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Background: Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

In the context of hepatocellular carcinoma (HCC) treatment, this study introduces a biomimetic “bomb” approach to target HCC by utilizing macrophages (MAs) as ultrasound-responsive carriers. This advanced biomimetic drug delivery system (MAs-DOX/PFP/Ms, MAs-DPM) encapsulates doxorubicin (DOX) and perfluoropentane (PFP) and is designed to precisely target HCC. MAs-DPM exhibits excellent drug loading capacity and biocompatibility, can effectively release DOX and enhance ultrasound imaging capabilities under ultrasound irradiation (UI). Experiments confirmed that MA maintained its biological activity and vitality during co-incubation and phagocytosis with DOX-loaded DPM, and microscopy confirmed that MA effectively engulfed DPM without changing cell morphology or function. Transwell experiments demonstrated that this bionic “bomb” (MAs-DPMs) not only retained the tumor targeting ability of macrophages, but also successfully delivered therapeutic drugs to tumor cells. Compared with samples without UI treatment, UI significantly increased the release of DOX from MAs-DPM, enhanced the drug release rate and inhibited the growth of HCC cells. Live/Dead staining experiments further intuitively revealed the precise “biobomb” effect of MAs-DPM under UI, effectively proving its ability to inhibit HCC cell proliferation. In vivo studies demonstrated that MAs-DPM was able to proficiently localize tumor sites within 24 h. Furthermore, the ultrasound-mediated phase transition of PFP enhanced the imaging efficacy, confirming the feasibility of macrophage-mimicking biological bombs for real-time in vivo ultrasound tracking. In the tumor-bearing nude mouse model, UI-treated MAs-DPMs remarkably delayed tumor growth and prolonged survival time compared with other groups. Subsequent histological and serum index evaluation further confirmed the in vivo safety of MAs-DPMs, and UI-treatment did not induce significant histological or pathological changes or statistical differences in vital organ or serum markers. These experiment results highlight the great potential of MAs-DPM as a strategic approach for the diagnosis and treatment of HCC.

Abstract Background Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis. Methods The expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People’s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied. Results LINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models. Conclusion We demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.

【Objective】Endophytic bacteria exert an important role in plant growth and development. The study aims to analyze the community structure and diversity of endophytic bacteria in pulp of different litchi varieties, and screen and utilize the potential endophytic bacteria resources, which would provide references for further research on the interaction between litchi and endophytic bacteria.【Method】The pulp tissues of 6 different litchi varieties were used as materials. MiSeq high-throughput sequencing technology was used to compare and analyze the community composition and dominant flora of endophytic bacteria at phylum, family, genus and species classification levels in pulp tissues after the V3~V4 region of 16S rDNA was amplified by PCR. The diversity of endophytic bacteria was evaluated combined with Alpha diversity analysis.【Result】A total of 2 139 086 sequences of endophytic bacteria 16S rDNA were obtained in the V3~V4 region of 6 litchi varieties, and the average length of amplified sequences was 376 bp. There was no significant difference in the abundance and diversity of endophytic bacteria in different litchi varieties. At the phylum classification level, Proteobacteria was the main dominant bacterial group in litchi pulp tissue, followed by Actinomyces. At the levels of family, genus and species classification, the endophytic bacterial community structure of different litchi varieties was similar, but the bacterial abundance proportion was different. Differential bacterial community analysis showed that the Pseudomonas, Pectobacterium, Ochrobactrum and Dickeya were significantly enriched in the high-quality varieties of 'Edanli', 'Nuomici' and 'Guanyinlv'. In addition, Bradyrhizobium and Snodgrassella were only enriched in the 'Edanli'. The clustering analysis of relative abundance of bacteria showed that 'Guanyinlv', 'Nuomici' and 'Edanli', had higher similarity. Alpha diversity analysis showed that there were differences in the abundance and diversity of endophytic flora in pulps of 6 litchi varieties, but the differences were not significant.【Conclusion】In this study, the community structure of endophytic bacteria in the pulp of six different litchi varieties was analyzed, and some unique microbial genera were enriched in the high-quality litchi varieties. The results could provide a theoretical basis and important references for the development and utilization of endophytic bacteria to improve litchi quality.

Abstract Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma.

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by substantial morbidity and mortality rates. It is a chronic condition characterized by intricate pathogenesis and uncontrollable factors. We summarized the pathological effects of estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification on PH. PH is not only a pulmonary vascular disease, but also a systemic disease. The findings emphasize that the onset of PH is not exclusively confined to the pulmonary vasculature, consequently necessitating treatment approaches that extend beyond targeting pulmonary blood vessels. Hence, the research on the pathological mechanism of PH is not limited to target organs such as pulmonary vessels, but also focuses on exploring other fields (such as estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification).

BackgroundAccurate detection of the histological grade of pancreatic neuroendocrine tumors (PNETs) is important for patients’ prognoses and treatment. Here, we investigated the performance of radiological image-based artificial intelligence (AI) models in predicting histological grades using meta-analysis.MethodA systematic literature search was performed for studies published before September 2023. Study characteristics and diagnostic measures were extracted. Estimates were pooled using random-effects meta-analysis. Evaluation of risk of bias was performed by the QUADAS-2 tool.ResultsA total of 26 studies were included, 20 of which met the meta-analysis criteria. We found that the AI-based models had high area under the curve (AUC) values and showed moderate predictive value. The pooled distinguishing abilities between different grades of PNETs were 0.89 [0.84-0.90]. By performing subgroup analysis, we found that the radiomics feature-only models had a predictive value of 0.90 [0.87-0.92] with I2 = 89.91%, while the pooled AUC value of the combined group was 0.81 [0.77-0.84] with I2 = 41.54%. The validation group had a pooled AUC of 0.84 [0.81-0.87] without heterogenicity, whereas the validation-free group had high heterogenicity (I2 = 91.65%, P=0.000). The machine learning group had a pooled AUC of 0.83 [0.80-0.86] with I2 = 82.28%.ConclusionAI can be considered as a potential tool to detect histological PNETs grades. Sample diversity, lack of external validation, imaging modalities, inconsistent radiomics feature extraction across platforms, different modeling algorithms and software choices were sources of heterogeneity. Standardized imaging, transparent statistical methodologies for feature selection and model development are still needed in the future to achieve the transformation of radiomics results into clinical applications.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022341852.

Starting from the idea of constructing the standard incidence rate, we take the effective contact times of individuals in the population per unit time as a contact function, $ T(\cdot) $, which depends on the population size. Considering the influence of disease on the contact function, the influence intensity factor of the disease affected by the infected person is integrated into the nonlinear incidence rate. We propose an epidemic model with a class of disease-related contact functions. Then, we analyze the well-posedness of the solutions of the model. By using the next generation matrix method, we get the basic reproduction number $ \mathcal{R}_0 $. We find that the existence and stability of the equilibria are not only related to $ \mathcal{R}_0 $, but also to the intensity of the disease affected for the infected person, $ \eta $, and the contact function, $ T(\cdot) $. We obtain some stability results under different assumptions about the contact function. Finally, we use MATLAB to simulate the system for several different contact functions. The numerical simulation results agree with our qualitative study. At the same time, we also prove that the system may have a Hopf bifurcation when the contact function $ T(\cdot) $ satisfies some corresponding conditions.

Abstract Background The incidence of pancreatic cancer (PC) is higher in diabetic patients due to disturbances in glucose and lipid metabolism caused by insulin resistance (IR). However, the effect of diabetes as well as IR on the prognosis of PC patients remains inconclusive. Our study aims to assess the impact of IR on the prognosis of PC patients with diabetes. Methods We conducted a retrospective analysis of 172 PC patients with diabetes in our institute from 2015 to 2021. Prognostic assessment was performed using univariate/multifactorial analysis and survival analysis. The predictive efficacy of metabolic indices was compared using receiver operator characteristic (ROC) curve analysis. Results One hundred twenty‐one of 172 patients died during follow‐up, with a median follow‐up of 477 days and a median overall survival (OS) of 270 days. Survival analysis showed a significant difference in OS by IR related parameters, which were triglyceride‐glucose index (TyG), triglyceride‐glucose index‐body mass index (TyG‐BMI), and triglyceride/high‐density lipoprotein cholesterol ratio (TG/HDL‐c). The ROC curve indicated that TyG, TyG‐BMI, and TG/HDL‐c had prognostic efficacy for PC with diabetes. We next optimized TyG‐BMI and obtained a new parameter, namely glucose‐lipid metabolism index (GLMI), and the patients were classified into GLMI low group and high group based on the calculated cutoff value. The GLMI high group had higher TyG, TyG‐BMI, TyG/HDL‐c, BMI, TG, total cholesterol (TC), TC/HDL‐c, fasting plasma glucose, CA199, and more advanced tumor stage compared to low group. Univariate and multivariate analyses showed that GLMI was an independent prognostic factor. Furthermore, the patients of GLMI high group had worse OS compared to low group and the ROC curves showed GLMI had better predictive ability than TyG and TyG‐BMI. Conclusions IR is associated with the outcome of PC patients with diabetes and higher level of IR indicates worse prognosis. GLMI has a good predictive value for PC with diabetes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an extremely poor prognosis. Cancer stem cells (CSCs) are considered to be responsible for the poor survival, recurrence and therapy resistance of PDAC. Ferroptosis plays a crucial role in the sustain and survival of CSCs. Here, we employed a rigorous evaluation of multiple datasets to identify a novel stemness-based and ferroptosis-related genes (SFRGs) signature to access the potential prognostic application. This work we retrieved RNA-sequencing and clinical annotation data from the TCGA, ICGC, GTEx and GEO database, and acquired 26 stem cell gene sets and 259 ferroptosis genes from StemChecker database and FerrDb database, respectively. Based on consensus clustering and ssGSEA analysis, we identified two expression patterns of CSCs traits (C1 and C2). Then, WGCNA analysis was implemented to screen out hub module genes correlated with stemness. Furthermore, differential expression analysis, Pearson correlation analysis, and the Least absolute shrinkage and selection operator (LASSO) and Cox regression were performed to identify the SFRGs and to construct model. In addition, the differences in prognosis, tumor microenvironment (TME) components and therapy responses were evaluated between two risk groups. Finally, we verified the most influential marker ARNTL2 experimentally by western blot, qRT-PCR, sphere formation assay, mitoscreen assay, intracellular iron concentration determination and MDA determination assays. In conclusion, we developed a stemness-based and ferroptosis-related prognostic model, which could help predict overall survival for PDAC patients. Targeting ferroptosis may be a promising therapeutic strategy to inhibit PDAC progression by suppressing CSCs.

Abstract Tumors usually display fetal‐like characteristics, and many oncofetal proteins have been identified. However, fetal‐like reprogramming of RNA splicing in hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with tumor progression. By combining RNA‐Seq with splicing analysis, it is identified that ESRP2 controls the fetal‐to‐adult switch of multiple splice isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12 protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1 kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint therapy achieved potent tumor regression in mice. Overall, the findings reveal a previously unexplored onco‐fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC.

Abstract The main issue limiting the performance of the solar evaporators is that water-thermal management is difficult to coordinate. Herein, we achieve integrated water-thermal management by designing hierarchical MXene-reduced graphene oxide sponges with anisotropic thermal conductivity and axial-directional water conveyance channels. The reduced graphene oxide acts as the sponge framework and carbon source for in situ synthesis of MXenes on the surface. The axial-oriented framework supports the structure and provides fast water transmission channels to the air-water interface. Meanwhile, the MXene nanosheets are vertically aligned on the framework surface, making the radial thermal conductivity of the sponges much greater than the axial one, which suppresses heat loss in the axial direction. The material exhibits an evaporation rate of 2.35 kg m−2 h−1 under one sunlight and maintains 85 % energy efficiency under weak sunlight (0.5-sun). Furthermore, the sponge shows a long working life with 96 % evaporation rate retention after a 30-day-sustained operation.

Abstract Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment. Graphical Abstract

Abstract Background Periampullary diverticulum (PAD) may make the performance of endoscopic retrograde cholangiopancreatography (ERCP) in patients with choledocholithiasis more difficult and may increase complication rates. The present study evaluated the effects of PAD on first-time ERCP in patients with choledocholithiasis. Methods Outcomes were compared in patients with and without PAD and in those with four types of PAD: papilla located completely inside the diverticulum (type I), papilla located in the inner (type II a) and outer (type II b) margins of the diverticulum; and papilla located outside the diverticulum (type III). Parameters compared included cannulation time and rates of difficult cannulation, post-ERCP pancreatitis (PEP) and perforation. Results The median cannulation times in patients with types I, II a, II b, III PAD and in those without PAD were 2.0 min, 5.0 min, 0.67 min, 3.5 min, and 3.5 min, respectively, with difficult cannulation rates in these groups of 7.4%, 31.4%, 8.3%, 18.9%, and 23.2%, respectively. The rates of PEP in patients with and without PAD were 5.3% and 5.1%, respectively. Four patients with and one without PAD experienced perforation. Conclusions The division of PAD into four types may be more appropriate than the traditional division into three types. Cannulation of type I and II b PAD was easier than cannulation of patients without PAD, whereas cannulation of type II a PAD was more challenging. PAD may not increase the rates of PEP.

The arabinoxylan was extracted from the vinegar residues by alkaline extraction. Single-factor experiments were carried out on the concentration of NaOH (containing 0.88% H2O2), extraction temperature, solid-liquid ratio, and extraction time, and the four parameter levels with the highest extraction rate of arabinoxylan were found. On this basis, the response surface method was used to optimize. The monosaccharide composition and molecular weight of the optimized polysaccharides were analyzed and their effects on the quality of steamed bread were studied. The results showed that the optimal experimental conditions for alkaline extraction of arabinoxylan were as follows: NaOH (containing 0.88% H2O2) concentration 0.92 mol/L, extraction temperature 75 ℃, solid-liquid ratio 1:35 g/mL, extraction time 1.5 h, the yield of arabinoxylan was 8.75%. The main monosaccharides extracted by this experiment were as follow: Arabinose, galactose, glucose, xylose, galacturonic acid, glucuronic acid with ration of 38.9%, 1.32%, 2.37%, 55.84%, 0.66%, 0.91%. The dispersion coefficient of the arabinoxylan extracted by this method was 2.45, average molecular weight was 245997, indicating arabinoxylan was a homogeneous polysaccharide. Additional, adding an appropriate amount of vinegar AX to the flour could reduce the hardness and viscosity of the steamed bread, improve the texture characteristics of the steamed bread, and improve the quality of the steamed bread. The arabinoxylan obtained in this study had good functional characteristics, which also provided data and theoretical support for the utilization of vinegar residues.

Abstract Stroke has caused tremendous social stress worldwide, yet despite decades of research and development of new stroke drugs, most have failed and rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. the complexity of the stroke mechanism has led to unsatisfactory efficacy of most drugs in clinical trials, indicating that there are still many gaps in our understanding of stroke. Pyroptosis is a programmed cell death (PCD) with inflammatory properties and are thought to be closely associated with stroke. Pyroptosis is regulated by the GSDMD of the gasdermin family, which when cleaved by Caspase-1/Caspase-11 into N-GSDMD with pore-forming activity can bind to the plasma membrane to form small 10–20 nm pores, which would allow the release of inflammatory factors IL-18 and IL-1β before cell rupture, greatly exacerbating the inflammatory response. The pyroptosis occurs mainly in the border zone of cerebral infarction, and glial cells, neuronal cells and brain microvascular endothelial cells (BMECs) all undergo pyroptosis after stroke, which largely exacerbates the breakdown of the blood-brain barrier (BBB) and thus aggravates brain injury. Therefore, pyroptosis may be a good direction for the treatment of stroke. In this review, we focus on the latest mechanisms of action of pyroptosis and the process by which pyroptosis regulates stroke development. We also suggest potential therapeutic stroke drugs that target the pyroptosis pathway, providing additional therapeutic strategies for the clinical management of stroke. The role of pyroptosis after stroke. After stroke, microglia first rush to the damaged area and polarize into M1 and M2 types. Under the influence of various stimuli, microglia undergo pyroptosis, release pro-inflammatory factors, and are converted to the M1 type; astrocytes and neuronal cells also undergo pyroptosis under the stimulation of various pro-inflammatory factors, leading to astrocyte death due to increased osmotic pressure in the membrane, resulting in water absorption and swelling until rupture. BMECs, the main structural component of the BBB, also undergo pyroptosis when stimulated by pro-inflammatory factors released from microglia and astrocytes, leading to the destruction of the structural integrity of the BBB, ultimately causing more severe brain damage. In addition, GSDMD in neutrophils mainly mediate the release of NETs rather than pyroptosis, which also aggravates brain injury. IL-10=interleukin-10; TGF-β = transforming growth factor-β; IL-18=interleukin-18; IL-1β = interleukin-1β; TNF-α = tumor necrosis factor-α; iNOS=induced nitrogen monoxide synthase; MMPs=Matrix metalloproteinases; GSDMD = gasdermin D; BMECs=brain microvascular endothelial cells; BBB = blood-brain barrier.

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) screening is a simple screening method for locating loci under specific conditions, and it has been utilized in tumor drug resistance research for finding potential drug resistance-associated genes. This screening strategy has significant implications for further treatment of malignancies with acquired drug resistance. In recent years, studies involving genome-wide CRISPR/Cas9 screening have gradually increased. Here we review the recent application of genome-wide CRISPR/Cas9 screening for drug resistance, involving mitogen-activated protein kinase (MAPK) pathway inhibitors, poly (ADP-ribose) polymerase inhibitors (PARPi), alkylating agents, mitotic inhibitors, antimetabolites, immune checkpoint inhibitors (ICIs), and cyclin-dependent kinase inhibitors (CDKI). We summarize drug resistance pathways such as the KEAP1/Nrf2 pathway MAPK pathway, and NF-κB pathway. Also, we analyze the limitations and conditions for the application of genome-wide CRISPR/Cas9 screening techniques.

Background Studies have shown a relationship between oestrogen and Alzheimer's disease. However, there is neither clear nor strong evidence on the use of oestrogen-only therapy in reducing the risk of Alzheimer's disease. Aims To assess the effects of oestrogen-only therapy on reducing the risk of Alzheimer's disease. Method Inclusion criteria was determined with the PICO framework. Outcome was cognitive function measured by neuropsychological tests and strict protocols. Exclusion criteria included non-Alzheimer's dementia, progesterone-only therapy and pre-menopausal women. Searches were conducted in nine electronic healthcare databases, last searched in July 2022. Quality assessments conducted on randomised controlled trials (RCTs) were performed with the GRADE assessment, and cohort studies and case–control studies were assessed with the Newcastle–Ottawa Scale. Extracted data were used to analyse participants, interventions and outcomes. Results Twenty-four studies satisfied the search criteria (four RCTs, nine cohort studies, 11 case–control studies). Fifteen studies showed positive associations for oestrogen-only therapy reducing the risk of Alzheimer's disease, and the remaining nine found no evidence of association. Conclusions Fifteen studies showed that oestrogen-only therapy effectively reduced the risk of Alzheimer's disease, whereas nine showed no correlation. Studies also investigated oestrogen-related variables such as length of oestrogen exposure, being an apolipoprotein E ε4 carrier and concomitant use of non-steroidal anti-inflammatory drugs, and their role in neuroprotection. This review was limited by the limited ranges of duration of oestrogen treatment and type of oestrogen-only therapy used. In conclusion, oestrogen-only therapy has potential for use in preventing Alzheimer's disease, although current evidence is inconclusive and requires further study.

【Objective】Xianjinfeng litchi is a new variety introduced in recent years. It is characterized by high quality and late ripening and has significant economic and social benefits in the middle and late ripening litchi producing areas, however, its efficient and high-yield cultivation technology needs to be studied. Shoot bending is an important shaping and pruning method in orchard management, which can effectively reduce the apex dominance and facilitate flowering and fruiting. Here, the effects of different bending treatments on Xianjinfeng litchi were explored in order to provide references for the application of shoot bending technology as well as the establishment of technology for stable and high yield.【Method】Xianjinfeng litchi grafted for four years was used as the test material, and three bending treatments were set: vertical (0°, CK), horizontal (90 °) and drooping (110 °). After treatments, the indicators including growth, flowering rate, and fruit setting rate were counted.【Result】Compared with the vertical treatment (CK), drooping and horizontal treatments had limited effects on the vegetative growth of the first and second shoots, but delayed the germination of the third shoot (the last autumn shoot) for more than seven days, and dramatically reduced germination number of shoots at the same time. In addition, drooping treatment had the strongest inhibitory effect. When the leaves of the last autumn shoot were mature, the branch diameter under bending treatments was slightly lower than that under CK, however, and there were no significant difference among all treatments. Both drooping and horizontal bending treatments could effectively control the length of the last autumn shoot to about 15 cm, promote the growth of short and medium shoots, which was conducive to flowering and fruiting. In the coming spring, the flowering rate and fruit setting rate of drooping and horizontal treatments were notably higher than those of vertical treatment (CK). The flowering rate of droop treatment reached 100%, and all of them were pure flowers with high quality, while vertical treatment (CK) produced more panicles with leaves in comparison with the other two treatments. There was no significant difference in the length of panicle among different treatments, however, the base diameter of panicle were observably reduced and vigorous growth of panicles were inhibited by bending treatments. Fifty days after blooming of pistillate flowers, the fruit setting rates under drooping and horizontal treatments were 9.81% and 7.61%, respectively, markedly higher than that under vertical treatment (CK, 5.54%).【Conclusion】For Xianjinfeng litchi, drooping and horizontal branch bending can effectively control the excessive growth of parent branches, improve the quality of flowers, and significantly increase fruit setting rate. The best results are obtained under drooping treatment (110°).

Objective: This study aims to explore the minimum number of lymph nodes (LNs) necessary for assessing the postoperative staging of adenocarcinoma of esophagogastric junction (AEG). Methods: We extracted the data of patients from the Surveillance Epidemiology and End Results (SEER) database, who were pathologically diagnosed with AEG between 2000 and 2017. We explored the associations between the number of LNs and overall survival (OS) by univariate and multivariate analyses and determined the proper cutoff value of the number of LNs necessary for accurate postoperative staging. Results: Of the patients with AEG in the SEER database, 2668 met our inclusion criteria. The total number of regional LNs dissected was found to be significantly associated with survival in analyses stratified by T stage. Univariate and multivariate regression showed that age, grade, positive LNs, number of LNs examined, and T stage were independently associated with OS. For patients with T1-2 tumors, the 5-year survival rate was 58.7%, and patients with more than 11 LNs examined obtained a greater survival benefit. Among patients with T3-4 tumors, the 5-year survival rates were 28.9% and 39.7% for those with 1–16 LNs examined and for those with more than 17 LNs examined, respectively. Conclusion: To accurately determine the pathological stage of patients with AEG, no less than 11 LNs must be resected for patients with stage T1-2 disease, and no less than 16 LNs must be resected for patients with stage T3-4 disease.

Abstract Pulmonary hypertension (PH) was a cardiovascular disease with high morbidity and mortality. PH was a chronic disease with complicated pathogenesis and uncontrollable factors. PH was divided into five groups according to its pathogenesis and clinical manifestations. Although the treatment and diagnosis of PH has made great progress in the past ten years. However, the diagnosis and prognosis of the PAH had a great contrast, which was not conducive to the diagnosis and treatment of PH. If not treated properly, it will lead to right ventricular failure or even death. Therefore, it was necessary to explore the pathogenesis of PH. The problem we urgently need to solve was to find and develop drugs for the treatment of PH. We reviewed the PH articles in the past 10 years or so as well as systematically summarized the recent advance. We summarized the latest research on the key regulatory factors (pyroptosis, apoptosis, necroptosis, ferroptosis, and endoplasmic reticulum stress) involved in PH. To provide theoretical basis and basis for finding new therapeutic targets and research directions of PH.

The ability of cancer stem cells (CSCs) to self-renew, differentiate, and generate new tumors is a significant contributor to drug resistance, relapse, and metastasis. Therefore, the targeting of CSCs for treatment is particularly important. Recent studies have demonstrated that CSCs are more susceptible to ferroptosis than non-CSCs, indicating that this could be an effective strategy for treating tumors. Ferroptosis is a type of programmed cell death that results from the accumulation of lipid peroxides caused by intracellular iron-mediated processes. CSCs exhibit different molecular characteristics related to iron and lipid metabolism. This study reviews the alterations in iron metabolism, lipid peroxidation, and lipid peroxide scavenging in CSCs, their impact on ferroptosis, and the regulatory mechanisms underlying iron metabolism and ferroptosis. Potential treatment strategies and novel compounds targeting CSC by inducing ferroptosis are also discussed.

Introduction: The application of Fe- (BC-Fe) and Mg-modified (BC-Mg) biochars for the remediation of heavy-metal-contaminated soil has become a research hotspot in recent years. It is critical to select suitable biochar for soil rejuvenation under the same pollution condition.Methods: In this study, the biochars were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM). In addition, the adsorption and passivation effects of BC-Fe and BC-Mg were comprehensively evaluated through batch adsorption experiments and soil incubation experiments, and the effects of Cd-contaminated soil on plant growth were also demonstrated by pot experiments.Results: SEM, FTIR, and XRD showed that MgO and Fe3O4 nanoparticles were successfully loaded on the biochar surface. The maximum adsorption efficiencies of BC-Fe and BC-Mg for Cd were 52.63 and 66.23 mg g−1, which was 9.05 and 7.19 times higher than that of the original biochar (7.32 mg g−1), respectively. Soil culture experiment showed that 5% BC-Fe and BC-Mg significantly reduced soil DTPA-Cd content by 38.86% and 50.85% at 120 days, respectively. In addition, BC-Fe and BC-Mg promoted the conversion of acid-soluble Cd to the oxidizable and residual states. Pot experiments revealed that BC-Fe and BC-Mg reduced the Cd content in shoots of the maize by 3.97 and 6.09 times, respectively, and both significantly increased the dry and fresh weights of the shoots and roots of the maize plants. Moreover, BC, BC-Fe, and BC-Mg provided nutrients required for plant growth to the soil and increased the activities of soil dehydrogenase, urease, and peroxidase. The adsorption–passivation mechanism of BC-Fe on Cd mainly included electrostatic attraction, while the adsorption–passivation mechanism of BC-Mg on Cd included precipitation and ion exchange.Discussion: Overall, the results showed that BC-Mg can be used as an efficient functional material for heavy-metal pollution remediation, and this study provided guidance on the selection of passivator materials for heavy-metal-contaminated soil remediation.

Hepatocellular carcinoma (HCC) is a heterogeneous and aggressive liver cancer that presents limited treatment options. Despite being the standard therapy for advanced HCC, sorafenib frequently encounters resistance, emphasizing the need to uncover the underlying mechanisms and develop effective treatments. This comprehensive review highlights the crucial interplay between the tumor microenvironment, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) in the context of sorafenib resistance. The tumor microenvironment, encompassing hypoxia, immune cells, stromal cells, and exosomes, exerts a significant impact on HCC progression and therapy response. Hypoxic conditions and immune cell infiltration create an immunosuppressive milieu, shielding tumor cells from immune surveillance and hindering therapeutic efficacy. Additionally, the presence of CSCs emerges as a prominent contributor to sorafenib resistance, with CD133+ CSCs implicated in drug resistance and tumor initiation. Moreover, CSCs undergo EMT, a process intimately linked to tumor progression, CSC activation, and further promotion of sorafenib resistance, metastasis, and tumor-initiating capacity. Elucidating the correlation between the tumor microenvironment, CSCs, and sorafenib resistance holds paramount importance in the quest to develop reliable biomarkers capable of predicting therapeutic response. Novel therapeutic strategies must consider the influence of the tumor microenvironment and CSC activation to effectively overcome sorafenib resistance in HCC.

Abstract The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross‐linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial‐to‐mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen‐enriched TME and revealed that collagen enrichment could induce 5‐fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia‐induced up‐regulation of lysyl oxidase‐like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross‐linking, enhances cell adhesion‐mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3‐kinase (PI3K)/rho‐associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen‐enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2‐targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis.

Objective To investigate the current status of job burnout, work-family conflict and resilience among nurses in the Department of Thoracic Surgery, and to analysis potential factors influencing the resilience of nurses. Methods A questionnaire-based survey using general information scale, Chinese revision of Connor-Davidson resilience scale(CD-RISC), Maslach Burnout Inventory(MBI) and Chinese revision of Work Family Conflict Inventory(WFCI) was conducted to 72 nurses. The Pearson correlation and hierarchical, stepwise multiple regression were performed for the analysis. Results There was negative relationship between resilience and job burnout (r=-0. 372, P＜0. 01)and between resilience and job burnout (r=-0. 295, P＜0. 01). Working age, number of night shifts per month, job burnout and work-family conflict were influencing factors of resilience of nurses. Conclusion Efforts should be made to develop countermeasures for relieving job burnout and work-family conflict of nurses, and improving resilience of nurses. (目的 了解胸外科护士的心理韧性、工作疲溃感及工作-家庭冲突现状, 探讨影响护士心理韧性的影响因素。方法 应用一般护士资料问卷、中文版心理韧性问卷、护士工作疲溃感问卷和工作-家庭冲突问卷对医院72名护士进行调查, 并采用Pearson相关检验和分层逐步多元回归进行分析。结果 心理韧性与工作疲溃感及工作-家庭冲突呈负相关(r=-0. 372, r=-0. 295, P＜0. 01), 影响护士心理韧性的因素为护龄、每月夜班数、工作疲溃感、工作-家庭冲突。结论 护理管理者应采取相应的积极措施降低护士工作疲溃感及工作-家庭冲突, 提高护士的心理韧性。)

Abstract Background Lymph node metastasis is one of most common determinants of the stage and prognosis of gastric cancer (GC). However, the key molecular events and mechanisms mediating lymph node metastasis remain elusive. Methods RNA sequencing was used to identify driver genes responsible for lymph node metastasis in four cases of gastric primary tumors, metastatic lesions of lymph nodes and matched normal gastric epithelial tissue. qRT–PCR and IHC were applied to examine RPRD1B expression. Metastatic functions were evaluated in vitro and in vivo. RNA-seq was used to identify target genes. ChIP, EMSA and dual luciferase reporter assays were conducted to identify the binding sites of target genes. Co-IP, RIP, MeRIP, RNA-FISH and ubiquitin assays were applied to explore the underlying mechanisms. Results The top 8 target genes (RPRD1B, MAP4K4, MCM2, TOPBP1, FRMD8, KBTBD2, ADAM10 and CXCR4) that were significantly upregulated in metastatic lymph nodes of individuals with GC were screened. The transcriptional cofactor RPRD1B (regulation of nuclear pre-mRNA domain containing 1B) was selected for further characterization. The clinical analysis showed that RPRD1B was significantly overexpressed in metastatic lymph nodes and associated with poor outcomes in patients with GC. The Mettl3-induced m6A modification was involved in the upregulation of RPRD1B. Functionally, RPRD1B promoted lymph node metastasis capabilities in vitro and in vivo. Mechanistic studies indicated that RPRD1B increased fatty acid uptake and synthesis by transcriptionally upregulating c-Jun/c-Fos and activating the c-Jun/c-Fos/SREBP1 axis. In addition, NEAT1 was upregulated significantly by c-Jun/c-Fos in RPRD1B-overexpressing cells. NEAT1, in turn, increased the stability of the RPRD1B mRNA by recruiting the m6A “reader” protein hnRNPA2B1 and reduced the degradation of the RPRD1B protein by inhibiting TRIM25-mediated ubiquitination. Notably, this functional circuitry was disrupted by an inhibitor of c-Jun/c-Fos/AP1 proteins (SR11302) and small interfering RNAs targeting NEAT1, leading to a preferential impairment of lymph node metastasis. Conclusions Based on these findings, RPRD1B facilitated FA metabolism and assisted primary tumor implantation in lymph nodes via the c-Jun/c-Fos/SREBP1 axis, which was enhanced by a NEAT1-mediated positive feedback loop, serving as a potential therapeutic target for GC treatment.

Beveloid gears have the advantages of compensating for axial error, providing smooth transmission, and eliminating turning error. Therefore, they are widely used in applications that require high transmission accuracy and stability. However, research on calculating the time-varying meshing stiffness of beveloid gears is still limited, and there is an urgent need to propose a method that can calculate the meshing stiffness of beveloid gears quickly and accurately. We first established the tooth profile expressions, assuming a pair of beveloid gears meshing with the same rack, and the contact line equations of parallel axis beveloid gear pairs were derived. Next, we analyzed the contact process of beveloid gears. We propose an analytical algorithm based on the slicing method to calculate the meshing stiffness of helical gears, straight beveloid gears, and helical beveloid gears. Then, the influence of different parameters on the meshing stiffness of helical beveloid gears was analyzed by changing the respective parameters. Finally, the finite element method (FEM) was used to verify the correctness of the analytical results, and then the errors were analyzed. The study demonstrates that the results obtained from the analytical algorithm we proposed have the same magnitude as those obtained by the FEM for the time-varying meshing stiffness calculation of beveloid gears.

Abstract Background Tumor cells exhibited phenotypic and molecular characteristics similar to their lineage progenitor cells. Liver developmental signaling pathways are showed to be associated with HCC development and oncogenesis. The similarities of expression profiling between liver progenitors (LPs) and HCC suggest that understanding the molecular mechanism during liver development could provide insights into HCC. Methods To profile the dynamic gene expression during liver development, cells from an in vitro liver differentiation model and two paired hepatocellular carcinoma (HCC) samples were analyzed using deep RNA sequencing. The expression levels of selected genes were analyzed by qRT-PCR. Moreover, the role of a key transcription factor, pituitary homeobox 2 (PITX2), was characterized via in vitro and vivo functional assays. Furthermore, molecular mechanism studies were performed to unveil how PITX2C regulate the key developmental factors in LPs, thereby increasing the stemness of HCC. Results PITX2 was found to exhibit a similar expression pattern to specific markers of LPs. PITX2 consists of three isoforms (PITX2A/B/C). The expression of PITX2 is associated with tumor size and overall survival rate, whereas only PITX2C expression is associated with AFP and differentiation in clinical patients. PITX2A/B/C has distinct functions in HCC tumorigenicity. PITX2C promotes HCC metastasis, self-renewal and chemoresistance. Molecular mechanism studies showed that PITX2C could up-regulate RALYL which could enhance HCC stemness via the TGF-β pathway. Furthermore, ChIP assays confirmed the role of PITX2C in regulating key developmental factors in LP. Conclusion PITX2C is a newly discovered transcription factor involved in hepatic differentiation and could increase HCC stemness by upregulating key transcriptional factors related to liver development.

Abstract Background Previous in vitro hepatocyte differentiation model showed that TROY was specifically expressed in liver progenitor cells and a small proportion of hepatocellular carcinoma cells, suggesting that TROY may participate in hepatocellular carcinoma (HCC) stemness regulation. Here, we aim to investigate the role and mechanism of TROY in HCC pathogenesis. Method Bioinformatics analysis of the TCGA dataset has been used to identify the function and mechanism of TROY. Spheroid, apoptosis, and ALDH assay were performed to evaluate the stemness functions. Validation of the downstream pathway was based on Western blot, co-immunoprecipitation, and double immunofluorescence. Results HCC tissue microarray study found that a high frequency of TROY-positive cells was detected in 53/130 (40.8%) of HCC cases, which was significantly associated with poor prognosis and tumor metastasis. Functional studies revealed that TROY could promote self-renewal, drug resistance, tumorigenicity, and metastasis of HCC cells. Mechanism study found that TROY could interact with PI3K subunit p85α, inducing its polyubiquitylation and degradation. The degradation of p85α subsequently activate PI3K/AKT/TBX3 signaling and upregulated pluripotent genes expression including SOX2, NANOG, and OCT4, and promoted EMT in HCC cells. Interestingly, immune cell infiltration analysis found that upregulation of TROY in HCC tissues was induced by TGF-β1 secreted from CAFs. PI3K inhibitor wortmannin could effectively impair tumor stemness to sorafenib. Conclusion We demonstrated that TROY is an HCC CSC marker and plays an important role in HCC stemness regulation. Targeting TROY-positive CSCs with PI3K inhibitor wortmannin combined with chemo- or targeted drugs might be a novel therapeutic strategy for HCC patients. Graphical abstract

Background: Hepatocellular carcinoma (HCC) is a malignant tumor harmful to human health. Ganji Fang (GJF) has good clinical efficacy in the treatment of HCC, but its mechanism is still unclear.Objective: The aim of this study was to investigate the mechanism of action of GJF in the treatment of HCC through network pharmacology, molecular docking and in vitro experiments.Methods: A series of network pharmacology methods were used to identify the potential targets and key pathways of GJF in the treatment of HCC. Then, molecular docking technology was used to explore the binding ability of key active ingredients and targets in GJF. Multiple external databases were used to validate the key targets. In in vitro experiments, we performed MTT assays, wound-healing assays, cell cycle assays, apoptosis assays and RT‒qPCR to verify the inhibitory effect of GJF on the Human hepatoma G2 (HepG2) cells.Result: A total of 162 bioactive components and 826 protein targets of GJF were screened, and 611 potential targets of HCC were identified. Finally, 63 possible targets of GJF acting on HCC were obtained. KEGG enrichment analyses showed that the top five pathways were the cell cycle, cellular senescence, p53 signaling pathway, PI3K/Akt signaling pathway, and progesterone-mediated oocyte maturation. Among them, we verified the PI3K/Akt signaling pathway. CCNE1, PKN1, CCND2, CDK4, EPHA2, FGFR3, CDK6, CDK2 and HSP90AAI were enriched in the PI3K/Akt pathway. The molecular docking results showed that the docking scores of eight active components of GJF with the two targets were all less than -5.0, indicating that they had certain binding activity. In vitro cell experiments showed that GJF could inhibit the proliferation and migration of HepG2 cells, block the cell cycle and induce apoptosis of HepG2 cells, which may be related to the PI3K/Akt signaling pathway. In summary, EPHA2 may be an important target of GJF in HCC, and pachymic acid may be an important critical active compound of GJF that exerts anticancer activity.Conclusion: In general, we demonstrated, for the first time, that the molecular mechanism of GJF in HCC may involve induction of G0/G1 phase cycle arrest through inhibition of the PI3K/Akt signaling pathway and promote apoptosis of hepatoma cell lines. This study provides a scientific basis for the subsequent clinical application of GJF and the in-depth study of its mechanism.

BackgroudThe high or low inferior mesenteric artery (IMA) ligation in rectal cancer remains a great debate. This study retrospectively discussed the outcomes of the perioperative period, defecation and urinary function and long-term prognosis in rectal cancer patients with high or low IMA ligation.MethodsThis study enrolled 220 consecutive rectal cancer cases, including 134 with high IMA ligation and 86 with low ligation. A comparison between the two groups was made for anastomotic leakage, low anterior resection syndrome (LARS), international prostate symptom score (IPSS), 5-year disease-free survival (DFS) and 5-year overall survival (OS).ResultsLow-ligation group had a longer operative time, and larger intraoperative blood loss. No significant difference was noted in anastomotic leakage incidence. In multivariable analysis, the male gender and tumor located at the lower rectum were identified as risk factors for anastomotic leakage. No significant differences were observed between groups in their LARS and IPSS questionnaire responses. The high-ligation vs. the low-ligation 5-year OS and DFS were 78.3% vs. 82.4% and 72.4% vs. 76.6%, respectively, which were not statistically different.ConclusionThe ligation level of the IMA had no significant effect on the anastomotic leakage incidence, defecation, urinary function, and long-term prognosis.

Human γδT cells are a special immune cell type which exist in small quantities in the body, do not require processing and presentation for antigen recognition, and have non-major histocompatibility complex (MHC)-restricted immune response. They play an important role in the body’s anti-tumor, anti-infection, immune regulation, immune surveillance and maintenance of immune tolerance. This article reviews the generation and development of human γδT cells, genetic characteristics, classification, recognition and role of antigens, and research progress in tumor immunotherapy.

Accurate bathymetric maps are essential to understand marine and coastal ecosystems. With the development of satellite and sensor technology, satellite-derived bathymetry (SDB) has been widely used to measure the depth of nearshore waters. Employment of physics-based methods requires a series of optical parameters of the water column and seafloor, which limits the application of these methods to shallow-water bathymetry. Due to convenience, low costs, and high efficiency, empirical methods based on in situ measurements and satellite imagery are increasingly used for nearshore bathymetry. These measurements are required to calibrate empirical models, so that reasonable accuracy can be achieved. The Ice, Cloud, and Land Elevation Satellite-2 (ICESat-2), equipped with the advanced topographic laser altimeter system, provides a novel opportunity for nearshore bathymetry. Using the new measurement strategy of photon counting, ICESat-2 can provide accurate bathymetric points from spaceborne observations, which can be used in place of in situ water depth data. In this study, ICESat-2 bathymetric points and multispectral images were used to train four typical models and produce bathymetric maps for Shanhu Island, Ganquan Island, and Lingyang Reef in the Xisha Islands of China. We evaluated the bathymetric results by comparing them with reference depth data from airborne light detection and ranging. All models had a satisfactory accuracy, as well as multimodel and multisource image consistency. With the ICESat-2 bathymetric points, SDB is no longer limited by in situ measurements. Hence, this approach could be extended to a larger scale to obtain nearshore bathymetric maps of coastal areas, surrounding islands, and reefs using free and open-access satellite data.

Lychee downy blight (LDB) is an oomycete pathogen (Peronophythora litchi) disease, which affects the fruits and leaves of lychee, resulting in economic losses. Chemical fungicides are commonly used for disease control, while for eco-safety measures, the study of molecular mechanisms involved in lychee resistance against LDB is necessary. Non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular (circRNAs), and microRNAs (miRNAs), play a crucial role in plant disease resistance. To examine lychee response (fruits and leaves) to LDB, we studied the expression patterns of ncRNAs and mRNAs under LDB treatment. By whole transcriptome sequencing analyses, a total of 36,885 mRNAs, 2627 lncRNAs, 4682 circRNAs, and 525 miRNAs were identified in lychee. A differential expression (DE) analysis revealed that there were 1095 DEmRNAs, 89 DElncRNAs, 28 DEcircRNAs, and 28 DEmiRNAs in the LDB-treated fruits, as well as 1158 DEmRNAs, 132 DElncRNAs, 13 DEcircRNAs, and 197 DEmiRNAs in the LDB-treated leaves. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the potential function of DEmRNAs and the targets of ncRNAs were involved in plant defense. Furthermore, co-expression networks of putative interacting ncRNAs and mRNAs were developed, in which mRNAs encoded some receptor proteins, pointing to potential ncRNAs associated with LDB infection. Our study provided a new, brief insight to the putative role of ncRNAs in lychee response to LDB.

Background: Although some improvements in the management of pancreatic cancer (PC) have been made, no major breakthroughs in terms of biomarker discovery or effective treatment have emerged. Here, we applied artificial intelligence (AI)-based methods to develop a model to diagnose PC and predict survival outcome. Methods: Multiple bioinformatics methods, including Limma Package, were performed to identify differentially expressed genes (DEGs) in PC. A Back Propagation (BP) model was constructed, followed by Genetic Algorithm (GA) filtering and verification of its prognosis capacity in the TCGA cohort. Furthermore, we validated the protein expression of the selected DEGs in 92 clinical PC tissues using immunohistochemistry. Finally, intro studies were performed to assess the function of SLC6A14 and SPOCK1 on pancreatic ductal adenocarcinoma (PDAC) cells proliferation and apoptosis. Results: Four candidate genes (LCN2, SLC6A14, SPOCK1, and VCAN) were selected to establish a four-gene signature for PC. The gene signature was validated in the TCGA PC cohort, and found to show satisfactory discrimination and prognostic power. Areas under the curve (AUC) values of overall survival were both greater than 0.60 in the TCGA training cohort, test cohort, and the entire cohort. Kaplan-Meier analyses showed that high-risk group had a significantly shorter overall survival and disease-free survival than the low-risk group. Further, the elevated expression of SLC6A14 and SPOCK1 in PC tissues was validated in the TCGA + GETx datasets and 92 clinical PC tissues, and was significantly associated with poor survival in PC. In PDAC cell line, SLC6A14 or SPOCK1 knockdown inhibited cells proliferation, migration and promoted cells apoptosis. Conclusions: Using Limma Package and GA-ANN, we developed and validated a diagnostic and prognostic gene signature that yielded excellent predictive capacity for PC patients' survival. In vitro studies were further conducted to verify the functions of SLC6A14 and SPOCK1 in PC progression.

MXene-based fibers are expected to have the hopeful potential for manufacturing multifunctional fabrics with permeability, lightweight, remarkable electrical conductivity, and outstanding mechanical properties. However, the weak interaction between fibers limits the performance of the fabrics, and researchers are still seeking a suitable solution and easily scalable production methods. Here a green and novel wet-assembly approach is proposed for producing non-woven MXene fiber fabrics (MFFs) constructed by random-oriented and well-connected interfused MXene fibers. The as-prepared fabrics are porous and lightweight while exhibiting high electrical conductivity (708 S cm−1). A maximum specific electrical conductivity is achieved with a relatively low density (0.24 g cm−3), even superior to individual MXene fibers. Moreover, the MFFs exhibit outstanding electromagnetic interference (EMI) shielding effectiveness of 75.0 dB at a thickness of 107 μm, exceptional Joule heating (up to 370 °C at a voltage of 3.5 V), and excellent photothermal conversion abilities, showing their great potential as high-performance and multifunctional fabrics in EMI shielding, wearable intelligent garments, and personal heating applications.

Photosynthetic microbial fuel cell (PMFC) based on algal cathode can integrate of wastewater treatment with microalgal biomass production. However, both the traditional suspended algae and the immobilized algae cathode systems have the problems of high cost caused by Pt catalyst and ion-exchange membrane. In this work, a new equipment for membrane-free PMFC is reported based on the optimization of the most expensive MFC components: the separator and the cathode. Using a revolving algae-bacteria biofilm cathode in a photosynthetic membrane-free microbial fuel cell (RAB-MFC) can obtain pollutants removal and algal biomass production as well as electrons generation. The highest chemical oxygen demand (COD) removal rates of the anode and cathode chambers reached 93.5 ± 2.6% and 95.8% ± 0.8%, respectively. The ammonia removal efficiency in anode and cathode chambers was 91.1 ± 1.3% and 98.0 ± 0.6%, respectively, corresponding to an ammonia removal rate of 0.92 ± 0.02 mg/L/h. The maximum current density and power density were 136.1 mA/m2 and 33.1 mW/m2. The average biomass production of algae biofilm was higher than 30 g/m2. The 18S rDNA sequencing analysis the eukaryotic community and revealed high operational taxonomic units (OTUs) of Chlorophyta (44.43%) was dominant phyla with low COD level, while Ciliophora (54.36%) replaced Chlorophyta as the dominant phyla when COD increased. 16S rDNA high-throughput sequencing revealed that biofilms on the cathode contained a variety of prokaryote taxa, including Proteobacteria, Bacteroidota, Firmicutes, while there was only 0.23–0.26% photosynthesizing prokaryote found in the cathode biofilm. Collectively, this work demonstrated that RAB can be used as a bio-cathode in PMFC for pollutants removal from wastewater as well as electricity generation.

Abstract Background The GRAS gene family plays crucial roles in multiple biological processes of plant growth, including seed development, which is related to seedless traits of litchi (Litchi chinensis Sonn.). However, it hasn’t been fully identified and analyzed in litchi, an economic fruit tree cultivated in subtropical regions. Results In this study, 48 LcGRAS proteins were identified and termed according to their chromosomal location. LcGRAS proteins can be categorized into 14 subfamilies through phylogenetic analysis. Gene structure and conserved domain analysis revealed that different subfamilies harbored various motif patterns, suggesting their functional diversity. Synteny analysis revealed that the expansion of the GRAS family in litchi may be driven by their tandem and segmental duplication. After comprehensively analysing degradome data, we found that four LcGRAS genes belong to HAM subfamily were regulated via miR171-mediated degradation. The various expression patterns of LcGRAS genes in different tissues uncovered they were involved in different biological processes. Moreover, the different temporal expression profiles of LcGRAS genes between abortive and bold seed indicated some of them were involved in maintaining the normal development of the seed. Conclusion Our study provides comprehensive analyses on GRAS family members in litchi, insight into a better understanding of the roles of GRAS in litchi development, and lays the foundation for further investigations on litchi seed development.

BackgroundDengue virus (DENV) infection induces various clinical manifestations and even causes organ injuries, leading to severe dengue haemorrhagic fever and dengue shock syndrome. Hepatic dysfunction was identified as a risk predictor of progression to severe disease during the febrile phase of dengue. However, the underlying mechanisms of hepatic injury remain unclear.MethodsA model of dengue disease was established in IFNAR−/− C57BL/6 mice by challenge with DENV-2. Body weight, symptoms, haematological parameters and liver pathological observations in mice were used to determine the effects of DENV infection. Liver transcriptome sequencing was performed to evaluate the features of the host response in IFNAR−/− mice challenged with DENV. Functional enrichment analysis and analysis of significantly differentially expressed genes (DEGs) were used to determine the critical molecular mechanism of hepatic injury.ResultsWe observed haemoconcentration, leukopenia and liver pathologies in mice, consistent with findings in clinical dengue patients. Some differences in gene expression and biological processes were identified in this study. Transcriptional patterns in the liver indicated that antiviral responses to DENV and tissue damage via abnormal expression of proinflammatory cytokines were induced. Further analysis showed that the upregulated DEGs were significantly enriched in the leukocyte transendothelial migration, complement and coagulation cascades, and cytokine-cytokine receptor interactions signalling pathways, which are considered to be closely associated with the pathogenic mechanism of dengue. IL6, IL 10, ICAM-1, VCAM-1, MMP9 and NLRP3 were identified as biomarkers of progression to severe disease.ConclusionsThe interactions of these cytokines, which activate inflammatory signalling, may lead to organ injury and haemoconcentration and even to vascular leakage in tissues, including the mouse liver. Our study identifies candidate host targets that could be used for further functional verification.

To date, most studies on building environments and walking behavior have utilized top-down approaches (e.g., big data or social media data) yet lack bottom-up approaches to verify their findings. Therefore, this study divided urban streets into three main settings (community streets, waterfront paths, and urban greenways) and collected data from a sample of 411 urban residents in Chengdu via an online questionnaire to examine the impact of street environmental factors on their choice of walking path. It was found that: (1) people with higher levels of education preferred streets with water bodies as walking paths; (2) the environmental quality of the physical and aesthetic aspects both had an impact on residents’ choices, and the aesthetic environmental quality had a stronger impact; (3) the impact of most infrastructures on community streets was stronger than on other streets; (4) residents were more concerned about the environmental quality of waterfront paths and urban greenways. Based on these findings, three design patterns for residents’ preferred street environments are proposed.

The primary cause for the limited shelf life of litchi fruit is rapid pericarp browning and decay. This study aims to evaluate the storability of 50 litchi varieties and establish a linear regression model for pericarp browning and decay based on 11 postharvest physical and chemical indices after 9 days of storage at room temperature. The results indicated that the average value of the browning index and decay rate significantly increased to 3.29% and 63.84% of 50 litchi varieties at day 9, respectively. Different litchi varieties showed different variations in appearance indicators, quality indicators, and physiological indicators. Furthermore, principal component analysis and cluster analysis revealed that Liu Li 2 Hao exhibited the highest resistance to storage, whereas Dong Long Mi Li, Jiao Pan Li, E Dan Li 2 Hao, and Ren Shan Li were not resistant. Stepwise multiple regression analysis further demonstrated that the factors were highly correlated with the decay index, with a partial correlation coefficient of 0.437 between the effective index and the decay index. Therefore, pericarp thickness, relative conductivity, pericarp laccase activity, and total soluble solids were significant indicators for the comprehensive evaluation of litchi browning and decay, and relative conductivity was the significant determinant causing fruit browning. These findings provide a new perspective on the sustainable development of the litchi industry.

Objective To investigate the use of anticoagulant drugs in hospitalized patients with nonvalvular atrial fibrillation (NVAF), and to explore the relevant factors that affect the efficacy of drug treatment in the patients. Methods A retrospective analysis was conducted on the NVAF inpatients admitted in our department from January 1, 2016 to December 31, 2019. Their clinical characteristics and usage of oral anticoagulants were collected and analyzed. According to the stratification of stroke risk, the patients with CHA2DS2-VASc score≥2 were selected to explore their use of anticoagulants. Logistic regression analysis was used to analyze the influencing factors of anticoagulation therapy. Results Among the 3 984 patients included, there were 2 438 (61.2%) anticoagulant patients, including 247 (39.0%), 316 (42.6%), 736 (65.3%), and 1 139 (76.9%) patients, respectively during the year of 2016 to 2019. The number of patients with CHA2DS2-VASc≥2 was 3 418, and 60.4% (2 065) of them took anticoagulants. Logistic regression analysis showed that age≥75 years (OR=0.494), vascular diseases (OR=0.838), acute coronary syndrome (ACS) (OR=0.583), history of percutaneous coronary intervention (PCI) (OR=0.651), bleeding history (OR=0.436), renal insufficiency (OR=0.625), drugs (OR=0.634), and before price reduction of new oral anticoagulants (NOAC) (OR=0.22) were influencing factors to reduce the rate of anticoagulation treatment (P < 0.05); While, atrial fibrillation ablation (OR=2.093) and stroke history (OR=1.351) were influencing factors to increase the treatment rate (P < 0.05). Conclusion Though the rate of anticoagulation treatment for NVAF patients is increasing year by year, but it is still lower than that in the European and American countries. Bleeding history, combined use of antiplatelet drugs, renal insufficiency, before NOAC price reduction, age ≥75 years, accompanied with vascular diseases, ACS, and post-PCI are influencing factors to reduce the rate, and atrial fibrillation ablation and stroke history are factors increasing the rate of anticoagulant treatment.

Abstract Background Hepatocellular carcinoma (HCC) is a disease with a high incidence and a poor prognosis. Growing amounts of evidence have shown that the immune system plays a critical role in the biological processes of HCC such as progression, recurrence, and metastasis, and some have discussed using it as a weapon against a variety of cancers. However, the impact of immune-related genes (IRGs) on the prognosis of HCC remains unclear. Methods Based on The Cancer Gene Atlas (TCGA) and Immunology Database and Analysis Portal (ImmPort) datasets, we integrated the ribonucleic acid (RNA) sequencing profiles of 424 HCC patients with IRGs to calculate immune-related differentially expressed genes (DEGs). Survival analysis was used to establish a prognostic model of survival- and immune-related DEGs. Based on genomic and clinicopathological data, we constructed a nomogram to predict the prognosis of HCC patients. Gene set enrichment analysis further clarified the signalling pathways of the high-risk and low-risk groups constructed based on the IRGs in HCC. Next, we evaluated the correlation between the risk score and the infiltration of immune cells, and finally, we validated the prognostic performance of this model in the GSE14520 dataset. Results A total of 100 immune-related DEGs were significantly associated with the clinical outcomes of patients with HCC. We performed univariate and multivariate least absolute shrinkage and selection operator (Lasso) regression analyses on these genes to construct a prognostic model of seven IRGs (Fatty Acid Binding Protein 6 (FABP6), Microtubule-Associated Protein Tau (MAPT), Baculoviral IAP Repeat Containing 5 (BIRC5), Plexin-A1 (PLXNA1), Secreted Phosphoprotein 1 (SPP1), Stanniocalcin 2 (STC2) and Chondroitin Sulfate Proteoglycan 5 (CSPG5)), which showed better prognostic performance than the tumour/node/metastasis (TNM) staging system. Moreover, we constructed a regulatory network related to transcription factors (TFs) that further unravelled the regulatory mechanisms of these genes. According to the median value of the risk score, the entire TCGA cohort was divided into high-risk and low-risk groups, and the low-risk group had a better overall survival (OS) rate. To predict the OS rate of HCC, we established a gene- and clinical factor-related nomogram. The receiver operating characteristic (ROC) curve, concordance index (C-index) and calibration curve showed that this model had moderate accuracy. The correlation analysis between the risk score and the infiltration of six common types of immune cells showed that the model could reflect the state of the immune microenvironment in HCC tumours. Conclusion Our IRG prognostic model was shown to have value in the monitoring, treatment, and prognostic assessment of HCC patients and could be used as a survival prediction tool in the near future.

Abstract There exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.

Abstract Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR–PI3K/AKT–mTOR–HIF1α signalling pathway. In brief, the HIF1α/HIF2α–EGF/EGFR–PI3K/AKT–mTOR–HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR–PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment.

RALYL is a liver progenitor cell-specific gene but its role in hepatocellular carcinoma (HCC) remains unknown. Here, the authors demonstrate that RALYL regulates HCC stemness through upregulation of TGF-β2 mRNA stability by decreasing N6-methyladenosine modification.