFT auction tasks on the sidechain. We use OpenZeppelin’s security library functions to standardize token operations, and carefully design the validator’s reward, punishment, and reputation mechanisms. Our comprehensive contract security audit and system analysis validate our solution’s effectiveness in mitigating common vulnerabilities and internal threats. Implementation and testing with Ethereum and its test network demonstrate substantial reductions in transmission time for key cross-chain token steps by nearly half. Moreover, our framework showcases efficiency and cost-effectiveness with an average gas cost of 693,379.

Objectives This study aimed to analyse whether safety and security equipment decreased patient and visitor violence (PVV) towards nurses in the COVID-19 period and quantify to what extent safety and security equipment affects PVV.Design Controlled before and after study and difference-in-difference (DID) analysis.Setting A large hospital medical group, consisting of three public tertiary teaching hospitals, namely, Xinjiekou Branch, Huilongguan Branch and Xinlongze Branch of Beijing Jishuitan Hospital, located in the west and north parts of Beijing, China.Participants A panel of nine departments recruited using two-step sampling method, administered online surveys in 2021 and 2022. A total of 632 eligible nurses participated in the survey in 2021 and 725 eligible nurses in 2022.Measures We assessed impacts of the safety and security equipment on the PVV. The policy had been enacted in June 2020, and the corresponding measures were established after mid-December 2020, and therefore, we use a DID design to evaluate changes in nurses’ PVV incidence. Departments are classified as either department installed or non installed, and nurses are classified based on their department.Results Within the treatment group, the incidence of physical PVV significantly decreased from 13.8% in 2020 to 2.0% in 2021. In the control group, the incidence of physical PVV increased from 0.6% in 2020 to 2.7% in 2021. The application of the safety and security equipment decreased the incidence of physical PVV by 13.93% (95% CI: −23.52% to −4.34%). In contrast, no difference was observed between the treatment and control groups for the incidence of psychological PVV (6.23%, 95% CI: −11.56% to 24.02%) and overall PVV (0.88, 95% CI: −20.90% to 22.66%).Conclusion The safety and security equipment reduced the incidence of physical PVV towards nurses. For hospital managers in public hospitals, longer-term strategies roadmap for PVV prevention measures are needed to create a more supportive work environment in employees.

With the proposal of “double carbon strategy” and new power system construction, the increasing proportion of renewable energy sources and the wide access of power line sub-devices, the inertia support capacity of the power grid is gradually weakened and shows low inertia characteristics, which seriously threatens the system operation safety and frequency stability. In order to comprehensively grasp the operation status of the new power system and ensure its frequency stability, this paper proposes a renewable energy virtual control theory based on the established frequency response model of new power systems considering multiple inertial resources. Secondly, the inertial safety region (ISR) of the new power system considering the virtual inertia and frequency regulation capability of renewable energy is proposed to determine the frequency stability boundary, and its estimation method and procedure are introduced in detail. Finally, a case study and analysis are conducted in the New England system with actual operational data to verify the feasibility and effectiveness of the proposed method. The simulation results show that the method can effectively identify the ISR of the new power system and analyze the mechanism of the influence of renewable energy on ISR, and relevant conclusions are drawn from the simulation results.

Abstract Retinal ganglion cells (RGCs), the sole output neurons in the eyes, are vulnerable to diverse insults in many pathological conditions, which can lead to permanent vision dysfunction. However, the molecular and cellular mechanisms that contribute to protecting RGCs and their axons from injuries are not completely known. Here, we identify that Porf-2, a member of the Rho GTPase activating protein gene group, is upregulated in RGCs after optic nerve crush. Knockdown of Porf-2 protects RGCs from apoptosis and promotes long-distance optic nerve regeneration after crush injury in both young and aged mice in vivo. In vitro, we find that inhibition of Porf-2 induces axon growth and growth cone formation in retinal explants. Inhibition of Porf-2 provides long-term and post-injury protection to RGCs and eventually promotes the recovery of visual function after crush injury in mice. These findings reveal a neuroprotective impact of the inhibition of Porf-2 on RGC survival and axon regeneration after optic nerve injury, providing a potential therapeutic strategy for vision restoration in patients with traumatic optic neuropathy.

Self-powered photoelectrochemical (PEC) ultraviolet photodetectors (UVPDs) are promising for next-generation energy-saving and highly integrated optoelectronic systems. Constructing a heterojunction is an effective strategy to increase the photodetection performance of PEC UVPDs because it can promote the separation and transfer of photogenerated carriers. However, both crystal defects and lattice mismatch lead to deteriorated device performance. Here, we introduce a structural regulation strategy to prepare TiO2 anatase-rutile heterophase homojunctions (A-R HHs) with oxygen vacancies (OVs) photoanodes through an in situ topological transformation of titanium metal–organic framework (Ti-MOF) by pyrolysis treatment. The cooperative interaction between A-R HHs and OVs suppresses carrier recombination and accelerates carrier transport, thereby significantly enhancing the photodetection performance of PEC UVPDs. The obtained device realizes a high on/off ratio of 10,752, a remarkable responsivity of 24.15 mA W−1, an impressive detectivity of 3.28 × 1011 Jones, and excellent cycling stability. More importantly, under 365 nm light illumination, a high-resolution image of “HUST” (the abbreviation of Harbin University of Science and Technology) was obtained perfectly, confirming the excellent optical imaging capability of the device. This research not only presents an advanced methodology for constructing TiO2-based PEC UVPDs, but also provides strategic guidance for enhancing their performance and practical applications.

Achieving effective control over microbial contamination necessitates the precise and concurrent identification of numerous pathogens. As a common bacterium in the environment, Pseudomonas is rich in variety. It not only has pathogenic strains, but also spoilage bacteria that cause food spoilage. In this research, we devised a remarkably sensitive duplex droplet digital PCR (dddPCR) reaction system to simultaneously detect pathogenic Pseudomonas aeruginosa (P. aeruginosa) and spoilage Pseudomonas fragi (P. fragi). By employing comparative genomics, we identified four genes of P. fragi. Through a specific analysis, the RS22680 gene was selected as the detection target for P. fragi, and the lasR gene was chosen for P. aeruginosa, which were applied to construct a dddPCR reaction. In terms of specificity, sensitivity and anti-interference ability, the constructed dddPCR detection system was verified and analyzed. The assay showed excellent sensitivity and applicability, as evidenced by a limit of detection of 100 cfu/mL. When the concentration of natural background bacteria in milk or fresh meat was 100 times that of the target detection bacteria, the method was still capable of completing the absolute quantification. In the simulation of actual sample contamination, P. aeruginosa could be detected after 3 h of enrichment culture, and P. fragi could be detected after 6 h. The established dddPCR detection system exhibits exceptional performance, serving as a foundation for the simultaneous detection of various pathogenic bacteria in food products.

Flower color is an important ornamental feature that is often modulated by the contents of flavonoids. Chalcone synthase is the first key enzyme in the biosynthesis of flavonoids, but little is known about the role of R. delavayi CHS in flavonoid biosynthesis. In this paper, three CHS genes (RdCHS1-3) were successfully cloned from R. delavayi flowers. According to multiple sequence alignment and a phylogenetic analysis, only RdCHS1 contained all the highly conserved and important residues, which was classified into the cluster of bona fide CHSs. RdCHS1 was then subjected to further functional analysis. Real-time PCR analysis revealed that the transcripts of RdCHS1 were the highest in the leaves and lowest in the roots; this did not match the anthocyanin accumulation patterns during flower development. Biochemical characterization displayed that RdCHS1 could catalyze p-coumaroyl-CoA and malonyl-CoA molecules to produce naringenin chalcone. The physiological function of RdCHS1 was checked in Arabidopsis mutants and tobacco, and the results showed that RdCHS1 transgenes could recover the color phenotypes of the tt4 mutant and caused the tobacco flower color to change from pink to dark pink through modulating the expressions of endogenous structural and regulatory genes in the tobacco. All these results demonstrate that RdCHS1 fulfills the function of a bona fide CHS and contributes to flavonoid biosynthesis in R. delavayi.

Abstract Traditional Chinese medicine (TCM) has been used for centuries to prevent and treat a variety of illnesses, and its popularity is increasing worldwide. However, the clinical applications of natural active components in TCM are hindered by the poor solubility and low bioavailability of these compounds. To address these issues, Chinese medicine self-assembly nanostrategy (CSAN) is being developed. Many active components of TCM possess self-assembly properties, allowing them to form nanoparticles (NPs) through various noncovalent forces. Self-assembled NPs (SANs) are also present in TCM decoctions, and they are closely linked to the therapeutic effects of these remedies. SAN is gaining popularity in the nano research field due to its simplicity, eco-friendliness, and enhanced biodegradability and biocompatibility compared to traditional nano preparation methods. The self-assembly of active ingredients from TCM that exhibit antitumour effects or are combined with other antitumour drugs has generated considerable interest in the field of cancer therapeutics. This paper provides a review of the principles and forms of CSAN, as well as an overview of recent reports on TCM that can be used for self-assembly. Additionally, the application of CSAN in various cancer diseases is summarized, and finally, a concluding summary and thoughts are proposed. We strongly believe that CSAN has the potential to offer fresh strategies and perspectives for the modernization of TCM.

Abstract Background Changes in China’s health care system in the last three decades was remarkable. The current study aims on examine the change of equality of health care utilization in mainland China based on a nationwide household interview survey. Methods We used household interview data extracted from six waves of National Health Service Survey between 1993 and 2018. Changes of health care utilization were descripted. Equality of the utilization were examined with univariate meta-regression across urban and rural areas, socioeconomic development regions and income groups. Results The proportion of outpatient visits within last two weeks experienced a decrease from 17.0% in 1993 to 13.0% in 2013 and bounced back to 24.0% in 2018. The age-standardized trend remained unchanged. Hospitalization in the last 12 month increased from 2.6% in 1998 to 13.8% in 2018. The perceived unmet need of hospital admission fell from 35.9% in 1998 to 21.5% in 2018. The gaps in health care utilization between urban and rural areas, across regions and by income groups have been narrowed, implying improved equality of using medical services in the last two and a half decades. Conclusion China has experienced significant increases in health care utilization over the past 25 years. Meanwhile, the unmet needs for health care decreased remarkably and the equality of health care utilization improved significantly. These results imply significant achievements in health service accessibility in China.

CO2 hydrogenation to yield long-chain hydrocarbons has attracted tremendous attention in both academic and industrial field. CuFe-based bimetal catalysts have been widely applied in CO2 hydrogenation owing to their low cost, facile preparation, and excellent performance. In this study, a series of CuFe-based catalysts with different Cu/Fe molar ratios have been synthesized from layered double hydroxide precursor. The optimized CuFe8-LDO catalyst with Cu:Fe=1:8 exhibits a C5+ selectivity of 45% at CO2 conversion of 9.5%. Through systematic characterizations including TEM, TPR, TPD, XPS, it is revealed the abundant and highly dispersed CuO favors the reduction of iron species, and enhances CO adsorption capacity of as-prepared catalysts. This study provides an in-deep understanding of Cu on CO2 hydrogenation performance of Fe-based catalysts.

ABSTRACTBackground Acute lung injury (ALI) is a severe and often fatal pulmonary disease. Current treatments for ALI and acute respiratory distress syndrome (ARDS) are limited. Natural product metabolites have shown promise as therapeutic alternatives. However, the effects of Licochalcone B (LCB) on ALI are largely unknown.Methods We investigated the effects of LCB on lipopolysaccharide-challenged mice and human pulmonary microvascular endothelial cells. Cell viability, apoptosis, and ROS production were assessed. Lung tissue histopathology and oxidative stress and inflammation markers were evaluated. Protein expression levels were measured.Results LCB had no cytotoxic effects on cells and increased cell viability. It reduced apoptosis and ROS levels in cells. In mice with ALI, LCB decreased lung tissue weight and improved oxidative stress and inflammation markers. It also enhanced expression levels of Nrf2, HO-1, and NQO1 while reducing Keap1.Conclusion LCB protects against LPS-induced acute lung injury in cells and mice. The Keap1/Nrf2 pathway may be involved in its protective effects. LCB shows potential as a strategy to alleviate ALI caused by LPS.

Objective To develop the first prediction model based on the common clinical symptoms of high-altitude pulmonary edema (HAPE), enabling early identification and an easy-to-execute self-risk prediction tool.Methods A total of 614 patients who consulted People’s Hospital of Tibet Autonomous Region between January 2014 and April 2022 were enrolled. Out of those, 508 patients (416 males and 92 females) were diagnosed with HAPE and 106 were patients without HAPE (33 females and 72 males). They were randomly distributed into training (n=431) and validation (n=182) groups. Univariate and multivariate analysis were used to screen predictors of HAPE selected from the 36 predictors; nomograms were established based on the results of multivariate analysis. The receiver operating characteristic curve (ROC) was developed to obtain the area under the ROC curve (AUC) of the predictive model, and its predictive power was further evaluated by calibrating the curve, while the Decision Curve Analysis (DCA) was developed to evaluate the clinical applicability of the model, which was visualised by nomogram.Results All six predictors were significantly associated with the incidence of HAPE, and two models were classified according to whether the value of SpO2 (percentage of oxygen in the blood) was available in the target population. Both could accurately predict the risk of HAPE. In the validation cohort, the AUC of model 1 was 0.934 with 95% CI (0.848 to 1.000), and model 2 had an AUC of 0.889, 95% CI (0.779 to 0.999). Calibration plots showed that the predicted and actual HAPE probabilities fitted well with internal validation, and the clinical decision curve shows intervention in the risk range of 0.01–0.98, resulting in a net benefit of nearly 99%.Conclusion The recommended prediction model (nomogram) could estimate the risk of HAPE with good precision, high discrimination and possible clinical applications for patients with HAPE. More importantly, it is an easy-to-execute scoring tool for individuals without medical professionals’ support.

Vasculogenic mimicry (VM) differs from the classical tumor angiogenesis model. VM does not depend on endothelial cells; instead, highly aggressive tumor cells mimic endothelial cells to form a vascular-like channel structure. VM mediated by tumor cells is significantly and positively associated with a poor prognosis and low survival rates in patients with highly aggressive cancer. In the treatment of highly aggressive malignancies, the presence of VM is considered an important reason for the unsatisfactory clinical efficacy of anti-tumor–angiogenesis therapy (e.g., therapy targeting vascular endothelial growth factor A). Many targeted therapeutic drugs based on traditional tumor blood vessels have been used clinically. Although some progress has been made in certain tumors, problems such as drug resistance have restricted the expected therapeutic effects. Thrombospondin 2 (THBS2) is one of the most important genes associated with angiogenesis, and this gene exerts angiogenesis-related functions through the PI3K/AKT signaling pathway. Although the PI3K/AKT/mTOR signaling pathway is closely related to the progression of VM, the mechanism by which the promising biomarker THBS2 participates in and regulates tumor VM by activating the PI3K/AKT/mTOR signaling pathway is unclear. In this review, we analyze the monomer structure and biological activity of THBS2, the structure and potential synthesis mechanisms of VM, and the complex mechanisms between THBS2, the PI3K/AKT/mTOR signaling pathway, and VM.

Abstract Background Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy. Methods Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models. Results The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases. Conclusion PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.

The clinical success of immune checkpoint inhibitors (ICIs) has initiated a new era in the treatment of metastatic cancer. Unfortunately, the overall response rate of ICIs in pretreated metastatic breast cancer (BC) is generally less than 20% due to many challenges, including low immunogenicity and immunosuppressive tumour microenvironment (ITM). Herein, we synthesized nanoliposomes that codelivered diclofenac (DC) and Mn (5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (PMnCl) (denoted MD@Lip) to overcome these challenges. DC could block lactate transporters (monocarboxylate transporters 1 and 4) on the cancer cell membrane, thus reducing the concentration of lactate, which acts as a critical regulator of the ITM. Meanwhile, PMnCl-induced sonodynamic therapy (SDT) could induce apoptotic and/or necrotic tumour cell death. Importantly, SDT could induce immunogenic cell death (ICD) during the tumour cell debris generation, which changed the state of tumour cells from nonimmunogenic to immunogenic. Thus, MD@Lip was verified to activate T cells, inactivate regulatory T cells and regulate the levels of immune cytokines, ultimately inhibiting primary and distant tumours by improving the antitumour effect of anti-PD1-based immunotherapy.

Objective: To investigate the anti-glioma effect and mechanism of AND on human glioma U251 cells via network pharmacology, bioinformatics and in vitro experiments. Methods: Network pharmacology was used to predict glioma-related targets based on the structure of AND. The hub genes were selected by bioinformatics, analyzed by gene ontology (GO) molecular function and kyoto encyclopedia of genes and genomes enrichment analysis (KEGG) to determine their related signaling pathways. Molecular docking was conducted to study the binding activity of AND with the above targets. Finally, gene set enrichment analysis (GSEA) was performed, analyzing the expression differences of hub genes and the Kaplan-Meier survival curve by comparing glioma samples with normal samples. On the above basis, the effects of AND on the growth and morphological changes of human glioma U251 cells were observed, the effects of AND on the PI3K/AKT pathway were detected. Results: A total of 40 glioma related targets of AND were identified by network pharmacology, and 10 hub genes were screened out by bioinformatics method. AND had high binding activity to hub genes. GO and KEGG enrichment analysis results showed that the hub genes were related to biological processes such as the regulation of neuronal apoptosis, reactive oxygen metabolism, and were related to PI3K/AKT signaling pathways. GSEA enrichment analysis suggested that PI3K/AKT-mTOR and other signaling pathways were significantly up-regulated in glioma cells. Among the hub genes, HSP90AA1, HSP90AB1, RHOA, CDK2 and MET showed significant differences between glioma samples and normal samples. Kaplan-Meier survival curve showed that low expression of genes like BCL2L1, CDK2, SOD2 and MET had higher survival rates. In the in vitro studies, AND inhibited the growth of U251 cells in both time-dependent and dose-dependent manners. After the administration of AND, U251 cells became round and shriveled, which significantly decreased the expression of p-PI3K, p-AKT, p-PI3K/PI3K, p-AKT/AKT to the PI3K/AKT pathway. Conclusion: AND can inhibit the proliferation of human glioma U251 cells, which mechanism is related to the PI3K/AKT signaling pathway.

Pomelo is cultivated worldwide due to its unique taste. Most of the pomelo peel is discarded, thus, wasting the beneficial ingredients contained in it. In order to effectively utilize these ingredients, a green and low-consumption method has been reported here to extract the cellulose nanofibrils (CNFs) from the pomelo peel by employing the sequential alkaline treatment, bleaching, acid hydrolysis, and ball milling. The results demonstrate that the impurities in the pomelo peel, such as hemicellulose and lignin, are gradually removed. The obtained CNFs still maintain their natural cellulose structure. The degree of crystallinity and thermal stability of CNFs are noted to be significantly improved as compared to the raw pomelo peel. The CNF diameter is observed to range between 6 and 47 nm. Compared with 10–17.5% NaOH/KOH and 60–65% HNO3/H2SO4 used in previous studies, the developed method requires a low concentration of the alkali solution and bleaching agent. Further, the lemon juice, used as an acidolysis agent, is inexpensive and environmentally friendly. The ball milling purifies the CNFs and effectively reduces the size of CNFs without consuming a significant amount of energy. This study lays a foundation for an effective use of the agricultural solid waste based on pomelo peel.

ObjectiveTo examine trends in patient and visitor violence (PVV) among large public hospitals from 2016 to 2020 in China, and investigate the effects of infection prevention and control (IPC) measures on PVV during the COVID-19 pandemic.MethodsThe hospital-level data of PVV used in this study from 2016 to 2020 in three cities in northern China were extracted from the database of the Medical Quality and Safety Notification System from 41 public hospitals. The difference-in-difference (DID) method was used to estimate the effects of IPC measures on PVV. The empirical strategy was to compare changes in the incidence rate of PVV in public hospitals where IPC measures were stricter to relatively weaker hospitals.ResultsFrom 2019 to 2020, the incidence rate of PVV decreases from 4.59 to 2.15% for high-IPC measure level hospitals and increases from 4.42 to 4.56% for medium-IPC measure level hospitals. The results from the DID models showed that as the IPC measure level increased, the incidence rate of PVV (β = −3.12, 95% CI = −5.74 ~ −0.50) decreased more significantly based on controlling for hospital fixed effects and time trends.ConclusionThe multi-dimensional and comprehensive IPC measures throughout the pandemic in China have not only controlled the pandemic, but also directly or indirectly reduced the incidence rate of PVV by alleviating the stress of health workers and the crowded working environment, creating a good order of admission, and reducing patient waiting time.

IntroductionThe geriatric nutritional risk index (GNRI), a nutritional screening tool specifically for the aging population, has been proven to be associated with worse outcomes in chronic kidney disease patients, especially in the hemodialysis population. However, the predictive validity of GNRI in critically ill elderly patients with acute kidney injury (AKI) is yet to be determined. This analysis sought to examine the prognostic effects of GNRI on elderly AKI patients in intensive care units (ICUs).MethodsWe collected elderly AKI patient-relevant data from the Medical Information Mart for Intensive Care III database. AKI was diagnosed and staged according to the “Kidney Disease Improving Global Outcomes” criteria. In the study, 1-year mortality was considered the primary outcome, whereas in-hospital, ICU, 28-day and 90-day mortality, and prolonged length of stay in ICU and hospital were selected as the secondary outcomes.ResultsIn all, 3,501 elderly patients with AKI were selected for this study, with a 1-year mortality rate of 36.4%. We classified the study population into low (≤98) and high (>98) GNRI groups based on the best cutoff value. The incidence of endpoints was remarkably lower in patients with elevated GNRI (p < 0.001). When stratified by the AKI stage, patients with high GNRI at AKI stages 1, 2, and 3 had markedly lower 1-year mortality than those with low GNRI (all p < 0.05). The multivariable regression analysis identified the independent prognostic ability of GNRI on the research outcomes (all p < 0.05). Restricted cubic spline exhibited a linear correlation between GNRI and 1-year death (p for non-linearity = 0.434). The prognostic implication of GNRI on 1-year mortality was still significant in patients with the most subgroups.ConclusionIn critically ill elderly patients with AKI, elevated GNRI upon admission was strongly correlated with a lower risk of unfavorable outcomes.

Mammals are frequently exposed to various environmental stimuli, and to determine whether to approach or avoid these stimuli, the brain must assign emotional valence to them. Therefore, it is crucial to investigate the neural circuitry mechanisms involved in the mammalian brain’s processing of emotional valence. Although the central amygdala (CeA) and the ventral tegmental area (VTA) individually encode different or even opposing emotional valences, it is unclear whether there are common upstream input neurons that innervate and control both these regions, and it is interesting to know what emotional valences of these common upstream neurons. In this study, we identify three major brain regions containing neurons that project to both the CeA and the VTA, including the posterior bed nucleus of the stria terminalis (pBNST), the pedunculopontine tegmental nucleus (PPTg), and the anterior part of the basomedial amygdala (BMA). We discover that these neural populations encode distinct emotional valences. Activating neurons in the pBNST produces positive valence, enabling mice to overcome their innate avoidance behavior. Conversely, activating neurons in the PPTg produces negative valence and induces anxiety-like behaviors in mice. Neuronal activity in the BMA, on the other hand, does not influence valence processing. Thus, our study has discovered three neural populations that project to both the CeA and the VTA and has revealed the distinct emotional valences these populations encode. These results provide new insights into the neurological mechanisms involved in emotional regulation.

BackgroundThe occurrence of ischemic stroke (IS) is associated with nonalcoholic fatty liver disease (NAFLD). The cancer burden of NAFLD complicated by IS also warrants attention. This study aimed to identify candidate immune biomarkers linked to NAFLD and IS and analyze their association with cancer.MethodsTwo of each of the NAFLD and IS datasets were downloaded, differentially expressed genes (DEGs) were identified, and module genes were screened via weighted gene coexpression network analysis (WGCNA). Subsequently, utilizing machine learning (least absolute shrinkage and selection operator regression, random forest and support vector machine-recursive feature elimination) and immune cell infiltration analysis, immune-related candidate biomarkers for NAFLD with IS were determined. Simultaneously, a nomogram was established, the diagnostic efficacy was assessed, and the role of candidate biomarkers in cancer was ascertained through pan-cancer analyses.ResultsIn this study, 117 and 98 DEGs were identified from the combined NAFLD and IS datasets, respectively, and 279 genes were obtained from the most significant modules of NAFLD. NAFLD module genes and IS DEGs were intersected to obtain nine genes, which were enriched in the inflammatory response and immune regulation. After overlapping the results of the three machine learning algorithms, six candidate genes were obtained, based on which a nomogram was constructed. The calibration curve demonstrated good accuracy, and the candidate genes had high diagnostic values. The genes were found to be related to the immune dysregulation of stroke, and RRS1 was strongly associated with the prognosis, immune cell infiltration, microsatellite instability (MSI), and tumor mutation burden (TMB).ConclusionSix common candidate immune-related genes (PTGS2, FCGR1A, MMP9, VNN3, S100A12, and RRS1) of NAFLD and IS were identified, and a nomogram for diagnosing NAFLD with IS was established. RRS1 may serve as a candidate gene for predicting the prognosis of patients with cancer who have NAFLD complicated by IS, which could aid in their diagnosis and treatment.

Immunotherapy shows great promise on treating tumors. However, insufficient antigen exposure and immunosuppressive tumor microenvironment (TME) caused by hypoxia impose a serial of constraints on the therapeutic efficacy. In this study, we developed an oxygen-carrying nanoplatform loaded with perfluorooctyl bromide (PFOB, a second-generation of perfluorocarbon-based blood substitute), IR780 (a photosensitizer) and imiquimod (R837, an immune adjuvant) to reprogram immunosuppressive TME and reinforce photothermal-immunotherapy. The obtained oxygen-carrying nanoplatforms (abbreviated as IR-R@LIP/PFOB) show highly efficient oxygen release behavior and excellent hyperthermia performance upon laser irradiation, thus achieving the attenuation of the inherent tumor hypoxia and the exposure of tumor associated antigens in situ, and transforming the immunosuppressive TME to an immunosupportive one. We found that the photothermal therapy of IR-R@LIP/PFOB together with anti-programmed cell death protein-1 (anti-PD-1) would elicit a robust antitumor immunity by increasing the tumor-infiltrating frequencies of cytotoxic CD8+ T cells and tumoricidal M1-phenotype macrophages, while reducing immunosuppressive M2-phenotype macrophages and regulatory T cells (Tregs). This study presents these oxygen-carrying IR-R@LIP/PFOB nanoplatforms are potent in removing some negative impacts of immunosuppressive TME caused by hypoxia, and suppressing tumor growth by initiating antitumor immune responses, especially in combination with anti-PD-1 immunotherapy.

The corona virus disease 2019 (COVID-19) global pandemic has had an unprecedented and persistent impact on oncological practice, especially for patients with lung cancer, who are more vulnerable to the virus than the normal population. Indeed, the onset, progression, and prognosis of the two diseases may in some cases influence each other, and inflammation is an important link between them. The original chronic inflammatory environment of lung cancer patients may increase the risk of infection with COVID-19 and exacerbate secondary damage. Meanwhile, the acute inflammation caused by COVID-19 may induce tumour progression or cause immune activation. In this article, from the perspective of the immune microenvironment, the pathophysiological changes in the lungs and whole body of these special patients will be summarised and analysed to explore the possible immunological storm, immunosuppression, and immune escape phenomenon caused by chronic inflammation complicated by acute inflammation. The effects of COVID-19 on immune cells, inflammatory factors, chemokines, and related target proteins in the immune microenvironment of tumours are also discussed, as well as the potential role of the COVID-19 vaccine and immune checkpoint inhibitors in this setting. Finally, we provide recommendations for the treatment of lung cancer combined with COVID-19 in this special group.

Despite the critical breakthrough achieved by immune checkpoint blockade (ICB) therapies in the clinic, the antitumor effect is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in the tumor microenvironment (TME) holds promise for ITM modulation. Herein, we fabricated a glutathione-responsive PEGylated hollow mesoporous organosilicon (HMOP), with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOX) loaded in/onto the HMOP (denoted as DC-HMOP-LOX). DC-HMOP-LOX could spontaneously be biodegraded in the TME due to the disulfide bonds, and then DC/LOX could be released to exhaust intra/extracellular lactate. DC-HMOP-LOX hindered the transmission of lactate effectively and oxidized lactate directly. Therefore, DC-HMOP-LOX collaboratively depleted lactate in the TME, which induced an immunocompetent TME by activating immune-promoting cells (dendritic cell, T cells, natural killer cells, and M1-macrophage), inactivating immunosuppressive cells (M2-macrophage and bone marrow-derived suppressor cells), and regulating the levels of immune cytokines (IFN-γ, TNF-α, IL-10, and IL-12). The immunocompetent TME ultimately strengthened the antitumor effect of anti-PD1-based immunotherapy.

Cervical cancer (CC) remains one of the leading causes of cancer-related deaths worldwide. However, cervical cancer is preceded by the pre-malignant cervical intraepithelial neoplasia (CIN) that can last for up to 20 years before becoming malignant. Therefore, early screening is the key to prevent the progression of cervical lesions into invasive cervical cancer and decrease the incidence. The genes, down-regulated and hypermethylated in cancers, may provide potential drug targets for cervical cancer. In our current study, using the datasets from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, we found that endothelin 3 (EDN3) was downregulated and hypermethylated in cervical squamous cell carcinoma (CSCC). The further analysis in GSE63514 (n=128) dataset and in our samples (n=221) found that the expression of EDN3 was decreased with the degree of cervical lesions. Pyrosequencing was performed to evaluate 4 CpG sites of the EDN3 promoter region in our samples (n=469). The data indicated that the methylation level of EDN3 was increased with the degree of cervical lesions. EDN3 silencing mediated by methylation can be blocked by 5-Azacytidine (5-Aza), a DNA methyltransferase 1 (DNMT1) inhibitor, treatment in cervical cancer cell lines. Ethynyldeoxyuridine (EdU) assay, would-healing assay, clone formation assay and transwell assay were conducted to investigate the biological function of EDN3 in cervical cancer cell lines. The results of these experiments confirmed that overexpression of EDN3 could inhibit the proliferation, clone formation, migration and invasion of cervical cancer cells. EDN3 may provide potential biomarker and therapeutic target for CSCC.

Aims: Ferroptosis plays important roles in tumorigenesis and cancer therapy. Zoledronic acid is known to inhibit the activity of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. We examined whether zoledronic acid can inhibit the growth of osteosarcoma cells by inducing ferroptosis.Methods: Cell viability was analyzed by using CCK8 reagent and counting cells with trypan blue exclusion. Ferroptosis markers including lipid peroxide and PTGS2 expression were examined by flow cytometry, western blot, and quantitative PCR analyses. Cellular ubiquinone content was determined using high performance liquid chromatography. Ferrostatin-1 and RSL3 were used as the ferroptosis inhibitor and inducer respectively.Results: Zoledronic acid treatment decreased cell viability and promoted the increase in lipid peroxide content and PTGS2 expression. Addition of ferrostatin-1 reverted these effects of zoledronic acid on osteosarcoma cells, supporting a role of zoledronic acid in inducing ferroptosis. Mechanistically, zoledronic acid significantly decreased ubiquinone, a metabolite of the mevalonate pathway. Treating cells with exogenous ubiquinone prevented zoledronic acid-induced ferroptosis and decrease in the growth of osteosarcoma cells. In addition, zoledronic acid enhanced the expression of HMOX1, whereas knockdown of HMOX1 inhibited the zoledronic acid-induced increase in lipid peroxide level and decrease in cell growth. Finally, zoledronic acid together with RSL3 significantly enhanced the inhibitory effect on the growth of osteosarcoma cells.Conclusion: Our results indicate that zoledronic acid induces ferroptosis by decreasing ubiquinone content and promoting HMOX1 expression in osteosarcoma cells. Zoledronic acid together with ferroptosis inducer may be a promising new strategy for the treatment of osteosarcoma.

Abstract Background Comprehensive antitumor therapy through integrated multimodal means has drawn increasing attention owing to its high efficiency and metastasis suppression. Results We describe a synergistic triple protocol combining photothermal and sonodynamic therapy (PTT and SDT), together with immune checkpoint blockade for the inhibition of breast cancer growth and metastases in the 4T1 mouse model. PTT and SDT are synergistically augmented by a novel multimodal imaging nanoprobe integrated with cancer cell membrane-biomimetic nanoparticles (CHINPs) loaded with superparamagnetic iron oxide (SPIO) and hematoporphyrin monomethyl ether (HMME). CHINPs exhibit excellent homologous tumor targeting, and are sequentially triggered by ultrasound and near infrared (NIR) light under the guidance of magnetic resonance, photoacoustic and photothermal imaging, leading to complete in situ tumor eradication and systemic anti-tumor immune activation. Further combination of this approach with immune checkpoint blockade therapy is shown to suppress tumor metastasis. Conclusion This work provides proof-of-principle for triple therapy using multimodal imaging-guided PTT/SDT based on biomimetic nanoprobes in combination with immunotherapy to eliminate tumors. Graphical Abstract

In real world industrial applications, the working environment of a bearing varies with time, and some unexpected vibration noises from other equipment are inevitable. In order to improve the anti-noise performance of neural networks, a new prediction model and a multi-channel sample generation method are proposed to address the above problem. First, we proposed a multi-channel sample representation method based on the envelope time–frequency spectrum of a different channel and subsequent three-dimensional filtering to extract the fault features of samples. Second, we proposed a multi-channel data fusion neural network (MCFNN) for bearing fault discrimination, where the dropout technique is used in the training process based on a dataset with a wide rotation speed and various loads. In a noise-free environment, our experimental results demonstrated that the proposed method can reach a higher fault classification of 99.00%. In a noisy environment, the experimental results show that for the signal-to-noise ratio (SNR) of 0 dB, the fault classification averaged 11.80% higher than other methods and 32.89% higher under a SNR of −4 dB.

Abstract The excessive consumption of sugars can cause health issues. Different strategies have been developed to reduce sugars in the diets. However, sugars in fruits and commercial products may be difficult to reduce, limiting their usage among certain populations of people. Zymomonas mobilis is a generally recognized as safe (GRAS) probiotic bacterium with the capability to produce levan-type prebiotics, and thrives in high-sugar environments with unique characteristics to be developed for lignocellulosic biofuel and biochemical production. In this study, the sugar reduction capabilities of Z. mobilis ZM4 were examined using two fruits of pear and persimmon and three high-sugar-content commercial products of two pear pastes (PPs) and one Chinese traditional wine (CTW). Our results demonstrated that Z. mobilis ZM4 can utilize sugars in fruits with about 20 g/L ethanol and less than 5 g/L sorbitol produced within 22 h using pears, and about 45 g/L ethanol and 30 g/L sorbitol produced within 34 h using persimmons. When PPs made from pears were used, Z. mobilis can utilize nearly all glucose (ca. 60 g/L) and most fructose (110 g/L) within 100 h with 40 ~ 60 g/L ethanol and more than 20 g/L sorbitol produced resulting in a final sorbitol concentration above 80 g/L. In the high-sugar-content alcoholic Chinese traditional wine, which contains mostly glucose and ethanol, Z. mobilis can reduce nearly all sugars with about 30 g/L ethanol produced, resulting in a final ethanol above 90 g/L. The ethanol yield and percentage yield of Z. mobilis in 50 ~ 60% CTW were 0.44 ~ 0.50 g/g and 86 ~ 97%, respectively, which are close to its theoretical yields—especially in 60% CTW. Although the ethanol yield and percentage yield in PPs were lower than those in CTW, they were similar to those in fruits of pears and persimmons with an ethanol yield around 0.30 ~ 0.37 g/g and ethanol percentage yield around 60 ~ 72%, which could be due to the formation of sorbitol and/or levan in the presence of both glucose and fructose. Our study also compared the fermentation performance of the classical ethanologenic yeast Saccharomyces cerevisiae BY4743 to Z. mobilis, with results suggesting that Z. mobilis ZM4 had better performance than that of yeast S. cerevisiae BY4743 given a higher sugar conversion rate and ethanol yield for sugar reduction. This work thus laid a foundation for utilizing the advantages of Z. mobilis in the food industry to reduce sugar concentrations or potentially produce alcoholic prebiotic beverages. Graphical Abstract

Abstract Background Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. Results The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusions This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment. Graphical Abstract

BackgroundGlobally, lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths. It is a progressive disorder that arises from multiple genetic and environmental factors. Dysregulated expression of vesicle-mediated transport-related genes (VMTRGs) have been reported in several cancers. However, the prognostic significance of VMTRGs in LUAD has yet to be established.MethodsThe VMTRG profiling data for 482 LUAD patients and 59 normal controls were downloaded from The Cancer Genome Altas (TCGA). Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct and optimize the risk model. Several GEO datasets were used to validate the risk model. The roles of these genes were investigated via the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses. Differences in immune cell infiltrations between risk groups were evaluated using five algorithms. “pRRophetic” was used to investigate anti-cancer drug sensitivities in two groups. Expression of these five genes in LUAD samples and adjacent normal tissues were evaluated by qRT-PCR. Colony formation and wound healing assays were performed to assess the significance of CNIH1 and AP3S1 in LUAD cells.ResultsWe identified 85 prognosis-associated VMTRGs that could be constructed a risk model for LUAD patients, indicating their potential importance in LUAD development. The risk model including the five VMTRGs (CNIH1, KIF20A, GALNT2, GRIA1, and AP3S1) was associated with clinical outcomes. Tumor stage and risk score were found to be independent prognostic factors for LUAD patients. The five VMTRGs were also correlated with activation of the Notch and p53 signaling pathways. The risk model was significantly associated with immune responses and with high-level expression of immune checkpoints. High-risk group patients were more sensitive to several chemotherapeutic drugs and Lapatinib. Furthermore, CNIH1 and AP3S1 promoted LUAD cell growth and migration in vitro.ConclusionWe constructed a VMTRG-based risk model for effective prediction of prognostic outcomes for LUAD patients. The risk model was associated with immune infiltration levels. These five hub genes are potential targets for immune therapy combined with chemotherapy in LUAD.

There is an increasing number of Chinese graduate students who study in Canada and have quite different educational backgrounds. Despite a large number of studies attending to the challenges and difficulties they encountered in life and study, not much research narratively explores Chinese international students’ academic adjustment experiences in graduate programs in Canada. To fill the gap, this research makes a narrative inquiry into three Chinese international students’ academic adjustment in the graduate and doctoral programs of two universities in Ontario, Canada. The three-dimensional framework (Clandinin, 2006) is employed to tell and retell their stories. Their narratives have revealed the importance of their native languages and how their past experiences before they came to Canada influenced their academic adjustment. The Eastern and Western cultures have had a lasting effect on their personal and professional development. In addition, they have played multiple roles as Chinese international students, novice researchers, and future educational practitioners.

This study aimed to investigate the immunomodulatory activation of low-molecular-weight peptides from monkfish (Lophius litulon) roe (named MRP) on cyclophosphamide (CTX)-induced immunosuppressed mice. Our results indicated that MRP (100 mg/kg/d BW) could significantly increase the body weight and immune organ index, and improve the morphological changes in the spleen and thymus of mice. These effects subsequently enhance the serum levels of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and immunoglobulin (Ig) A, IgM, and IgG. Furthermore, MRP could also improve CTX-induced oxidative stress, and activate the NF-κB and MAPK pathways in the spleen tissues. The findings reported herein indicate that MRP has a good immunomodulatory activation toward immunosuppressed mice, hence can potentially be developed as an immune adjuvant or functional food.

Oocyte quality is essential for a successful pregnancy. 1-Nitropyrene (1-NP) is a widely distributed pollutant in the environment and is well-known for its mutagenicity and carcinogenicity. However, whether 1-NP has toxic effects on mammalian oocyte quality remains unknown. In the present study, we focused on the effect of 1-NP on oocyte maturation using mouse oocytes as an in vitro model. Our study showed that 1-NP exposure disrupted the meiotic spindle assembly and caused chromosome misalignment, further impaired first polar body extrusion, and significantly decreased the fertilization capability in mouse oocytes. Further investigation showed that the mitochondrial membrane potential (MMP) and ATP levels were decreased, and the expression of genes encoding components of the mitochondrial respiratory chain was inhibited in 1-NP exposed oocytes. Meanwhile, 1-NP exposure increased the levels of reactive oxygen species (ROS), inhibited the expression of genes encoding antioxidant enzymes, and increased the frequency of early apoptotic oocytes. Overall, our data suggest that 1-NP exposure disrupts mitochondrial function and intracellular redox balance, ultimately impairing oocyte maturation. These findings reveal the adverse effect of 1-NP exposure on oocyte quality.

The incidence of hyperuricemia (HUA) and gout continuously increases and has become a major public health problem. The gut microbiota, which colonizes the human intestine, has a mutually beneficial and symbiotic relationship with the host and plays a vital role in the host’s metabolism and immune regulation. Structural changes or imbalance in the gut microbiota could cause metabolic disorders and participate in the synthesis of purine-metabolizing enzymes and the release of inflammatory cytokines, which is closely related to the occurrence and development of the metabolic immune disease HUA and gout. The gut microbiota as an entry point to explore the pathogenesis of HUA and gout has become a new research hotspot. This review summarizes the characteristics of the gut microbiota in patients with HUA and gout. Meanwhile, the influence of different dietary structures on the gut microbiota, the effect of the gut microbiota on purine and uric acid metabolism, and the internal relationship between the gut microbiota and metabolic endotoxemia/inflammatory factors are explored. Moreover, the intervention effects of probiotics, prebiotics, and fecal microbial transplantation on HUA and gout are also systematically reviewed to provide a gut flora solution for the prevention and treatment of related diseases.

Oocyte quality is a determinant of a successful pregnancy. The final step of oocyte development is oocyte maturation, which is susceptible to environmental exposures. Aristolochic acids (AAs), widely existing in Aristolochia and Asarum plants that have been used in traditional medicine, can result in a smaller ovary and fewer superovulated oocytes after in vivo exposure to mice. However, whether AAs affect oocyte maturation and the underlying mechanism(s) are unclear. In this study, we focused on the effect of Aristolochic acid I (AAI), a major compound of AAs, on the maturation of in vitro cultured mouse oocytes. We showed that AAI exposure significantly decreased oocyte quality, including elevated aneuploidy, accompanied by aberrant chiasma patterns and spindle organization, and decreased first polar body extrusion and fertilization capability. Moreover, embryo development potential was also dramatically decreased. Further analyses revealed that AAI exposure significantly decreased mitochondrial membrane potential and ATP synthesis and increased the level of reactive oxygen species (ROS), implying impaired mitochondrial function. Insufficient ATP supply can cause aberrant spindle assembly and excessive ROS can cause premature loss of sister chromatid cohesion and thus alterations in chiasma patterns. Both aberrant spindles and changed chiasma patterns can contribute to chromosome misalignment and thus aneuploidy. Therefore, AAI exposure decreases oocyte quality probably via impairing mitochondrial function.

Long-term hypercaloric intake such as a high-fat diet (HFD) could act as negative regulators on bone remodeling, thereby inducing bone loss and bone microarchitecture destruction. Currently, food-derived natural compounds represent a promising strategy to attenuate HFD-induced bone loss. We previously prepared a whey protein hydrolysate (WPH) with osteogenic capacity. In this study, we continuously isolated and identified an osteogenic and antioxidant octapeptide TPEVDDA from WPH, which significantly promoted the alkaline phosphatase activities on MC3T3-E1 cells and exerted DPPH radical scavenging capacity. We then established an HFD-fed obese mice model with significantly imbalanced redox status and reduced bone mass and further evaluated the effects of different doses of WPH on ameliorating the HFD-induced bone loss and oxidative damages. Results showed that the administration of 2% and 4% WPH for 12 weeks significantly restored perirenal fat mass, improved serum lipid levels, reduced oxidative stress, and promoted the activity of antioxidant enzymes; meanwhile, WPH significantly preserved bone mass and bone mechanical properties, attenuated the degradation of trabecular microstructure, and regulated serum bone metabolism biomarkers. The protein levels of Runx2, Nrf2, and HO-1, as well as the phosphorylation level of GSK-3β in tibias, were notably activated by WPH. Overall, we found that the potential mechanism of WPH on ameliorating the HFD-induced bone loss mainly through its antioxidant and osteogenic capacity by activating Runx2 and GSK-3β/Nrf2 signaling pathway, demonstrating the potential of WPH to be used as a nutritional strategy for obesity and osteoporosis.

ObjectiveTo analyze the patient and visitor workplace violence (PVV) toward health workers (HWs) and identify correlations between worker characteristics, measures against violence and exposure to PVV in COVID-19 pandemic.MethodsA cross-sectional survey utilizing the international questionnaires in six public tertiary hospitals from Beijing in 2020 was conducted, and valid data from 754 respondents were collected. Multilevel logistic regression models were used to determine the association between independents and exposure to PVV.ResultsDuring COVID-19 pandemic and regular epidemic prevention and control, doctors were 5.3 times (95% CI = 1.59~17.90) more likely to suffer from physical PVV than nurses. HWs most frequently work with infants were 7.2 times (95% CI = 2.24~23.19) more likely to suffer from psychological PVV. More than four-fifth of HWs reported that their workplace had implemented security measures in 2020, and the cross-level interactions between the security measures and profession variable indicates that doctors in the workplace without security measures were 11.3 times (95% CI = 1.09~116.39) more likely to suffer from physical PVV compared to nurses in the workplace with security measures.ConclusionDoctors have higher risk of physical PVV in COVID-19 containment, and the security measures are very important and effective to fight against the physical PVV. Comprehensive measures should be implemented to mitigate hazards and protect the health, safety, and well-being of health workers.

Abstract Background Sonodynamic therapy (SDT) is an emerging non-invasive therapeutic technique. SDT-based cancer therapy strategies are presently underway, and it may be perceived as a promising approach to improve the efficiency of anti-cancer treatment. In this work, multifunctional theranostic nanoparticles (NPs) were synthesized for synergistic starvation therapy and SDT by loading glucose oxidase (GOx, termed G) and 5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (T (p-Cl) PPMnCl, termed PMnC) in Poly (lactic-co-glycolic) acid (PLGA) NPs (designated as MG@P NPs). Results On account of the peroxidase-like activity of PMnC, MG@P NPs can catalyze hydrogen peroxide (H2O2) in tumor regions to produce oxygen (O2), thus enhancing synergistic therapeutic effects by accelerating the decomposition of glucose and promoting the production of cytotoxic singlet oxygen (1O2) induced by ultrasound (US) irradiation. Furthermore, the NPs can also serve as excellent photoacoustic (PA)/magnetic resonance (MR) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusion Multifunctional MG@P NPs can effectuate the synergistic amplification effect of cancer starvation therapy and SDT by hypoxia modulation, and act as contrast agents to enhance MR/PA dual-modal imaging. Consequently, MG@P NPs might be a promising nano-platform for highly efficient cancer theranostics. Graphical Abstract