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Abstract Ampullary carcinoma (AC) of the intestinal type represents a distinct variant within the broader category of ampullary neoplasms. The scarcity of pertinent cellular models has constrained investigations centered on this particular malignancy. This research effectively generated a cell line (CL) of intestinal-type AC (DPC-X3). This newly developed CL has been continuously cultured for 1 year and has demonstrated stable passaging exceeding 60 generations. Morphologically, DPC-X3 exhibited characteristic attributes of an epithelial tumor. The cell proliferation rate of DPC-X3 exhibited a doubling interval of 79 h. Short tandem repeat (STR) analysis validated the high consistency between DPC-X3 and the patient’s primary tumor. Characteristically, DPC-X3 displayed sub diploid karyotypes, primarily featuring 44, XY inv (9), -18, -20, -22, and + mar. Under suspension culture conditions, DPC-X3 could efficiently form organoids, and DPC-X3 cells inoculated subcutaneously into NXG mice could form transplanted tumors. Drug susceptibility assays demonstrated that DPC-X3 resisted paclitaxel, oxaliplatin, 5-fluorouracil(5-FU), and gemcitabine. Immunohistochemical (IHC) evaluation revealed affirmative reactivity for CK7 and CK20 within DPC-X3 cells, while CDX2 exhibited no detectable expression. E-cadherin and Vimentin demonstrated positive immunoreactivity, whereas CEA and CA19-9 displayed faint positivity. The Ki-67 proliferation index was determined to be approximately 40%. DPC-X3 presents a valuable experimental platform for elucidating the pathogenesis of intestinal-type AC and can serve as a driver for drug development efforts.

Abstract In this study, we successfully established a novel gallbladder cancer cell line, designated as GBC-X1, derived from a primary tumor of a gallbladder cancer patient. By comprehensively analyzing the cell line’s phenotype, molecular characteristics, biomarkers, and histological characteristics, we confirmed that GBC-X1 serves as a valuable model for investigating the pathogenesis of gallbladder cancer and developing therapeutic agents. GBC-X1 has been continuously cultured for one year, with over 60 stable passages. Morphologically, GBC-X1 exhibits typical features of epithelial tumors. The population doubling time of GBC-X1 is 32 h. STR analysis validated a high consistency between GBC-X1 and the patient’s primary tumor. Karyotype analysis revealed an abnormal hypertetraploid karyotype for GBC-X1, characterized by representative karyotypes of 98, XXXX del (4) p (12) del (5) p (21) der (10). Under suspension culture conditions, GBC-X1 efficiently forms tumor balls, while subcutaneous inoculation of GBC-X1 cells into NXG mice leads to xenograft formation with a rate of 80%. Drug sensitivity testing demonstrated that GBC-X1 is resistant to oxaliplatin and sensitive to 5-FU, gemcitabine, and paclitaxel. Immunohistochemistry revealed positive expression of CK7, CK19, E-cadherin, MMP-2, CD44, SOX2, and TP53 in GBC-X1 cells, weak positive expression of Vimentin, and a Ki67 positive rate of 35%. Our research highlights GBC-X1 as a novel gallbladder cancer cell line and emphasizes its potential as an effective experimental model for investigating the pathogenesis of gallbladder cancer and drug development.

Abstract Drug resistance remains a significant challenge in the treatment of pancreatic cancer. The development of drug-resistant cell lines is crucial to understanding the underlying mechanisms of resistance and developing novel drugs to improve clinical outcomes. Here, a novel pancreatic cancer cell line, PDAC-X1, derived from Chinese patients has been established. PDAC-X1 was characterized by the immune phenotype, biology, genetics, molecular characteristics, and tumorigenicity. In vitro analysis revealed that PDAC-X1 cells exhibited epithelial morphology and cell markers (CK7 and CK19), expressed cancer-associated markers (E-cadherin, Vimentin, Ki-67, CEA, CA19-9), and produced pancreatic cancer-like organs in suspension culture. In vivo analysis showed that PDAC-X1 cells maintained tumorigenicity with a 100% tumor formation rate. This cell line exhibited a complex karyotype, dominated by subtriploid karyotypes. In addition, PDAC-X1 cells exhibited intrinsic multidrug resistance to multiple drugs, including gemcitabine, paclitaxel, 5-fluorouracil, and oxaliplatin. In conclusion, the PDAC-X1 cell line has been established and characterized, representing a useful and valuable preclinical model to study the underlying mechanisms of drug resistance and develop novel drug therapeutics to improve patient outcomes.

Cordyceps sinensis (CS) has been widely used as a dietary supplement or traditional medicine for the prevention, treatment, and prognostication of various diseases, because of its pleiotropic pharmacological properties. However, the potential pharmacological action of CS in sepsis-associated acute kidney injury (S-AKI) remains poorly understood. Herein, we investigated the potential pharmacological action of CS against S-AKI and the underlying mechanisms. CS treatment effectively ameliorated renal dysfunction and injury in mice with lipopolysaccharide (LPS)-induced S-AKI, as indicated by the suppression of inflammatory cytokine expression and secretion. Multi-omic analyses suggested that the promotion of mitochondrial energy metabolism might be a potential mechanism through which CS protects mice against S-AKI induced by LPS. Subsequent validation assays confirmed that CS treatment substantially restored the activity of mitochondrial complexes, mitochondrial membrane potential, and ATP production. Moreover, CS concomitantly promoted transition of M1 macrophages to M2 macrophages with increased oxidative phosphorylation, thus indicating that macrophage polarization may also be a potential target for S-AKI treatment. Our findings demonstrated that CS significantly ameliorated renal injury and inflammation in S-AKI by regulating mitochondrial energy metabolism and macrophage polarization, thus providing new insights into the clinical use of CS for the prevention and treatment of S-AKI.

The phospholipid bilayer nanodiscs (LNDs), as a rapidly-developing tool in recent years, provide a natural bio-memebrane environment to maintain the native conformation and functions of membrane proteins as well as a versatile delivery vehicle for a variety of hydrophobic and hydrophilic drugs. We have seen unprecedented advantages of phospholipid bilayer nanodiscs in membrane protein structure characterization, biochemical and physiological studies of membrane proteins, membrane environment studies, drug discovery & development, and drug delivery. Many previous reviews have been mainly focused on the advantages of nanodiscs in membrane protein researches, but few have touched upon the importance and potential application of nanodiscs in pharmaceutical industries. This review will provide general description of the structural characteristics, advantages, classification, and applications of phospholipid nanodiscs, with particular focus on nanodisc-enabled membrane protein drug discovery & development as well as drug delivery.

Abstract Idiopathic pulmonary fibrosis (IPF) represents a chronic interstitial lung disease with an unclear underlying mechanism and currently lacks a definitive treatment. Cordyceps sinensis (CS), renowned for its pharmacological properties in traditional Chinese medicine and extensive use in lung disease treatment, holds promise as a therapeutic agent for IPF. However, the specific role of CS in treating IPF remains unclear. In this study, we aimed to assess the efficacy of CS in treating IPF and unravel potential underlying mechanisms. Our results demonstrate that CS treatment effectively mitigated pulmonary inflammation and collagen deposition in bleomycin‐induced IPF mice. Proteomics analysis revealed that the regulation of mitochondrial oxidative phosphorylation may serve as a potential protective mechanism of CS against IPF in mice. Further investigation unveiled that CS could suppress the excessive production of mitochondrial reactive oxygen species in lung tissues induced by bleomycin through moderating the expression and activity of mitochondrial complexes, thus safeguarding the integrity and function of mitochondria. Overall, our findings not only underscore the effectiveness of CS in preventing bleomycin‐induced IPF but also highlight mitochondrial‐mediated oxidative stress as a promising therapeutic target for treating IPF.

Abstract Chemotherapy resistance poses clinical challenges in pancreatic cancer treatment. Developing cell lines resistant to chemotherapy is crucial for investigating drug resistance mechanisms and identifying alternative treatment pathways. The genetic and biological attributes of pancreatic cancer depend on its aetiology, racial demographics and anatomical origin, underscoring the need for models that comprehensively represent these characteristics. Here, we introduce PDAC-X2, a pancreatic cancer cell line derived from Chinese patients. We conducted a comprehensive analysis encompassing the immune phenotype, biology, genetics, molecular characteristics and tumorigenicity of the cell line. PDAC-X2 cells displayed epithelial morphology and expressed cell markers (CK7 and CK19) alongside other markers (E-cadherin, Vimentin, Ki-67, CEA and CA19-9). The population doubling time averaged around 69 h. In vivo, PDAC-X2 cells consistently maintained their tumorigenicity, achieving a 100% tumour formation rate. Characterised by a predominantly tetraploid karyotype, this cell line exhibited a complex genetic markup. Notably, PDAC-X2 cells demonstrated resistance to multiple drugs, including gemcitabine, paclitaxel, 5-fluorouracil and oxaliplatin. In conclusion, PDAC-X2 presents an invaluable preclinical model. Its utility lies in facilitating the study of drug resistance mechanisms and the exploration of alternative therapeutic approaches aimed at enhancing the prognosis of this tumour type.

Abstract Background The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored. Methods House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed. Results Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum. Conclusion Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation. Graphical Abstract

Abstract Background Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive. Methods We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays. Results The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects. Conclusions In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel. Video Abstract

Abstract Background Fatigue is a common symptom of long COVID syndrome. Compared to male survivors, females have a higher incidence of post-COVID fatigue. Therefore, long-term follow-up is necessary to understand which groups of females are more vulnerable to post-COVID fatigue. Methods This is a nested case–control study of female COVID-19 survivors who were discharged from two designated hospitals in Wuhan, China in 2020, and received 2-year follow-up from March 1 to April 6, 2022. All patients completed the Checklist Individual Strength-subscale subjective fatigue (CIS-fatigue), a chronic obstructive pulmonary disease (COPD) assessment test (CAT), and the Hospital Anxiety and Depression Scale (HADS; including the HADS-Anxiety [HADS-A] and the HADS-Depression [HADS-D]). Individuals with CIS-fatigue scores of 27 or higher were classified as cases. The risk factors for fatigue was analysed with multivariable logistic regression analysis. Results A total of 899 female COVID-19 survivors were enrolled for analysis, including 47 cases and 852 controls. Compared with controls, cases had higher CAT, HADS-A and HADS-D scores, and showed a higher prevalence of symptoms, including anxiety (cases vs. controls, 44.7% vs. 4.0%, p

The selective control and manipulation of nanoparticles require developing and researching new methods for designing optical tweeters, mainly based on a photonic hooks (PHs) effect. This paper first proposes a tunable PH in which a structured beam illuminates an anisotropic cutting liquid crystal microcylinder based on the Finite-DifferenceTime-Domain (FDTD) method. The PHs generated by plane wave, Gaussian, and Bessel beam are analyzed and compared. The impact of beams and LC particle parameters on the PHs are discussed. Where the influence of the extraordinary refractive index (ne) on PHs is emphasized. Our results reveal that introducing birefringence can change the bending direction of PH. Besides, the maximum intensity of the PHs increases as ne increases regardless of the beam type. The PH generated by a plane wave has a higher maximum intensity and smaller FWHM than that generated by the Gaussian and Bessel beams. The smallest FWHM and maximum intensity of the PHs generated by the Gaussian falls between that generated by the plane wave and the Bessel beam. The PH generated by a Bessel beam has the minor maximum intensity and the largest FWHM. Still, it exceeds the diffraction limit and exhibits bending twice due to its self-recovery property. This paper provides a new way to modulate PH. This work offers novel theoretical models and the degree of freedom for the design of PHs, which is beneficial for the selective manipulation of nanoparticles. It has promising applications in Mesotronics and biomedicine.

Abstract In this paper, we propose a new type of nonlinear strict distance and similarity measures for intuitionistic fuzzy sets (IFSs). Our proposed methods not only have good properties, but also improve the drawbacks proposed by Mahanta and Panda (Int J Intell Syst 36(2):615–627, 2021) in which, for example, their distance value of $$d_{_{\textrm{MP}}}(\langle \mu , \nu \rangle , \langle 0, 0\rangle )$$ d MP ( ⟨ μ , ν ⟩ , ⟨ 0 , 0 ⟩ ) is always equal to the maximum value 1 for any intuitionistic fuzzy number $$\langle \mu , \nu \rangle \ne \langle 0, 0\rangle $$ ⟨ μ , ν ⟩ ≠ ⟨ 0 , 0 ⟩ . To resolve these problems in Mahanta and Panda (Int J Intell Syst 36(2):615–627, 2021), we establish a nonlinear parametric distance measure for IFSs and prove that it satisfies the axiomatic definition of strict intuitionistic fuzzy distances and preserves all advantages of distance measures. In particular, our proposed distance measure can effectively distinguish different IFSs with high hesitancy. Meanwhile, we obtain that the dual similarity measure and the induced entropy of our proposed distance measure satisfy the axiomatic definitions of strict intuitionistic fuzzy similarity measure and intuitionistic fuzzy entropy. Finally, we apply our proposed distance and similarity measures to pattern classification, decision making on the choice of a proper antivirus face mask for COVID-19, and medical diagnosis problems, to illustrate the effectiveness of the new methods.

Abstract Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin‐free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

Microplastics (MPs) are environmental pollutants and can be inhaled by humans to threaten health. The lung tissue, responsible for the gas exchange between the body and the environment, is vulnerable to MPs exposure. However, from the perspective of cellular senescence, the effect of MPs on lung cells and tissues has not yet been deeply dissected. In this study, we reported that all the four typical MPs exhibited the significant biological effects in term of inducing senescence of human lung derived cells A549 and BEAS-2B in vitro. We further found that polyvinyl chloride (PVC) increased the reactive oxygen species (ROS) level in A549 cells and that PVC-induced senescent characteristics could be largely reversed by antioxidant treatment. Importantly, intratracheal instillation of PVC MPs in mice could effectively impair their physical function, induce the increased systemic inflammation level, cause the accumulation of senescent cells. Our study demonstrates that MPs induce senescence in human lung epithelial cells and mouse lungs by activating ROS signaling, and provides new insight into the potential pathogenesis of MPs on lung diseases.

Exposure to environmentally hazardous substances is recognized as a significant risk factor for neurological associated disorders. Among these substances, polystyrene microplastics (PS-MPs), widely utilized in various consumer products, have been reported to exhibit neurotoxicity. However, the potential association of PS-MPs with abnormal anxiety behaviors, along with the underlying molecular mechanisms and key proteins involved, remains insufficiently explored. Here, we delineated the potential mechanisms of PS-MPs-induced anxiety through proteomics and molecular investigations. We characterized the PS-MPs, observed their accumulation in the brain, leading to anxiety-like behavior in mice, which is correlated with microglia activation and pro-inflammatory response. Consistent with these findings, our studies on BV2 microglia cells showed that PS-MPs activated NF-κB-mediated inflammation resulting in the upregulation of pro-inflammatory cytokines such as TNFα and IL-1β. Of particular significance, HRAS was identified as a key factor in the PS-MPs induced pro-inflammatory response through whole proteomics analysis, and knockdown of H-ras effectively inhibited PS-MPs induced PERK-NF-κB activation and associated pro-inflammatory response in microglia cells. Collectively, our findings highlight that PS-MPs induce anxiety of mice via the activation of the HRAS-derived PERK-NF-κB pathway in microlglia. Our results contribute valuable insights into the molecular mechanisms of PS-MPs-induced anxiety, and may offer implications for addressing neurotoxicity and prevention the adverse effects of environmentally hazardous substances, including microplastics.

PurposeMetabolic and immune changes in the early stages of osteoporosis are not well understood. This study aimed to explore the changes in bone metabolites and bone marrow lymphocyte subsets and their relationship during the osteoporosis onset.MethodsWe established OVX and Sham mouse models. After 5, 15, and 40 days, five mice in each group were sacrificed. Humeri were analyzed by microCT. The bone marrow cells of the left femur and tibia were collected for flow cytometry analysis. The right femur and tibia were analyzed by LC-MS/MS for metabolomics analysis.ResultsBone microarchitecture was significantly deteriorated 15 days after OVX surgery. Analysis of bone metabolomics showed that obvious metabolite changes had happened since 5 days after surgery. Lipid metabolism was significant at the early stage of the osteoporosis. The proportion of immature B cells was increased, whereas the proportion of mature B cells was decreased in the OVX group. Metabolites were significantly correlated with the proportion of lymphocyte subsets at the early stage of the osteoporosis.ConclusionLipid metabolism was significant at the early stage of the osteoporosis. Bone metabolites may influence bone formation by interfering with bone marrow lymphocyte subsets.

Seed weight is a component of seed yield in rapeseed (Brassica napus L.). Although quantitative trait loci (QTL) for seed weight have been reported in rapeseed, only a few causal quantitative trait genes (QTGs) have been identified, resulting in a limitation in understanding of seed weight regulation. We constructed a gene coexpression network at the early seed developmental stage using transcripts of 20,408 genes in QTL intervals and 1017 rapeseed homologs of known genes from other species. Among the 10 modules in this gene coexpression network, modules 1 and 2 were core modules and contained genes involved in source–flow–sink processes such as synthesis and transportation of fatty acid and protein, and photosynthesis. A hub gene SERINE CARBOXYPEPTIDASE-LIKE 19 (SCPL19) was identified by candidate gene association analysis in rapeseed and functionally investigated using Arabidopsis T-DNA mutant and overexpression lines. Our study demonstrates the power of gene coexpression analysis to prioritize candidate genes from large candidate QTG sets and enhances the understanding of molecular mechanism for seed weight at the early developmental stage in rapeseed.

Carbon storage services play an important role in maintaining ecosystem stability. Land use/cover change (LUCC) is the main factor leading to changes in ecosystem carbon storage. Understanding the impact of LUCC on regional carbon storage changes is crucial for protecting regional ecosystems and promoting sustainable socio-economic development. This paper selects Shanxi province as the study area and explores the spatial and temporal evolution characteristics of carbon storage in Shanxi province based on the InVEST model and univariate spatial autocorrelation. The results show that the total carbon storage in Shanxi Province in 2000, 2010, and 2020 is 513.51 × 104 t C, 513.46 × 104 t C, and 509.29 × 104 t C, respectively. High carbon storage areas are distributed in forest and grassland land types, while low carbon storage areas are widely distributed in building land in urban metropolitan areas. Shanxi Province is mainly dominated by farmland, which has decreased by 3448.60 km2 in the past 20 years. Grassland has decreased by 1588.31 km2 and the area of building land has increased by 4205.73 km2. Due to the influence of carbon conversion among different land use types, the total carbon storage loss of Shanxi Province in the past 20 years was 4.21 × 104 t C. The transfer of farmland resulted in an increase in carbon stock of 14.46 × 104 t C. The transfer of grassland resulted in an increase of 17.15 × 104 t C, while the transfer of forest resulted in a decrease of 41.44 × 104 t C. The increase in land use types with low carbon density and the decrease in land use types with high carbon density led to the decrease in carbon storage in Shanxi Province. Furthermore, social factors were more likely to influence the carbon storage than natural factors, and the influence of social factors was often negative. On this basis, regional development countermeasures were proposed for the current situation of carbon storage in Shanxi Province and provide a scientific basis for Shanxi Province to achieve the carbon neutrality target.

MicroRNAs (miRNAs) are highly conserved endogenous single-stranded non-coding RNA molecules that play a crucial role in regulating gene expression to maintain normal physiological functions in fish. Nevertheless, the specific physiological role of miRNAs in lower vertebrates, particularly in comparison to mammals, remains elusive. Additionally, the mechanisms underlying the control of antiviral responses triggered by viral stimulation in fish are still not fully understood. In this study, we investigated the regulatory impact of miR-1388 on the signaling pathway mediated by IFN regulatory factor 3 (IRF3). Our findings revealed that following stimulation with the viral analog poly(I:C), the expression of miR-1388 was significantly upregulated in primary immune tissues and macrophages. Through a dual luciferase reporter assay, we corroborated a direct targeting relationship between miR-1388 and tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3). Furthermore, our study demonstrated a distinct negative post-transcriptional correlation between miR-1388 and TRAF3. We observed a significant negative post-transcriptional regulatory association between miR-1388 and the levels of antiviral genes following poly(I:C) stimulation. Utilizing reporter plasmids, we elucidated the role of miR-1388 in the antiviral signaling pathway activated by TRAF3. By intervening with siRNA-TRAF3, we validated that miR-1388 regulates the expression of antiviral genes and the production of type I interferons (IFN-Is) through its interaction with TRAF3. Collectively, our experiments highlight the regulatory influence of miR-1388 on the IRF3-mediated signaling pathway by targeting TRAF3 post poly(I:C) stimulation. These findings provide compelling evidence for enhancing our understanding of the mechanisms through which fish miRNAs participate in immune responses.

In China, Jiang Fructus aurantii (JFA) has attracted increasing interest as a famous traditional herbal medicine and valuable economic food for its valuable medicinal and industrial properties. In the current work, contrasted with conventional extraction techniques, natural flavonoids from JFA (naringin and neohesperidin) were extracted with remarkable effectiveness utilizing a sustainable deep eutectic solvents combined ultrasonic-assisted extraction (DESs-UAE) protocol. The optimal extraction capacity can be achieved by mixing 30 % water with a molar ratio of 1:3 for choline chloride and ethylene glycol, as opposed to the classical extraction solvents of 95 % ethanol, methanol, and water. Moreover, the DESs-UAE extraction programs were also systematically optimized employing Box-Behnken design (BBD) trials, and the eventual findings suggested that the best parameters were a 27 % water content in DES, a 16 mL/g liquid–solid ratio, a 72 min extraction time, and a 62 °C extraction temperature, along with the corresponding greatest contents of NAR (48.18 mg/g) and NEO (34.50 mg/g), respectively. Notably, by comparison with the pre-optimization data, the optimized DES extraction efficiency of flavonoids is markedly higher. Thereafter, the characterization of the solvents before and after extraction, as well as the differences between the four extraction solvent extracts, were compared using the FT-IR analyses. Furthermore, SEM results suggested that the penetration and erosion abilities of the plant cell wall of DES-1 were stronger than those of the other three traditional solvents, thus allowing more release of flavonoid compounds. In conclusion, the present research develops a straightforward, sustainable, and exceedingly efficient approach for the extraction of bioactive flavonoids from JFA, which has the potential to facilitate the efficient acquisition of active ingredients from TCM.

As an important part of terrestrial carbon cycle research, net primary productivity is an important parameter to evaluate the quality of terrestrial ecosystem and plays an important role in the analysis of global climate change and carbon balance. Anhui Province is in the Yangtze River Delta region in eastern China. Based on the theoretical basis of CASA model, this paper uses MODIS NDVI, vegetation type data, meteorological data, and LUCC to estimate the NPP of Anhui Province during 2001-2020 and analyzes its spatial-temporal pattern. The results showed that the average NPP in Anhui province was 508.95 gC· (m2 ·a) -1, and the spatial heterogeneity of NPP was strong, and the high value areas were mainly distributed in the Jiangnan Mountains and Dabie Mountains. NPP increased in most areas of Anhui Province, but decreased significantly in 17.60% of the area, mainly in the central area affected by urban and rural expansion and the transformation of the Yangtze River. The dynamic change of NPP in Anhui province is the result of climate change and land use change. Meteorological data are positively correlated with NPP. Among them, the correlation between temperature and solar radiation is higher, and the correlation between NPP and precipitation is the lowest among the three. The NPP of all land cover types was more affected by temperature than precipitation, especially forest land and grassland. The decrease of cultivated land and the increase of Artificial Surfaces (AS) may have contributed to the decrease of NPP in Anhui Province. Human activities have weakened the increase in NPP caused by climate change. In conclusion, this study refined the drivers of spatial heterogeneity of NPP changes in Anhui province, which is conducive to rational planning of terrestrial ecosystems and carbon balance measures.

BackgroundSubjective cognitive decline (SCD) is considered a preclinical stage of Alzheimer’s disease. However, reliable prevalence estimates of SCD in the Chinese population are lacking, underscoring the importance of such metrics for policymakers to formulate appropriate healthcare strategies.ObjectiveTo systematically evaluate SCD prevalence among older Chinese adults.MethodsPubMed, Web of Science, The Cochrane Library, Embase, CNKI, Wanfang, VIP, CBM, and Airiti Library databases were searched for studies on SCD in older Chinese individuals published before May 2023. Two investigators independently screened the literature, extracted the information, and assessed the bias risk of the included studies. A meta-analysis was then conducted using Stata 16.0 software via a random-effects model to analyze SCD prevalence in older Chinese adults.ResultsA total of 17 studies were included (n = 31,782). The SCD prevalence in older Chinese adults was 46.4% (95% CI, 40.6–52.2%). Further, subgroup analyzes indicated that SCD prevalence was 50.8% in men and 58.9% among women. Additionally, SCD prevalence in individuals aged 60–69, 70–79, and ≥ 80 years was 38.0, 45.2, and 60.3%, respectively. Furthermore, SCD prevalence in older adults with BMI 24.0 was 59.3, 54.0, and 52.9%, respectively. Geographically, SCD prevalence among older Chinese individuals was 41.3% in North China and 50.0% in South China. In terms of residence, SCD prevalence was 47.1% in urban residents and 50.0% among rural residents. As for retired individuals, SCD prevalence was 44.2% in non-manual workers and 49.2% among manual workers. In the case of education, individuals with an education level of “elementary school and below” had an SCD prevalence rate of 62.8%; “middle school, “52.4%; “high school, “55.0%; and “college and above, “51.3%. Finally, SCD prevalence was lower among married individuals with surviving spouses than in single adults who were divorced, widowed, or unmarried.ConclusionOur systematic review and meta-analysis identified significant and widespread SCD prevalence in the older population in China. Therefore, our review findings highlight the urgent requirement for medical institutions and policymakers across all levels to prioritize and rapidly develop and implement comprehensive preventive and therapeutic strategies for SCD.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023406950, identifier: CRD42023406950.

The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment.

Abstract Patients with intrahepatic cholangiocarcinoma (ICC) require chemotherapy due to late detection, rapid disease progression, and low surgical resection rate. Tumor cell lines are extremely important in cancer research for drug discovery and development. Here, we established and characterized a new intrahepatic cholangiocarcinoma cell line, ICC-X1. STR testing confirmed the absence of cross-contamination and high similarity to the original tissue. ICC-X1 exhibited typical epithelial morphology and formed tumor spheres in the suspension culture. The population doubling time was approximately 48 h. The cell line had a complex hypotriploid karyotype. The cell line exhibited a strong migration ability in vitro and cell inoculation into BALB/c nude mice led to the formation of xenografts. Additionally, ICC-X1 cells were sensitive to gemcitabine and paclitaxel but resistant to 5-fluorouracil and oxaliplatin. RNA sequencing revealed that the upregulated cancer-related genes were mainly enriched in several signaling pathways, including the TNF signaling pathway, NOD-like receptor signaling pathway, and NF-κB signaling pathway. The downregulated cancer-related genes were mainly enriched in the Rap1 signaling pathway and Hippo signaling pathway among other pathways. In conclusion, we have created a new ICC cell line derived from Chinese patients. This cell line can be used as a preclinical model to study ICC, specifically tumor metastasis and drug resistance mechanisms.

Abstract Background Circulating tumor DNA (ctDNA) has made a breakthrough as an early biomarker in operable early‐stage cancer patients. However, the function of ctDNA combined with cell‐free DNA (cfDNA) as a predictor in advanced non‐small cell lung cancer (NSCLC) remains unknown. Here, we explored its potential as a biomarker for predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in patients with advanced NSCLC. Methods A retrospective analysis was undertaken. Plasma collected from 51 patients with advanced NSCLC prior to and serially after starting treatment with EGFR‐TKIs was analyzed by next‐generation sequencing (NGS). The performance of ctDNA, cfDNA, and combining ctDNA with cfDNA were evaluated for their ability to predict survival outcomes. Results Patients with early undetectable ctDNA and increasing cfDNA had a markedly better progression‐free survival (PFS) (p

IntroductionTumor-associated macrophage 2 (TAM2) abundantly infiltrates pancreatic ductal adenocarcinoma (PAAD), and its interaction with malignant cells is involved in the regulation of tumor metabolism. In this study, we explored the metabolic heterogeneity involved in TAM2 by constructing TAM2-associated metabolic subtypes in PAAD.Materials and methodsPAAD samples were classified into molecular subtypes with different metabolic characteristics based on a multi-omics analysis strategy. 20 PAAD tissues and 10 normal pancreatic tissues were collected for proteomic and metabolomic analyses. RNA sequencing data from the TCGA-PAAD cohort were used for transcriptomic analyses. Immunohistochemistry was used to assess TAM2 infiltration in PAAD tissues.ResultsThe results of transcriptomics and immunohistochemistry showed that TAM2 infiltration levels were upregulated in PAAD and were associated with poor patient prognosis. The results of proteomics and metabolomics indicated that multiple metabolic processes were aberrantly regulated in PAAD and that this dysregulation was linked to the level of TAM2 infiltration. WGCNA confirmed pyruvate and glycolysis/gluconeogenesis as co-expressed metabolic pathways of TAM2 in PAAD. Based on transcriptomic data, we classified the PAAD samples into four TAM2-associated metabolic subtypes (quiescent, pyruvate, glycolysis/gluconeogenesis and mixed). Metabolic subtypes were each characterized in terms of clinical prognosis, tumor microenvironment, immune cell infiltration, chemotherapeutic drug sensitivity, and functional mechanisms.ConclusionOur study confirmed that the metabolic remodeling of pyruvate and glycolysis/gluconeogenesis in PAAD was closely related to TAM2. Molecular subtypes based on TAM2-associated metabolic pathways provided new insights into prognosis prediction and therapy for PAAD patients.

In the study of atmospheric dynamics, the vorticity equation in a rotating coordinate system plays a crucial role. However, a paradox arises when one considers the term related to spatial variations in Coriolis parameters known as the “β-term”. The β-term should not appear in the vorticity equation because the three-dimensional (3D) planetary vorticity is a constant vector. However, it is always in the vorticity equation. In this article, the source of the β-term in different rotating coordinates are investigated. The results show that in the spherical coordinate system, the β-term comes from the directions changing of one of the unit vectors (j→) with the spatial position and originates from the tilting term. By contrast, in the height coordinate system, the β-term cannot be derived from the tilting term as the individual changes of the coordinate frames with time are omitted, Instead it is proven to be related to the advection term. Although the both coordinate systems are rotating coordinate systems, the sources of their β-terms differ due to the simplification levels of the coordinate systems. Although the 3D planetary vorticity is a constant vector in the spherical coordinate system, the conversions between its components are allowable and spatial derivatives of its components can be observed, eliminating the paradox of the β-term. However, in the height coordinate system, the 3D planetary vorticity vector is not a constant vector in order to maintain the conservation of the absolute angular momentum and mechanical energy. To account for the influence of the earth’s curvature on atmospheric motion, the β-term of the Coriolis parameters varying with the latitude appears. So, the origin of the β-term paradox proposed in the height coordinate system comes from a misunderstanding of the physical constraints of the height coordinate system.

Abstract Ionic liquids (ILs) have attracted intensive research interest due to their outstanding physiochemical properties. However, comprehensive design is necessary for targeted applications and has rarely been conducted. As a result, the industry‐scale application of ILs is still very limited. In this academia–industry collaborative research among the University of Pittsburgh, Virginia Tech. University, and Seagate Technology LLC, we report the design, synthesis, molecular dynamics (MD) simulation, and characterization of a nanometer‐thick IL, which contains abundant fluorinated segments and a hydroxyl endgroup, as the next‐generation nano‐lubricant for hard disk drives (HDDs). The lab‐ and industry‐level testing results indicate that the IL lubricant performs significantly better than the state‐of‐the‐art lubricant, that is, perfluoropolyether (PFPE) that has been utilized for three decades in the HDD industry in two key functions: thermal stability and fly clearance. Meanwhile, the IL lubricant also shows excellent lubricity and durability. The outstanding performance of the IL has been attributed to its unique molecular structure on the solid substrate, which is supported by MD simulation results. Our work establishes the IL as a promising candidate among the next‐generation media lubricants in HDD industry. Meanwhile, the finding obtained here has important implications in many other applications involving nano‐lubricants.

Osteoporosis is partially caused by dysfunctions in the commitment, differentiation or survival of osteoblasts. Bone marrow fatty acids affect bone resorption and formation. In this study, we aimed to explore the role of fatty acids in the early stages of postmenopausal osteoporosis and determine whether they influence osteogenic differentiation through microRNAs. A quantitative analysis of bone marrow fatty acids early after ovariectomy or sham surgery in a rat osteoporotic model was performed using gas chromatography/mass spectrometry. The results showed that palmitoleate was significantly decreased on postoperative day 3 while both pentadecanoate and palmitoleate were significantly decreased on postoperative day 5 in rats in the ovariectomized group compared with those in the sham group. Palmitoleate promotes osteogenic differentiation, whereas pentadecanoate inhibits this process. Palmitoleate levels were higher than those of pentadecanoate; therefore, the early overall effect of significant bone marrow fatty acid changes was a decrease in osteogenic differentiation. We also found that miR-92b-3p inhibited osteoblastogenesis via the miR-92b-3p/phosphatase and tensin homolog regulatory axis. Palmitoleate, pentadecanoate, and palmitate influenced the osteoblastogenesis of MC3T3-E1 cells through miR-92b-3p. Taken together, we propose that miR-92b-3p mediates the effect of bone marrow fatty acids on osteoblast differentiation in the early stages of osteoporosis. These findings may provide molecular insights for the treatment of osteoporosis.

Abstract Background Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine (CQ) has played an indispensable role, however, its mechanism of action (MoA) is not fully understood. Methods We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling (ABPP) and mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays. Results We developed a novel clickable, photo-affinity chloroquine analog probe (CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photo-crosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods. Conclusions We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled (ABPP) and label-free (MS-CETSA) methods.

The ubiquitous Gram-negative bacterial pathogen Aeromonas veronii (A. veronii) can easily cause inflammatory reactions in aquatic organisms, resulting in high mortality and huge economic losses. MicroRNAs (miRNAs) participate in immune regulation and have certain conserved properties. MiRNAs are involved in the immune responses of a variety of teleost fish infected with bacteria, whereas there is no related report in silver carp (Hypophthalmichthys molitrix). Therefore, we identified the expression profiles of miRNA in silver carp stimulated by A. veronii and LPS. Among them, the quantity of differentially expressed miRNAs (DEmiRNAs) obtained in the silver carp challenge group was 73 (A. veronii) and 90 (LPS). The GO enrichment and analysis of KEGG pathways have shown that the predicted target genes are mainly associated with lipid metabolism and the immune response in silver carp. This indicates the possibility that miRNAs play a role in regulating immune-related pathways. In addition, a total of eight DEmiRNAs validated the accuracy of the sequencing result via quantitative real-time PCR (qRT-PCR). Finally, we selected the silver carp head kidney macrophage cells (HKCs) as model cells and proved that miR-30b-5p can regulate the inflammatory response in silver carp HKCs. This study lays the foundation for exploring miRNA regulation in silver carp during pathogenic bacterial infection. In addition, it provides a reference for the future development of non-coding RNA antibacterial drugs.

Many bacteria use the second messenger c-di-GMP to regulate exopolysaccharide production, biofilm formation, motility, virulence, and other phenotypes. The c-di-GMP level is controlled by the complex network of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) that synthesize and degrade c-di-GMP. In addition to chromosomally encoded DGCs, increasing numbers of DGCs were found to be located on mobile genetic elements. Whether these mobile genetic element-encoded DGCs can modulate the physiological phenotypes in recipient bacteria after horizontal gene transfer should be investigated. In our previous study, a genomic island encoding three DGC proteins (Dgc137, Dgc139, and Dgc140) was characterized in Vibrio alginolyticus isolated from the gastric cavity of the coral Galaxea fascicularis. Here, the effect of the three DGCs in four Pseudoalteromonas strains isolated from coral Galaxea fascicularis and other marine environments was explored. The results showed that when dgc137 is present rather than the three DGC genes, it obviously modulates biofilm formation and bacterial motility in these Pseudoalteromonas strains. Our findings implied that mobile genetic element-encoded DGC could regulate the physiological status of neighboring bacteria in a microbial community by modulating the c-di-GMP level after horizontal gene transfer.

Abstract Lorlatinib is a promising third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that has been approved for treating ALK-positive non-small-cell lung cancer (NSCLC) patients with previous ALK-TKI treatment failures. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A more comprehensive understanding of the acquired resistance mechanisms to lorlatinib will enable the development of more efficacious therapeutic strategies. The efficacy of chloroquine (CQ) in combination with lorlatinib in ALK-positive NSCLC cells in vitro and in vivo was assessed using CCK-8, colony formation, immunofluorescence staining, flow cytometry analysis, western blot analysis, and xenograft implantation. Here, we show that lorlatinib induced apoptosis and protective autophagy in ALK-positive NSCLC cells. However, the protective autophagy can gradually lead to decreased cytotoxicity of loratinib in ALK-positive NSCLC cells. Meanwhile, we found that the combination of lorlatinib and CQ, an inhibitor of autophagy, inhibited autophagy and promoted apoptosis both in vitro and in vivo, which sensitized cells to lorlatinib through the dephosphorylation of Foxo3a and promoted nuclear translocation, then activation of Foxo3a/Bim axis. Taken together, our results suggest that inhibition of protective autophagy might be a therapeutic target for delaying the occurrence of acquired resistance to lorlatinib in ALK-positive NSCLC patients.

Protected areas (PAs) play a key role in mitigating ecological crises. Currently, priority protected areas (PPAs) focus on biological conservation, and a few studies have considered the connectivity between patches. Few studies have formulated future conservation measures from the two dimensions of ecological security pattern (ESP) and reserve effectiveness. To fill this gap, this study considered the use of the ESP to identify areas that meet future conservation objectives. We take the Wuhan metropolitan area as the research area. We constructed a framework for formulating conservation development plans based on priority protected areas. The framework constructed a complete method system, and we focused on the construction of the evaluation index system based on landscape connectivity. Then, the effectiveness of the PAs could be evaluated, and the PPAs could be identified. The results showed that there were five isolated PAs among the existing PAs. Moreover, the total area of PPAs was 9328.91 km2, and they had high connectivity and ecological value. Due to the low protection rate of PPAs, PPAs are not the main protection target of PAs; thus, we take PPAs as a new area of future PAs. According to our plan, PPAs with different classes will achieve different functions in future protection work. Our framework focuses on achieving sustainable conservation and formulates new environmental protection and land planning measures to balance ecological conservation and urban development. It can provide key information to support the realization of the 2030 vision of sustainable development.

Background and aimsComplement activation is essential for tuberculosis pleural effusion. However, little is known about the value of complement regulatory protein (CD46, CD55, and CD59) in the differential diagnosis of tuberculosis.Materials and methodsNinety-nine patients with exudative pleural effusion admitted to Xiangya Hospital of Central South University from June 1, 2021to November 14, 2022 were enrolled. The expression levels of soluble CD46 (sCD46), soluble CD55 (sCD55), and soluble CD59 (sCD59) in pleural effusion were quantified by enzyme-linked immunosorbent assay, and the receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic and co-diagnostic values.ResultsThe ADA level is higher in TPE patients than non-TPE patients. It is well-found that TPE patients had lower levels of sCD46, sCD55, and sCD59 compared with non-TPE patients. Moreover, the expression of sCD46, sCD55, and sCD59 in pleural effusion was negatively correlated with ADA. In addition, the diagnostic efficacy of sCD46, sCD55 and sCD59 was comparable to that of ADA, with 0.896, 0.857, 0.858 and 0.893, respectively. Furthermore, combine detection of sCD46, sCD55, sCD59 and ADA could improve the diagnostic accuracy.ConclusionsComplement regulatory factors (CD46, CD55, and CD59) were validated by this project to be promising candidate biomarkers for the diagnosis of TPE with high accuracy. The combination of the CD46, CD55, and CD59 and ADA assay exist a better diagnostic value in TPE.

This review provides an updated assessment of the safety of recanalization therapy for Acute Ischemic Stroke (AIS) patients receiving direct oral anticoagulants (DOAC) therapy. We checked the literature for published observational from 1st January 1950 to 31st March 2021. The rate of symptomatic intracerebral hemorrhage (sICH), arterial recanalization rate, good functional recovery, and mortality at 3 months were investigated, and data were expressed as Risk ratio (RR) with a 95% confidence interval (CI). Publication bias, sensitivity analysis, and meta-regression analyses were conducted utilizing STATA software. 17 articles [14 for endovascular therapy (EVT) and 3 intravenous thrombolysis for (IVT)] were finally included in the review. AIS patients with DOAC therapy showed a decreased rate of sICH (RR = 0.85, 95% CI = 0.72 to 1.00, P = 0.04), and lower probability of good functional recovery at three months (RR = 0.79, 95% CI = 0.73 to 0.85, P < 0.001) than patients without anticoagulation therapy post EVT. However, no significant differences in sICH rates in AIS patients with DOAC therapy after IVT (RR = 0.87, 95% CI = 0.48 to 1.58, P = 0.64) were observed. AIS patients not prescribed DOAC after EVT had a higher mortality risk (RR = 1.29, 95% CI = 1.15–1.44, P < 0.001). Patients with AIS on DOAC therapy were found to have a lower incidence of sICH following EVT. However, no evidence of an increased bleeding risk in patients previously treated with DOAC after IVT was observed. Therefore, more detailed studies with biological data to monitor compliance and details on the size and etiology/severity of the incident ischemic lesion is needed.

Abstract During mid‐July 2021, an extreme heavy rainfall event (HRE) occurred in Henan Province (hereafter “21.7” HRE), with extreme hourly precipitation of 201.9 mm appearing at Zhengzhou station. Our preliminary analyses of the “21.7” HRE using the observations and ECMWF (European Centre for Medium‐Range Weather Forecasts) ERA5 reanalysis data, reached the following conclusions. Favorable configurations of various synoptic weather systems (e.g., strong upper‐level high‐pressure ridge, intense middle‐level low‐pressure trough) acted as crucial background conditions for the occurrence of the “21.7” HRE. A 21‐h long‐lived mesoscale convective vortex (MCV), mainly located in the middle and lower troposphere west of Zhengzhou city, was a key system that produced the extreme hourly rainfall of 201.9 mm·h−1. The MCV's development/sustainment was dominated by the vertical transport of cyclonic vorticity and tilting, as well as the horizontal import of cyclonic vorticity to the vortex's key region. In contrast, the divergence‐related vertical shrinking was the most detrimental factor. Lagrangian moisture transport analysis showed that moisture for the extreme heavy rainfall in Zhengzhou on July 20 mainly came from levels below 2200 m, driven by airflows on the peripheries of tropical cyclones IN‐FA and CEMPAKA. To enhance the understanding of “21.7” HRE, we suggest more in‐depth investigations in the future.

This work addresses the declining physical fitness levels observed in both football players and the general population. The objective is to investigate the impact of functional strength training on the physical capabilities of football players and to develop a machine learning-based approach for posture recognition. A total of 116 adolescents aged 8 to 13 participating in football training are randomly assigned to either an experimental group (n = 60) or a control group (n = 56). Both groups underwent 24 training sessions, with the experimental group engaging in 15-20 minutes of functional strength training after each session. Machine learning techniques, specifically the backpropagation neural network (BPNN) in deep learning, are utilized to analyze the kicking actions of football players. Movement speed, sensitivity, and strength are employed as input vectors for the BPNN to compare the images of players' movements, while the similarity between the kicking actions and standard movements served as the output result to enhance training efficiency. The experimental group's kicking scores are compared to their pre-experiment scores, demonstrating a statistically significant improvement. Moreover, statistically significant differences are observed in the 5*25m shuttle running, throwing, and set kicking between the control and experimental groups. These findings highlight the significant enhancement in strength and sensitivity achieved through functional strength training in football players. The results contribute to the development of training programs for football players and the overall improvement of training efficiency.

Background: Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established. Methods: Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened. The samples of pre-osimertinib and osimertinib-resistance were all detected by next-generation sequencing (NGS) panels. Statistical analyses were carried out using SPSS 23.0 software. Survival analyses were performed using the Kaplan–Meier method and compared using a log-rank test between groups. Results: Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA). A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%). A total of 15 patients received subsequent treatments, with mPFS of 7.3 months (95% CI 5.0 months -NA). Among them, 7 patients with EGFR C797 S or/and MET amplification received subsequent second-line targeted therapy, achieving mPFS of 7.3 months (95% CI 4.5 months -NA). Of note, 3 patients received immunotherapy as second- or third-line treatment after osimertinib resistance, achieving median clinical benefit of 37.3 months. Conclusions: MET amplification and C797S mutation are main resistance mechanisms, which could be targeted by crizotinib and gefitinib, respectively. More than 50% patients could receive subsequent anticancer targetable therapies after first-line osimertinib resistance. Immunotherapy may also be an acceptable choice after osimertinib resistance.

Rapeseed oil is an important source of edible oil in the human diet and is also highly susceptible to oxidative deterioration. It has been demonstrated that rosemary extract (RE) can increase the oxidative stability of oils. In this work, the antioxidant capacity of rapeseed oil after the addition of RE during storage and the optimum addition of RE in rapeseed oil were investigated. Oxidative stability evaluation results demonstrate that the shelf life of rapeseed oil with the incorporation of 100 mg/kg of RE was equivalent to that with the addition of 50 mg/kg of tert-butyl hydroxyquinone (TBHQ). Storage test analysis results show that RE remarkably delayed the oxidation of rapeseed oil when the storage container was unsealed. The optimum amount of RE as an addition was 50–200 mg/kg under room temperature storage, while it was 150 mg/kg under Schaal oven storage. The antioxidant capacity of rapeseed oil with 50 mg/kg of RE added was remarkably higher than that with 50 mg/kg of TBHQ added after 20 d of storage, according to the Schaal oven test. Additionally, the addition of RE delayed the degradation of endogenous α-tocopherol in rapeseed oil. This study comprehensively evaluated the antioxidant properties of rapeseed oil when RE was added and it provides a new strategy for establishing healthy, nutritious, and safe oil preservation measures.

Sports videos are blowing up over the internet with enriching material life and the higher pursuit of spiritual life of people. Thus, automatically identifying and detecting helpful information from videos have arisen as a relatively novel research direction. Accordingly, the present work proposes a Human Pose Estimation (HPE) model to automatically classify sports videos and detect hot spots in videos to solve the deficiency of traditional algorithms. Firstly, Deep Learning (DL) is introduced. Then, amounts of human motion features are extracted by the Region Proposal Network (RPN). Next, an HPE model is implemented based on Deep Convolutional Neural Network (DCNN). Finally, the HPE model is applied to motion recognition and video classification in sports videos. The research findings corroborate that an effective and accurate HPE model can be implemented using the DCNN to recognize and classify videos effectively. Meanwhile, Big Data Technology (BDT) is applied to count the playing amounts of various sports videos. It is convinced that the HPE model based on DCNN can effectively and accurately classify the sports videos and then provide a basis for the following statistics of various sports videos by BDT. Finally, a new outlook is proposed to apply new technology in the entertainment industry.

The purpose of this study was to optimize the preparation method of injectable Octreotide microspheres. To explore the correlation between the solvent system and the general properties of microspheres to reduce burst release and enable them to be used for portal hypertension. Octreotide microspheres were prepared by modified double emulsion solution evaporation method after optimizing preparation conditions. The results showed that Octreotide microspheres had a particle size of 57.48 ± 15.24 μm, and the initial release was significantly reduced. In vitro release and in vivo pharmacokinetic data indicated that Octreotide was released stably within 1200 h. The effects on portal vein pressure, liver tissue morphology and other related indexes were observed after administration. As obvious results, injection of Octreotide microspheres could significantly reduce portal vein pressure and reduce the portal vein lumen area in experimental cirrhotic portal hypertensive rats. The optimized Octreotide PLGA microsphere preparation has been proved to have a good effect on PHT in vivo after detecting aminotransferase (AST) and alanine aminotransferase (ALT) activity, liver tissue hydroxyproline (Hyp) content, serum and liver tissue malondialdehyde (MDA) levels, plasma prostacyclin (PGI2) levels, and liver tissue tumor necrosis factor (TNFα) content. In addition, serum and liver tissue superoxide dismutase (SOD) activity and liver tissue glutathione (GSH) content, plasma thromboxane (TXA2), serum nitric oxide (NO), liver tissue nitric oxide synthase (NOS), and plasma and liver tissue endothelin (ET) were significantly increased.

White matter hyperintensities (WMHs), which have a significant effect on human health, have received increasing attention since their number of publications has increased in the past 10 years. We aimed to explore the intellectual structure, hotspots, and emerging trends of publications on WMHs using bibliometric analysis from 2012 to 2021. Publications on WMHs from 2012 to 2021 were retrieved from the Web of Science Core Collection. CiteSpace 5.8.R3, VOSviewer 1.6.17, and an online bibliometric analysis platform (Bibliometric. com) were used to quantitatively analyze the trends of publications from multiple perspectives. A total of 29,707 publications on WMHs were obtained, and the number of annual publications generally increased from 2012 to 2021. Neurology had the most publications on WMHs. The top country and institution were the United States and Harvard University, respectively. Massimo Filippi and Stephen M. Smith were the most productive and co-cited authors, respectively. Thematic concentrations primarily included cerebral small vessel disease, diffusion magnetic resonance imaging (dMRI), schizophrenia, Alzheimer’s disease, multiple sclerosis, microglia, and oligodendrocyte. The hotspots were clustered into five groups: white matter and diffusion tensor imaging, inflammation and demyelination, small vessel disease and cognitive impairment, MRI and multiple sclerosis, and Alzheimer’s disease. Emerging trends mainly include deep learning, machine learning, perivascular space, convolutional neural network, neurovascular unit, and neurite orientation dispersion and density imaging. This study presents an overview of publications on WMHs and provides insights into the intellectual structure of WMH studies. Our study provides information to help researchers and clinicians quickly and comprehensively understand the hotspots and emerging trends within WMH studies as well as providing direction for future basic and clinical studies on WMHs.

Lung cancer is one of the main causes of cancer-related deaths. At present, the main treatment method for lung cancer is chemotherapy. Gemcitabine (GEM) is widely applied in lung cancer treatment, but its lack of targeting ability and serious side effects limit its application. In recent years, nanocarriers have become the focus of research to solve the above problems. Here, we prepared estrone (ES)-modified GEM-loaded PEGylated liposomes (ES-SSL-GEM) for enhanced delivery by identifying the overexpressed estrogen receptor (ER) on lung cancer A549 cells. We studied the characterization, stability, release behavior, cytotoxicity, targeting ability, endocytosis mechanism, and antitumor ability to prove the therapeutic effect of ES-SSL-GEM. The results showed that ES-SSL-GEM presented a uniform particle size of 131.20 ± 0.62 nm, a good stability, and a slowly released behavior. Moreover, ES-SSL-GEM enhanced tumor-targeting ability, and the endocytosis mechanism studies confirmed that the ER-mediated endocytosis had the most crucial effect. Furthermore, ES-SSL-GEM had the best inhibitory effect on A549 cell proliferation and significantly suppressed the tumor growth in vivo. These results suggest that ES-SSL-GEM is a promising agent for treating lung cancer.

The concept of a perfect electromagnetic conductor (PEMC) material, which is a class of a magneto-electric metamaterial, has been recently examined in the context of the optical radiation force theory [J. Quant. Spectr. Rad. Transfer, 233 (2019) 21–28; ibid 256 (2020) 107280], with particular emphasis on the rotary polarization effect and the contribution of the cross-polarized waves to the transfer of linear momentum, assuming an illumination of linearly-polarized plane progressive waves. The present investigation shows that additional cross-interference factors, which cannot be ignored, contribute to the time-averaged optical radiation force exerted on an absorptive electromagnetic conductor (AEMC) sphere when the incident field becomes circularly-polarized. Moreover, the analysis is extended to investigate the co-polarized, cross-polarized and cross-interference components of the time-averaged optical spin radiation torque. The multipole series expansion method in spherical coordinates is utilized to derive exact mathematical partial-wave series for the co-polarized, cross-polarized and cross-interference components of the radiation force and torque based on the integration of Maxwell’s radiation stress tensor and its moment over a spherical surface of large radius enclosing the sphere suspended in a lossless medium of wave propagation. Numerical results for the radiation force and spin torque efficiencies and their corresponding co-polarized, cross-polarized and cross-interference components illustrate the analysis with emphasis on the size parameter of the sphere ka, its electromagnetic admittance M as well as its imaginary part amounting to absorption. The computations are of importance from the standpoint of the fundamentals of the linear and angular momenta of circularly-polarized electromagnetic waves transferred to an AEMC and related applications in optical tweezers and particle manipulation of objects exhibiting circular dichroism.

The aim of this study was to investigate the changes in bone marrow fatty acids early after ovariectomy-induced osteoporosis in rats, and explore the potential function of the bone marrow fatty acids. Ninety-six female Sprague Dawley rats (12 weeks) were randomly divided into an ovariectomized (OVX) group and Sham group (N = 48/group) and received ovariectomy or Sham surgery, respectively. After 3, 5, 7,14, 21 and 28 days, eight rats in each group were sacrificed to detect the composition of bone marrow fatty acids by means of gas chromatography-mass spectrometry and evaluate the trabecular bone microarchitecture by means of microCT. Bone marrow rinsing fluid and serum were collected for the detection of nitric oxide synthase/nitric oxide (NOS/NO) and bone metabolism related parameters, respectively. Our results demonstrated that the bone microstructure was damaged significantly from 14 days after OVX surgery onwards. Sample clustering and group separation were observed between the OVX group and Sham group 3 and 14 days after surgery, which suggested the role of bone marrow fatty acids in the early stage of postmenopausal osteoporosis. Palmitoleate, myristate and arachidonate were found to play an important role in classification between the OVX group and Sham group on the 3rd day after surgery (VIP > 1, p < 0.05). Palmitoleate, myristate, alpha linolenate, stearate and eicosenoate were found to play an important role in classification between the OVX group and Sham group on the 14th day after surgery (VIP > 1, p < 0.05). The levels of myristate, palmitoleate, alpha linolenate and eicosenoate were significantly decreased in the OVX group, while the levels of arachidonate and stearate were significantly increased in OVX group (p < 0.05). Additionally, myristate, palmitoleate, alpha linoleate and eicosenoate were negatively correlated with C-terminal telopeptide of type 1 collagen (CTX-1, a bone resorption marker), while arachidonate was negative correlated with osteocalcin (OCN, a bone formation marker) (p < 0.05). A significant correlation was also found between eicosenoate and NOS (p < 0.05). Profound bone marrow fatty acids changes have taken place in the early stage of post-menopausal osteoporosis. They may affect bone formation though affecting the differentiation and function of osteoclasts or osteoblasts, respectively. The NOS/NO system may mediate the influence of eicosenoate on bone formation.

Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA’s impact on TGT-induced acute liver injury by regulating oxidative stress remain unelucidated. In this study, TGT-induced acute liver injury models were established in vitro and in vivo. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were quantified. The anti-apoptotic effect of GA was tested using flow cytometry. Potential target proteins of GA were profiled via activity-based protein profiling (ABPP) using a cysteine-specific (IAA-yne) probe. The results demonstrate that GA markedly decreased the concentrations of ALT, AST, AKP, MDA, LDH, TNF-α, IL-1β and IL-6, whereas those of SOD, GSH and CAT increased. GA could inhibit TGT-induced apoptosis in BRL-3A cells. GA bound directly to the cysteine residue of PKM2. The CETSA and enzyme activity results validate the specific targets identified. GA could mitigate TGT-induced acute liver injury by mediating PKM2, reducing oxidative stress and inflammation and reducing hepatocyte apoptosis.

Objective: This study assessed the characteristics of intravenous thrombolysis (IVT) with respect to early neurological deterioration (END) and functional outcome in mild ischemic stroke patients.Methods: Data were obtained from acute mild ischemic stroke patients (defined as having a National Institute of Health Stroke Score (NIHSS) ≤ 5) treated with IVT in our hospital from July 2017 to December 2020. END was defined as the NIHSS increased ≥1 over the baseline at 24 h after IVT. A modified Rankin scale (mRS) ≤ 1 at 3 months was considered as a favorable outcome, and an mRS ≥2 at 3 months was an unfavorable outcome.Results: Two hundred thirty-three acute mild ischemic stroke patients (all patients underwent MRI and DWI restriction) with IVT were included in this study. Thirty-one patients experienced END, and 57 patients experienced an unfavorable outcome at 3 months. With multivariate analysis, END was associated with an elevated baseline systolic blood pressure (SBP) (OR = 1.324, 95% CI, 1.053–1.664, p = 0.016) and coronary heart disease (OR = 4.933, 95% CI, 1.249–19.482, p = 0.023). An unfavorable outcome at 3 months after IVT was independently associated with a baseline elevated SBP (OR = 1.213, 95% CI, 1.005–1.465, p = 0.045), baseline NIHSS (OR = 1.515, 95% CI, 1.186–1.935, p = 0.001), prior hyperlipemia (OR = 3.065, 95% CI, 1.107–8.482, p = 0.031), cardioembolic stroke (OR = 0.323, 95% CI, 0.120–0.871, p = 0.025), and END at 24 h (OR = 4.531, 95% CI, 1.950–10.533, p < 0.001) in mild ischemic stroke patients.Conclusion: In mild ischemic stroke patients with IVT, an elevated baseline SBP and coronary heart disease were associated with END. The elevated baseline SBP, baseline NIHSS, a history of prior hyperlipemia, cardioembolic stroke, and END at 24 h after IVT were useful in predicting an unfavorable outcome at 3 months.

For better understanding the variation of helicity and its governing mechanisms, based on the primary momentum equation under the local Cartesian coordinate, a set of horizontal and vertical helicity equations are derived in this study. On this basis, a storm-relative helicity budget equation is derived, the main factors that govern the variation of helicity are discussed, and the key mechanisms underlying the helicity variation are illustrated by using schematic images. Both scale analysis and real case diagnosis are used to compare the relative importance of different factors on the variation of helicity. For a meso-α system, it is found that: (i) horizontal helicity is much larger than vertical helicity, and they show significantly different variation mechanisms; (ii) for the vertical helicity, the vertical perturbation pressure gradient force, buoyancy, the divergence-related effect, and the conversion between vertical and horizontal helicity govern its variation (whereas, the conversion is negligible for the evolution of horizontal helicity); and (iii) baroclinity is crucial for the variation of horizontal helicity, but it is only of secondary importance for the vertical helicity variation.