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Abstract Sepiolite-modified nano-zero-valent iron (S-nZVI) is used as an amendment and incubated to remediate As-Cd-contaminated soil under three different soil‒water management conditions [moderately wet (MW), continuously flooded (CF) and alternately wet and dry (AWD)]. The results showed that soil pH is in the order of CF > AWD > MW. The soil pH increased approximately 0.5 to 1 unit by 3% and 5% doses after 36 d of incubation. Soil pH was negatively correlated with available As-Cd content under the three water regimes (p

Abstract As China's demand for imported oil continues to grow, large‐scale oil storage facilities have become increasingly important. Currently, China primarily uses underground salt cavern spaces and newly excavated underground water‐sealed caverns for oil storage, which places high demands on the rock formations. China has abundant and widely distributed gypsum mineral resources, and utilizing abandoned gypsum mines for oil storage could not only turn waste into treasure by controlling underground space but also generate significant economic and social value. This article aims to systematically evaluate the mechanical properties of gypsum rock through long‐term immersion tests in crude oil to assess the impact of crude oil immersion on the mechanical performance of gypsum rock and explore the feasibility of using gypsum mines as long‐term stable oil storage caverns. The results show that oil immersion treatment reduces the uniaxial tensile strength of gypsum samples, but has little effect on their compressive strength and long‐term strength. From a mechanical performance perspective, it is feasible to use gypsum mine voids for crude oil storage.

Abstract The significance of health literacy for elderly individuals with chronic illnesses lies in managing and delaying disease development, which is affected by personal and environmental factors. Family communication can provide an emotional support environment; self-efficacy is an important factor of subjective initiative and personality. A relatively persistent thinking and behavior pattern can affect the environment, subjective initiative, and individual health outcomes. This study aims to explore the effects of the Big Five personality traits on the health literacy of elderly individuals with chronic illnesses and to hypothesize that family communication and self-efficacy mediate the Big Five personalities and health literacy. A cross-sectional study of 2251 elderly individuals with chronic diseases was conducted through nationwide random quota sampling. The structural equation model was used to explore the mediating role of family communication and self-efficacy between the Big Five personality and health literacy. Family communication played a simple mediating role in the influence of extraversion, agreeableness, conscientiousness, and neuroticism on health literacy. Self-efficacy played a simple mediating role in the influence of the Big Five personalities on health literacy. Self-efficacy and family communication played a chain mediating role between extraversion, agreeableness, conscientiousness, neuroticism, and health literacy. Nurses can enhance the health literacy of elderly individuals with chronic illnesses with extraversion, agreeableness, conscientiousness, and neuroticism through family communication and self-efficacy while promoting the health literacy of those with openness through self-efficacy.

Terahertz (THz) computed tomography (THz CT) exhibits the potential to provide a wealth of data, surpassing that of THz tomographic imaging in applications such as detecting embedded defects, particularly defect evolution within a glass fiber-reinforced polymer. To realize high-resolution THz CT, a systematic approach guided by wave propagation simulation was employed. First, the front wave of the THz beam was fine-tuned to realize a beam diameter of

Abstract N6-methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA and played a significant role in various cancers. However, the mechanism by which m6A modification influences cervical cancer (CC) tumorigenesis remains unclear. Therefore, we aim to elucidate the role and mechanism of METTL3 in CC progression. In the present study, we observed a significant upregulation of METTL3 in CC tissues and cell lines. Knockdown of METTL3 resulted in reduced growth, migration, and invasion of CC cells, as well as affected apoptosis, while overexpression of METTL3 reversed these effects. Through a combined analysis of meRIP-seq and Ribo-seq data following METTL3 knockdown, NEK2 was identified as a key target of METTL3 in CC cells. Correlation analysis, MeRIP-qPCR, and luciferase reporter assay suggested that METTL3 regulates NEK2 expression through m6A modification. NEK2 synergized with METTL3 to mediate the malignant phenotype of CC cells. The METTL3-NEK2 axis promoted CC progression by activating the Wnt/β-catenin pathway and inhibiting the apoptosis pathway. In conclusion, METTL3 facilitated the malignant progression of CC and contributed to the formation of the METTL3-NEK2 regulatory axis in an m6A-dependent manner, which represented a potential target for CC therapy.

Abstract Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1–Nrf2–PHB2 pathway, thereby contributing to the cognitive decline in DE.

Abstract Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people’s lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional ‘natural’ nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy.

Ovarian cancer is a common gynecologic malignancy. In clinical practice, recurrent ovarian cancer is mainly classified into two categories on the basis of platinum-free interval, platinum-resistant and platinum-sensitive, corresponding to different treatment modalities and prognoses. The treatment of platinum-resistant ovarian cancer is challenging. Some scholars have pointed out limitations in the binary classification of platinum-free interval. In this article, the classification of recurrent ovarian cancer, the treatment challenges of platinum-resistant ovarian cancer, the limitations of the platinum-free interval binary classification, and new classification perspectives were reviewed to help physicians enhance their understanding on the research progress in ovarian cancer classification and develop more effective treatment strategies.

Abstract Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.

Abstract Over the past decade, there has been a growing interest in ferritin-based vaccines due to their enhanced antigen immunogenicity and favorable safety profiles, with several vaccine candidates targeting various pathogens advancing to phase I clinical trials. Nevertheless, challenges associated with particle heterogeneity, improper assembly and unanticipated immunogenicity due to the bulky protein adaptor have impeded further advancement. To overcome these challenges, we devise a universal ferritin-adaptor delivery platform based on structural insights derived from the natural ferritinophagy complex of the human ferritin heavy chain (FTH1) and the nuclear receptor coactivator 4 (NCOA4). The engineered ferritinophagy (Fagy)-tag peptide demonstrate significantly enhanced binding affinity to the 24-mer ferritin nanoparticle, enabling efficient antigen presentation. Subsequently, we construct a self-assembling rabies virus (RABV) vaccine candidate by noncovalently conjugating the Fagy-tagged glycoprotein domain III (GDIII) of RABV to the ferritin nanoparticle, maintaining superior homogeneity, stability and immunogenicity. This vaccine candidate induces potent, rapid, and durable immune responses, and protects female mice against the authentic RABV challenge after single-dose administration. Furthermore, this universal, ferritin-based antigen conjugating strategy offers significant potential for developing vaccine against diverse pathogens and diseases.

The Upper Cretaceous Qingshankou Formation in the Songliao Basin contains thick, widespread, and organic matter-rich shale layers, offering abundant shale oil resources. Studying the sedimentary environment during shale formation and exploring the oil-bearing characteristics of shale oil enrichment intervals provide a theoretical basis for the prediction of the intervals and sweet spots. Based on previous research, the study compared organic carbon content, pyrolysis data, types of organic macerals, and major and trace elements of samples from two typical wells of different sags, well GY8HC in the Gulong Sag and well ZY1 in the Sanzhao Sag, in the central depression zone of the Songliao Basin. The analysis delved into the differences in oil-bearing characteristics and sedimentary environment of the Qingshankou Formation shales in two different sags, further analyzing the factors influencing these differences. The oil-bearing indicators of shales from the two wells in the Qingshankou Formation of the Songliao Basin showed that the total organic carbon (TOC) content in well ZY1 was significantly higher than that in well GY8HC. However, the free hydrocarbon content (S1) and oil saturation index (OSI) in well ZY1 were lower than those in well GY8HC. The geochemical environment during shale formation controlled organic matter enrichment. Comparing major and trace elements in samples from both wells, it was found that the climate in well ZY1 was more humid during its sedimentary period, the water body had stronger reducing conditions, and its paleoproductivity and paleo-water depth were significantly higher than those in well GY8HC. These conditions were favorable for the preservation of organic matter, thereby forming a higher organic matter abundance in the shale of well ZY1. In addition, it was found that the organic matter type in well GY8HC is mainly Type Ⅰ, sapropelic kerogen, at a mature to highly mature stage, whereas well ZY1 contains mainly Type Ⅱ1 kerogen, with less Type Ⅰ, at a low to mature stage. Therefore, the shale in well GY8HC possesses better oil generation potential.

Abstract Recent advances in cancer research have highlighted the pivotal role of tertiary lymphoid structures (TLSs) in modulating immune responses, particularly in breast cancer (BRCA). Here, we performed an integrated analysis of bulk transcriptome data from over 6000 BRCA samples using biological network-based computational strategies and machine learning (ML) methods, and identified LGALS2 as a key marker within TLSs. Single-cell sequencing and spatial transcriptomics uncover the role of LGALS2 in TLS-associated dendritic cells (DCs) stimulation and reveal the complexity of the tumor microenvironment (TME) at both the macro and micro levels. Elevated LGALS2 expression correlates with prolonged survival, which is associated with a robust immune response marked by diverse immune cell infiltration and active anti-tumor pathways leading to a ‘hot’ tumor microenvironment. The colocalization of LGALS2 with TLS-associated DCs and its role in immune activation in BRCA were confirmed by hematoxylin-eosin (HE), immunohistochemistry (IHC), and in vivo validation analyses. The identification of LGALS2 as a key factor in BRCA not only highlights its therapeutic potential in novel TLS-directed immunotherapy but also opens new avenues in patient stratification and treatment selection, ultimately improving clinical management.

Abstract Fungal natural products from various species often feature hydroxamic acid motifs that have the ability to chelate iron. These compounds have an array of medicinally and ecologically relevant activities. Through genome mining, gene deletion in the host Aspergillus terreus, and heterologous expression experiments, this study has revealed that a nonribosomal peptide synthetase (NRPS) TamA and a specialized cytochrome P450 monooxygenase TamB catalyze the sequential biosynthetic reactions in the formation of terramides A-C, a series of diketopiperazines (DKPs) with hydroxamic acid motifs. Feeding experiments showed that TamB catalyzes an unprecedented di-hydroxylation of the amide nitrogens in the diketopiperazine core. This tailoring reaction led to the formation of two bidentate iron-binding sites per molecule with an unusual iron-binding stoichiometry. The structure of the terramide A-Fe complex was characterized by liquid chromatography-mass spectrometry (LC-MS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and electron paramagnetic resonance spectroscopy (EPR). Antimicrobial assays showed that the iron-binding motifs are crucial for the activity against bacteria and fungi. Murine infection experiments indicated that terramide production is crucial for the virulence of A. terreus and could be a potential antifungal drug target.

Abstract N6-methyladenosine (m6A) is a prevalent mRNA modification known for its implications in various cancer types, yet its role in chromophobe renal cell carcinoma (chRCC) remains largely unexplored. In this study, we performed m6A-SEAL-seq and RNA-seq analyses on tissues from three chRCC subjects, aiming to uncover m6A alterations in chRCC. Our findings revealed reduced expression levels of four m6A regulators in chRCC tissues and highlighted differences in m6A levels compared to normal tissues. Furthermore, we identified specific genes and cancer-related pathways affected by these differences, including notable candidates like NOTCH1 and FGFR1, implicated in chRCC development. Additionally, we developed a predictive model based on the expression level of m6A associated genes, demonstrating promising prognostic capabilities for patient survival prediction. Overall, our study provides valuable insights into the role of m6A in chRCC and its potential as a prognostic indicator.

Abstract Psychiatric disorders are severe health challenges that exert a heavy public burden. Air pollution has been widely reported as related to psychiatric disorder risk, but their casual association and pathological mechanism remained unclear. Herein, we systematically investigated the large genome-wide association studies (6 cohorts with 1,357,645 samples), single-cell RNA (26 samples with 157,488 cells), and bulk-RNAseq (1595 samples) datasets to reveal the genetic causality and biological link between four air pollutants and nine psychiatric disorders. As a result, we identified ten positive genetic correlations between air pollution and psychiatric disorders. Besides, PM2.5 and NO2 presented significant causal effects on schizophrenia risk which was robust with adjustment of potential confounders. Besides, transcriptome-wide association studies identified the shared genes between PM2.5/NO2 and schizophrenia. We then discovered a schizophrenia-derived inhibitory neuron subtype with highly expressed shared genes and abnormal synaptic and metabolic pathways by scRNA analyses and confirmed their abnormal level and correlations with the shared genes in schizophrenia patients in a large RNA-seq cohort. Comprehensively, we discovered robust genetic causality between PM2.5, NO2, and schizophrenia and identified an abnormal inhibitory neuron subtype that links schizophrenia pathology and PM2.5/NO2 exposure. These discoveries highlight the schizophrenia risk under air pollutants exposure and provide novel mechanical insights into schizophrenia pathology, contributing to pollutant-related schizophrenia risk control and therapeutic strategies development. Graphical Abstract

Abstract Background The objectives of this study were twofold: (1) to compare gait characteristics between cerebral small vessel disease (CSVD) patients with low-risk oral frailty (OF) and high-risk OF, particularly during dual-task walking (DTW); (2) to investigate the association of OF, the gait characteristics of DTW, and falls among older adults patients with CSVD. Methods A total of 126 hospitalized patients diagnosed with CSVD were recruited and classified into a low-risk group (n = 90) and a high-risk group (n = 36) based on OF status in our study. Comprehensive data pertaining to basic parameters (cadence, as well as stride time, velocity and length), variability, asymmetry, and coordination were gathered during both single-task walking (STW) and DTW. Additionally, the number of falls was calculated. Subsequently, t-test or chi-squared test was used for comparison between the two groups. Furthermore, linear regression analysis was employed to elucidate the association of the OF index-8 score and gait parameters during cognitive DTW. Also, logistic regression models were utilized to assess the independent association of OF risk and falls. Results During cognitive DTW, the high-risk group demonstrated inferior performance in terms of basic parameters (p

Abstract Background Loss-of-function mutations of ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, resulting in recurrent and sometimes fatal respiratory and gastrointestinal infections. The genotype–phenotype correlation in patients with ICF2 indicates an essential role of ZBTB24 in the terminal differentiation of B cells. Methods We used the clustered regularly interspaced short palindromic repeats (CRISPER)/Cas9 technology to generate B cell specific Zbtb24-deficient mice and verified the deletion specificity and efficiency by quantitative polymerase chain reaction (Q-PCR) and western blotting analyses in fluorescence-activated cell sorting (FACS)-sorted cells. The development, phenotype of B cells and in vivo responses to T cell dependent or independent antigens post immunization were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Adoptive transfer experiment in combination with in vitro cultures of FACS-purified B cells and RNA-Seq analysis were utilized to specifically determine the impact of Zbtb24 on B cell biology as well as the underlying mechanisms. Results Zbtb24 is dispensable for B cell development and maintenance in naive mice. Surprisingly, B cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary and secondary antibody responses induced by T cell dependent antigens (TD-Ags), but significantly inhibits T cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells. Conclusions Zbtb24 seems to regulate antibody responses against TD-Ags B cell extrinsically, but it specifically promotes the plasma cell differentiation of B1 cells via heme synthesis in mice. Our study also suggests that defected B1 functions contribute to recurrent infections in patients with ICF2.

Abstract Objective To compile a scale of Chinese college students’ perception of teachers’ differential behavior and to provide a reference for college students to establish correct life values, promote college students’ physical and mental health, and reduce teachers’ differential treatment. Methods Open-ended questionnaires and expert interviews were used to conduct interviews and correspondence with 58 college students, ten psychologists, and six psychologists to form an initial questionnaire. Then, the scale’s exploratory factor analysis, confirmatory factor analysis, and reliability and validity test were conducted on 7053 college students from 18 universities in 6 provinces (municipalities directly under the Central Government). Results The Chinese college students’ perception of teachers’ differential behavior scale has two dimensions: teacher prejudice and preference. Each dimension includes three aspects: emotional feedback, behavior orientation, and opportunity privilege, and each aspect have a total of 4 items. The consistency test coefficients of each dimension and each factor of the prepared scale are all above 0.7, and the split-half reliability is above 0.6. Confirmatory factor analysis shows that the six-factor structural model fits well (χ 2/df = 4.287, RMSEA = 0.066, CFI = 0.950, TLI = 0.919). Using the generalized anxiety disorder scale and the patient health questionaire-9items as empirical criteria, each factor in the scale demonstrated significant correlations with both the GAD scale and the patient health questionaire-9items. Conclusions The Chinese college students’ perception of teachers’ differential behavior scale has a two-dimensional six-factor structure and has good reliability and validity. It can be used as an effective tool to measure Chinese college students’ perceived teacher differential behavior.

Abstract Metastasis accounts for almost 90% of breast cancer-related fatalities, making it frequent malignancy and the main reason of tumor mortality globally among women. LSD1 is a histone demethylase, which plays an important role in breast cancer. In order to explore the effect of LSD1 on invasion and migration of breast cancer, we treated breast cancer cells with MCF7 and T47D exosomes knocked down by LSD1, and the invasion and migration of breast cancer cells were significantly enhanced. This phenomenon indicates that LSD1 can inhibit the invasion and migration of breast cancer cells. miR-1290 expression was downregulated in LSD1 knockdown MCF7 exosomes. By analyzing the database of miR-1290 target gene NAT1, we verified that miR-1290 could regulate the expression of NAT1. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells’ invasion and migration via controlling exosomal miRNA.

Abstract In March 2023, our pediatric intensive care unit (PICU) retrospectively examined six cases of pediatric necrotizing tracheobronchitis (NTB), focusing on co-infections with influenza A virus (IAV) and Staphylococcus aureus (S. aureus). This study aimed to elucidate NTB’s clinical characteristics, diagnostics, and therapeutic approaches. Diagnostics included symptom assessment, microbiological testing that confirmed all patients were positive for IAV H1N1 with a predominant S. aureus co-infection, and bronchoscopy. The patients predominantly exhibited fever, cough, and dyspnea. Laboratory analysis revealed decreased lymphocyte counts and elevated infection markers like C-reactive protein and procalcitonin. Chest computed tomography (CT) scans detected tracheobronchial obstructions in half of the cases, while bronchoscopy showed severe mucosal congestion, edema, necrosis, and purulent-hemorrhagic exudates. Treatments encompassed comprehensive strategies like oxygen therapy, intubation, bronchoscopic interventions, thoracentesis, oseltamivir, and a regimen of antibiotics. Our findings suggested potential correlations between clinical markers, notably lymphocyte count and procalcitonin, and clinical interventions such as the number of rescues and intensive care unit (ICU) duration. This research highlights the importance of early detection and the role of bronchoscopy and specific markers in assessing NTB, advocating for continued research in larger cohorts to better understand its clinical trajectory and refine treatment approaches for this challenging pediatric disease.

AbstractLung cancer is a dangerous disease that is lacking in an ideal therapy. Here, we evaluated the anti-lung cancer effect in nude mice of a fully human single-chain antibody (scFv) against the associated antigen 7 transmembrane receptor (Ts7TMR), which is also called G protein-coupled receptor, between A549 cells and Trichinella spiralis (T. spiralis). Our data showed that anti-Ts7TMR scFv could inhibit lung cancer growth in a dose-dependent manner, with a tumour inhibition rate of 59.1%. HE staining did not reveal any obvious tissue damage. Mechanistically, immunohistochemical staining revealed that the scFv down-regulated the expression of PCNA and VEGF in tumour tissues. Overall, this study found that anti-Ts7TMR scFv could inhibit A549 lung cancer growth by suppressing cell proliferation and angiogenesis, which may provide a new strategy for treating lung cancer.

Abstract Clear cell renal cell carcinoma (ccRCC) demonstrates enhanced glycolysis, critically contributing to tumor development. Programmed death-ligand 1 (PD-L1) aids tumor cells in evading T-cell-mediated immune surveillance. Yet, the specific mechanism by which glycolysis influences PD-L1 expression in ccRCC is not fully understood. Our research identified that the glycolysis-related gene (GRG) HK3 has a unique correlation with PD-L1 expression. HK3 has been identified as a key regulator of O-GlcNAcylation in ccRCC. O-GlcNAcylation exists on the serine 900 (Ser900) site of EP300 and can enhance its stability and oncogenic activity by preventing ubiquitination. Stably expressed EP300 works together with TFAP2A as a co-transcription factor to promote PD-L1 transcription and as an acetyltransferase to stabilize PD-L1 protein. Furthermore, ccRCC exhibits interactive dynamics with tumor-associated macrophages (TAMs). The uridine 5′-diphospho-N-acetylglucosamine (UDP-GlcNAc), which serves as a critical substrate for the O-GlcNAcylation process, facilitates TAMs polarization. In ccRCC cells, HK3 expression is influenced by IL-10 secreted by M2 TAMs. Our study elucidates that HK3-mediated O-GlcNAcylation of EP300 is involved in tumor immune evasion. This finding suggests potential strategies to enhance the efficacy of immune checkpoint blockade therapy.

Abstract Cadmium, a common metal pollutant, has been demonstrated to induce type 2 diabetes by disrupting pancreatic β cells function. In this study, transcriptome microarray was utilized to identify differential gene expression in oxidative damage to pancreatic β cells following cadmium exposure. The results indicated that a series of mRNAs, LncRNAs, and miRNAs were altered. Of the differentially expressed miRNAs, miR-29a-3p exhibited the most pronounced alteration, with an 11.62-fold increase relative to the control group. Following this, the target gene of miR-29a-3p was identified as Col3a1 through three databases (miRDB, miRTarbase and Tarbase), which demonstrated a decrease across the transcriptome microarray. The upstream target gene of miR-29a-3p was identified as NONMMUT036805, with decreased expression observed in the microarray. Finally, the expression trend of NONMMUT036805/miR-29a-3p/Col3a1 was reversed following NAC pretreatment. This was accompanied by a reduction in oxidative damage indicators, MDA/ROS/GSH-Px appeared to be negatively affected to varying degrees. In conclusion, this study has demonstrated that multiple RNAs are altered during cadmium exposure-induced oxidative damage in pancreatic β cells. The NONMMUT036805/miR-29a-3p/Col3a1 axis has been shown to be involved in this process, which provides a foundation for the identification of potential targets for cadmium toxicity intervention.

Abstract Recent observational studies suggest that gut microorganisms are involved in the onset and development of coronavirus disease 2019 (COVID-19), but the potential causal relationship behind them remains unclear. Exposure data were derived from the MiBioGen consortium, encompassing 211 gut microbiota (n = 18,340). The outcome data were sourced from the COVID-19 host genetics initiative (round 7), including COVID-19 severity (n = 1,086,211), hospitalization (n = 2,095,324), and susceptibility (n = 2,597,856). First, a two-sample Mendelian randomization (TSMR) was performed to investigate the causal effect between gut microbiota and COVID-19 outcomes. Second, a two-step MR was used to explore the potential mediators and underlying mechanisms. Third, several sensitivity analyses were performed to verify the robustness of the results. Five gut microbes were found to have a potential causality with COVID-19 severity, namely Betaproteobacteria (beta = 0.096, p = 0.034), Christensenellaceae (beta = -0.092, p = 0.023), Adlercreutzia (beta = 0.072, p = 0.048), Coprococcus 1 (beta = 0.089, p = 0.032), Eisenbergiella (beta = 0.064, p = 0.024). Seven gut microbes were found to have a potential causality with COVID-19 hospitalization, namely Victivallaceae (beta = 0.037, p = 0.028), Actinomyces (beta = 0.047, p = 0.046), Coprococcus 2 (beta = -0.061, p = 0.031), Dorea (beta = 0.067, p = 0.016), Peptococcus (beta = -0.035, p = 0.049), Rikenellaceae RC9 gut group (beta = 0.034, p = 0.018), and Proteobacteria (beta = -0.069, p = 0.035). Two gut microbes were found to have a potential causality with COVID-19 susceptibility, namely Holdemanella (beta = -0.024, p = 0.023) and Lachnospiraceae FCS020 group (beta = 0.026, p = 0.027). Multi-omics mediation analyses indicate that numerous plasma proteins, metabolites, and immune factors are critical mediators linking gut microbiota with COVID-19 outcomes. Sensitivity analysis suggested no significant heterogeneity or pleiotropy. These findings revealed the causal correlation and potential mechanism between gut microbiota and COVID-19 outcomes, which may improve our understanding of the gut-lung axis in the etiology and pathology of COVID-19 in the future.

Abstract Low-dose X-CT scanning method effectively reduces radiation hazards, however, reducing the radiation dose will introduce noise and artifacts during the projection process, resulting in a decrease in the quality of the reconstructed image. To address this problem, we combined 2D variational modal decomposition and dictionary learning. We proposed a low-dose CT (LDCT) image denoising algorithm based on an improved K-SVD algorithm with image decomposition. The dictionary obtained by K-SVD training lacks consideration of image structure information. To address this problem, we employ the two-dimensional variational mode decomposition (2D-VMD) method to decompose the image into distinct modal components. Through the adaptive learning of dictionaries based on the characteristics of each modal component, independent denoising processing is applied to each component, avoiding the loss of structural and detailed information in the image. In addition, we introduce the regularized orthogonal matching pursuit algorithm (ROMP) and dictionary atom optimization method to improve the sparse representation ability of the dictionary and reduce the impact of noise atoms on denoising performance. The experiments show that the proposed method outperforms other denoising methods regarding peak signal-to-noise ratio and structural similarity. The proposed method maintains the denoised image details and structural information while removing LDCT image noise and artifacts. The image quality after denoising is significantly improved and facilitates more accurate detection and analysis of lesion areas.

Abstract Background Universal skin cancer screening for the Latino population is impractical. Objectives We focused on melanoma education by conducting an online education campaign and collected baseline, postintervention, and 3‐month follow‐up surveys to assess sun‐protective behaviors. Methods Participants were recruited through (1) social media ads and (2) emails sent to Mayo Clinic Latino patients. Results Total social media impressions were 508,442 and 413,007 in Spanish and English, respectively. There were 18,790 and 11,731 clicks for the Spanish and English ads, respectively, resulting in 175 baseline survey responses. From email distribution, 4151 emails translated to 219 baseline participants. Of the 394 patients who participated in the baseline survey, 89 completed the postintervention survey, and 57 completed the 3‐month follow‐up survey (28 from social media and 29 Mayo Clinic patients). Social media provides a unique opportunity for the medical community to promote melanoma education, distribute content quickly, and provide medical education in disparate healthcare areas. Our Spanish ad click‐through rate was 3.70% compared to 2.84% for English. The click‐to‐action rate was 0.57%, and the baseline‐to‐completion rate was 16.00%. Conclusions Our study suggests social media could be a unique tool for distributing melanoma educational materials to Latino populations. The click‐through rates for this study were several‐fold higher than other studies' reported click‐through rates (0.4%–0.93%). It is important to develop melanoma educational materials that are culturally relevant and focused on Latino populations that can provide persistent improvements in mitigating melanoma risk behaviors such as sunscreen application and self‐skin examinations.

Abstract User requirements serve as the primary reference content in product design. The effective capture of crucial user requirements, followed by the development of a product technical solution aligned with these requirements, stands as a pivotal approach to enhancing design efficiency. In order to explore the problem of generating and decision-making of product technical solutions in the case of complex user demands, this study constructs a user requirements driven product optimization design model, which is used to complete the generation and decision-making of product design solutions in a more reasonable way. The model unfolds across three key stages: Firstly, a user requirements importance ranking system is crafted leveraging Kano Model and Pairwise Analysis. Next, employing the Functional Analysis System Techniques (FAST) theory and the Quality Function Deployment (QFD) theory, user requirements undergo transformation into technical solutions. Finally, these technical solutions are amalgamated into diverse technical combinations, with decisions facilitated by a game theory model to yield the optimal overall design solution. The new optimal design model reduces the influence of subjectivity and ambiguity in the process of user requirements analysis, increases the reliability of the transformation of user requirements into technical solutions, and improves the efficiency of the generation and decision-making of product design solutions under multiobjective situations. The model proposed in this study is exemplified through the development of a medicated bath water heater. Results indicate that the technical solution derived from the model surpasses similar products in terms of user satisfaction, thereby validating its feasibility.

Abstract The concept of volume fracturing has revolutionized the conventional limits of low permeability, expanded the effective resource space, and significantly enhanced oil well production in tight oil reservoir development. This paper elucidates the mechanism of volume fracturing technology for tight sandstone reservoirs by considering multiple factors such as the initiation range of multi-fractures, influence of far-well horizontal principal stress on fracture initiation and propagation, degree of natural fractures development, and mechanical parameters of reservoir rock. Through simulation based on the mechanical parameters of reservoir rock, a comparative analysis was conducted between the model-calculated rock fracture pressure value and measured data from fracturing construction wells in the study area. The results revealed that there was a discrepancy within 10% between the model calculations and actual data. By simulating the effects of different injection volumes of fracturing fluid, pumping rates, and perforation methods on the fracture geometry, optimal design parameters for volume fracturing technology were obtained. Additionally, we propose optimization ideas and suggestions for construction parameters applicable to field operations. The simulation results indicate that a minimum recommended fluid volume scale exceeding 1800 m3 is advised for the reservoir. Based on frictional calculations, it is recommended to have an on-site construction rate not less than 18.0 m3/min along with 36–48 holes/section for perforation purposes. The numerical simulation research presented in this paper provides a theoretical reference basis and practical guidance for the application of fracturing network technology in tight sandstone reservoirs.

Abstract Rapid urbanization increases psychological stress among pedestrians, potentially heightening mental health disorders. This study examines the role of street walls' visual and textural characteristics in stress recovery, using Qingdao as a case study. Virtual reality is employed to simulate five distinct street walls: yellow mortar, brown stone, red brick, green plant, and white mortar. The stress recovery effectiveness of these walls was evaluated through psychological and physiological indicators from 48 young college students. Results indicated that street walls with warm tones, particularly brown stone, significantly aid stress recovery. Psychologically, Restorative Components Scale was highest for brown stone at 1.13. Physiologically, it was linked with notable reductions in diastolic and pulse pressure (decreases of 2.95 mmHg and 2.27 mmHg, respectively), and enhanced parasympathetic activity, as evidenced by the fastest decrease in low frequency/high frequency ratio (LF/HF), and increases in pNN50 and RR (0.14–2.01% and 1.57–11.81 ms, respectively). For urban design, the incorporation of warm-toned materials and natural elements like stone is recommended for their superior restorative benefits.

Abstract Objective The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS. Methods A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5–10 days after the first evaluation. Results The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p 0.05). The Cronbach’s α of the CNS-BFSC was 0.972. Conclusion The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.

The reuse of reclaimed water is a cost-effective way to alleviate water resource scarcity, but the residual pathogenic microorganisms inevitably influence the safety of its reuse. The transport behavior of pathogenic microorganisms in receiving porous media varies under different environmental factors and could be harmful to the natural ecology and even human health if not well treated. Biochar is expected to be an effective, environmentally-friendly functional material to inhibit the transport of pathogenic microorganisms, with unreplaceable advantages of low price, simple preparation method, and strong adsorption capacity. In the present paper, we start from identifying the transport behavior of typical pathogenic microorganisms in porous media, including protozoa, bacteria, and viruses, and then analyzing the primary factors affecting the transport of pathogenic microorganisms from the aspects of biology, physics, and chemistry. Furthermore, the effects of types of raw materials, pyrolysis temperature, particle size, and functional modification methods on the remediation performance of biochar for the transport of pathogenic microorganisms are clearly reviewed. Finally, we aim to clarify the transport rules of pathogenic microorganisms in porous media and provide biochar-based technical means for effectively inhibiting the transport of pathogenic microorganisms, thereby improving the ecological and health safety of reclaimed water reuse. HIGHLIGHTS Pathogenic microorganisms could spread widely through transport behavior in porous media.; The biological, physical, and chemical factors affecting the transport of pathogenic microorganisms were reviewed.; Parameters of biochar impacting the transport of pathogenic microorganisms were discussed.; Biochar is expected to have practical applications in inhibiting the transport of pathogenic microorganisms.;

Abstract It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.

Abstract Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

ABSTRACT Importance Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G‐protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods We performed whole‐exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep‐targeted sequencing was conducted to validate the somatic mutations. A genotype‐phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype‐phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

Abstract Background Cucurbita pepo cv Dayangua (CPD) is an edible plant with diverse pharmacological properties. The current research on CPD has primarily focused on initial investigations of its chemical composition and pharmacological effects, and no comprehensive toxicity assessment has been conducted to date. Methods In the present study, the toxicity of CPD was evaluated through both acute and sub-chronic oral toxicity tests in mice. 16S rDNA sequencing was used to analyze the composition of the gut microbiota of mice at different time points to observe the effect of CPD on these microbial communities. Results In the acute toxicity test, CPD exhibited low toxicity, with a median lethal dose (LD50) > 2000 mg/kg. The sub-chronic toxicity test indicated that CPD administration at doses of 200, 400, and 600 mg/kg did not cause mortality or significant organ damage in mice. Furthermore, analysis of the gut microbiota after gavage administration of CPD at 400 and 600 mg/kg revealed an improved abundance of some beneficial gut bacteria. Conclusions In summary, no acute or sub-chronic toxic effects were observed in mice following the oral administration of CPD. CPD did not affect the structure and diversity of the gut microbiota and may contribute to an increase in the number of beneficial gut bacteria.

Abstract When INS/GNSS (inertial navigation system/global navigation satellite system) integrated system is applied, it will be affected by the insufficient number of visible satellites, and even the satellite signal will be lost completely. At this time, the positioning error of INS accumulates with time, and the navigation accuracy decreases rapidly. Therefore, in order to improve the performance of INS/GNSS integration during the satellite signals interruption, a novel learning algorithm for neural network has been presented and used for intelligence integrated system in this article. First of all, determine the input and output of neural network for intelligent integrated system and a nonlinear model for weighs updating during neural network learning has been established. Then, the neural network learning based on strong tracking and square root UKF (unscented Kalman filter) is proposed for iterations of the nonlinear model. In this algorithm, the square root of the state covariance matrix is used to replace the covariance matrix in the classical UKF to avoid the filter divergence caused by the negative definite state covariance matrix. Meanwhile, the strong tracking coefficient is introduced to adjust the filter gain in real-time and improve the tracking capability to mutation state. Finally, an improved calculation method of strong tracking coefficient is presented to reduce the computational complexity in this algorithm. The results of the simulation test and the field-positioning data show that the proposed learning algorithm could improve the calculation stability and robustness of neural network. Therefore, the error accumulation of INS/GNSS integration is effectively compensated, and then the positioning accuracy of INS/GNSS intelligence integrated system has been improved.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal tumors and is associated with a unfavorable prognosis. Disulfidptosis is a recently identified form of cell death mediated by disulfide bonds. Numerous studies have highlighted the significance of immune checkpoint genes (ICGs) in ccRCC. Nevertheless, the involvement of disulfidptosis-related immune checkpoint genes (DRICGs) in ccRCC remains poorly understood. Methods The mRNA expression profiles and clinicopathological data of ccRCC patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The associations between disulfidptosis-related genes (DRGs) and immune checkpoint genes (ICGs) were assessed to identify DRICGs. Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis were conducted to construct a risk signature. Results A total of 39 differentially expressed immune-related candidate genes were identified. A prognostic signature was constructed utilizing nine DRICGs (CD276, CD80, CD86, HLA-E, LAG3, PDCD1LG2, PVR, TIGIT, and TNFRSF4) and validated using GEO data. The risk model functioned as an independent prognostic indicator for ccRCC, while the associated nomogram provided a reliable scoring system for ccRCC. Gene set enrichment analysis indicated enrichment of phospholipase D, antigen processing and presentation, and ascorbate and aldarate metabolism-related signaling pathways in the high-risk group. Furthermore, the DRICGs exhibited correlations with the infiltration of various immune cells. It is noteworthy that patients with ccRCC categorized into distinct risk groups based on this model displayed varying sensitivities to potential therapeutic agents. Conclusions The novel DRICG-based risk signature is a reliable indicator for the prognosis of ccRCC patients. Moreover, it also aids in drug selection and correlates with the tumour immune microenvironment in ccRCC.

Abstract Silkworm pupae as widely consumed insect products are good biosources of protein and micronutrients. Silkworm rearing throughout the year can be achieved by feeding them an artificial diet instead of native plants, facilitating extensive pupa production. However, artificial diets are prone to spoilage caused by bacterial contamination. Here, we evaluated the antiseptic effect of ethylparaben (EP, chemical preservative) and medium-chain fatty acids (MCFA, natural preservative) in a silkworm artificial diet. Results showed that both preservatives effectively inhibited pathogenic bacterial growth. Furthermore, the addition of EP or MCFA did not negatively impact the production capacity of silkworms and the homeostasis of gut microbiota. However, the expression of genes involved in detoxification such as Ugt2, and immune response such as Cecropin B, were upregulated after EP consumption. Therefore, natural preservative MCFA emerges as a suitable option from a safety perspective. These findings highlight future directions for improving insect artificial diet formulation.

Abstract This study aimed to quantify the association between body mass index (BMI) and postoperative nausea and vomiting (PONV) within the initial 48 h following thoracic surgery for lung cancer. We then explored whether changes in serum inflammatory factor concentrations were related to BMI during the early postoperative period. We conducted a propensity score-matched (PSM), retrospective cohort study at a specialized tertiary medical center. A total of 194 patients aged 18–80 years who underwent thoracic surgery for lung cancer at Shanghai Pulmonary Hospital between January and June 2021 were enrolled. The primary outcome was the incidence of PONV during the first 48 h after surgery. Nausea, vomiting or retching at different time periods, severe pain, and concentrations of perioperative serum inflammatory factors including CRP, IL-6, IL-12, and IFN-γ were also assessed. Patients in the high BMI group (BMI ≥ 25 kg/m2) had a lower incidence of PONV than those in the normal BMI group (18.5–25 kg/m2) within the first 48 h after surgery (22 vs. 50%, p = 0.004). The incidence of nausea was lower at 0–12 h (14.5 vs. 37.1%, p = 0.004) and 12–24 h (8.1 vs. 22.6%, p = 0.025) in the high BMI group after surgery, and the incidence of vomiting was lower at 0–12 h (12.9 vs. 30.6%, p = 0.017) in higher BMI after surgery. We found no significant difference in the incidence of severe pain [severe static pain (p = 0.697) and severe dynamic pain (p = 0.158)]. Moreover, higher concentrations of IL-12 (2.24 ± 2.67 pg/ml vs. 1.48 ± 1.14 pg/ml, p = 0.048) and IFN-γ [1.55 (1.00) pg/ml vs. 1.30 (0.89) pg/ml, p = 0.041] were observed in patients with normal BMI on the first day after surgery. Given this finding, patients with a normal BMI should receive more attention for the prevention of PONV than those with a high BMI following thoracic surgery for lung cancer. Trial registration: http://www.chictr.org.cn and ChiCTR2100052380 (24/10/2021).

Abstract Background Previous observational studies have indicated a potential link between insomnia and bladder cancer, yet the underlying causal relationship remains uncertain. The current study employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate this association. Methods A two-sample MR analysis was conducted utilizing publicly available summary data from genome-wide association studies (GWAS) on insomnia and bladder cancer. Various regression methods including the inverse variance weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode methods were employed for the MR analysis. The presence of pleiotropy and heterogeneity in the MR results was also assessed. Furthermore, additional sensitivity tests were performed to mitigate potential biases. Results No significant causal relationship was detected between insomnia and bladder cancer using IVW method (OR = 0.761, 95% CI 0.996–1.005; P = 0.76). Similarly, the IVW model did not reveal any causal effect of bladder cancer on the risk of insomnia (OR = 1.47, 95% CI 0.772–2.799; P = 0.24). Consistent results were obtained from the other four methods employed. There was no evidence of horizontal pleiotropy or heterogeneity in our MR analysis (P > 0.05). The sensitivity analyses further supported the reliability of the estimated causal effects. Conclusions This study presents no evidence for a causal relationship between insomnia and bladder cancer.

Abstract Background Accumulating evidence suggests that the gut microbiota and metabolites can modulate tumor responses to immunotherapy; however, limited data has been reported on biliary tract cancer (BTC). This study used metagenomics and metabolomics to identify characteristics of the gut microbiome and metabolites in immunotherapy-treated BTC and their potential as prognostic and predictive biomarkers. Methods This prospective cohort study enrolled 88 patients with BTC who received PD-1/PD-L1 inhibitors from November 2018 to May 2022. The microbiota and metabolites significantly enriched in different immunotherapy response groups were identified through metagenomics and LC-MS/MS. Associations between microbiota and metabolites, microbiota and clinical factors, and metabolites and clinical factors were explored. Results Significantly different bacteria and their metabolites were both identified in the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups. Of these, 20 bacteria and two metabolites were significantly associated with survival. Alistipes were positively correlated with survival, while Bacilli, Lactobacillales, and Pyrrolidine were negatively correlated with survival. Predictive models based on six bacteria, four metabolites, and the combination of three bacteria and two metabolites could all discriminated between patients in the DCB and NDB groups with high accuracy. Beta diversity between two groups was significantly different, and the composition varied with differences in the use of immunotherapy. Conclusions Patients with BTC receiving immunotherapy have specific alterations in the interactions between microbiota and metabolites. These findings suggest that gut microbiota and metabolites are potential prognostic and predictive biomarkers for clinical outcomes of anti-PD-1/PD-L1-treated BTC.

Objective: To investigate the protective effects of Ganoderma lucidum spore polysaccharide (GLSP) on liver injury caused by acetaminophen (APAP). Methods: Fifty mice were randomly divided into five groups: Blank group, model group, positive drug group, GLSP low-dose group and GLSP high-dose group, with 10 mice in each group. After each group was pre-administered according to the corresponding dose for 14 consecutive days, the liver index, serum indexes (glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT)) and liver tissue plasma indexes (glutathione (GSH), malonaldehyde (MDA), superoxide dismutase (SOD), Caspase-3, Bax and Bcl-xl) were determined. Results: Compared with the blank group, ALT, AST, MDA and proapoptotic genes Caspase-3 and Bax were very significantly increased in the model group (P

Dysregulated calcium (Ca2+) signaling pathways are associated with tumor cell death and drug resistance. In non-excitable cells, such as hepatocellular carcinoma (HCC) cells, the primary pathway for Ca2+ influx is through stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE). Previous studies have demonstrated the involvement of STIM1-mediated SOCE in processes such as genesis, metastasis, and stem cell self-renewal of HCC. However, it remains unclear whether STIM1-mediated SOCE plays a role in developing acquired resistance to sorafenib in HCC patients. In this study, we established acquired sorafenib-resistant (SR) HCC cell lines by intermittently exposing them to increasing concentrations of sorafenib. Our results showed higher levels of STIM1 and stronger SOCE in SR cells compared with parental cells. Deleting STIM1 significantly enhanced sensitivity to sorafenib in SR cells, while overexpressing STIM1 promoted SR by activating SOCE. Mechanistically, STIM1 increased the transcription of SLC7A11 through the SOCE-CaN-NFAT pathway. Subsequently, up-regulated SLC7A11 increased glutathione synthesis, resulting in ferroptosis insensitivity and SR. Furthermore, combining the SOCE inhibitor SKF96365 with sorafenib significantly improved the sensitivity of SR cells to sorafenib both in vitro and in vivo. These findings suggest a potential strategy to overcome acquired resistance to sorafenib in HCC cells.

ABSTRACT Aims To develop multiple machine learning (ML) models based on the prognostic nutritional index (PNI) and determine the optimal model for predicting long‐term survival outcomes in hepatocellular carcinoma (HCC) patients after local ablation. Methods From January 2009 to December 2019, we analyzed data from 848 primary HCC patients who underwent local ablation. ML models were constructed and evaluated using the concordance index (C‐index), concordance‐discordance area under curve (C/D AUC), and Brier scores. The optimal ML model was interpreted using the partial dependence plot (PDP) and SHapley Additive exPlanations (SHAP) framework. Additionally, the prognostic performance of our model was compared with other models. Results Alkaline phosphatase, preoperation alpha‐fetoprotein level, PNI, tumor number, and tumor size were identified as independent prognostic factors for ML model construction. Among the 19 ML algorithms tested, the Aorsf model showed superior performance in both the training cohort (C/D AUC: 0.733; C‐index: 0.736; Brier score: 0.133) and validation cohort (C/D AUC: 0.713; C‐index: 0.793; Brier score: 0.117). The time‐dependent AUC of the Aorsf model for predicting overall survival was as follows: 1‐, 3‐, 5‐, 7‐, and 9‐year were 0.828, 0.765, 0.781, 0.817, and 0.812 in the training cohort, 0.846, 0.859, 0.824, 0.845, and 0.874 in the validation cohort, respectively. The PDP and SHAP algorithms were employed for visual interpretation. Furthermore, time‐AUC and decision curve analysis demonstrated that the Aorsf model provided superior clinical benefits compared to other models. Conclusion The PNI‐based Aorsf model effectively predicts long‐term survival outcomes after ablation therapy, making a significant contribution to HCC research by improving surveillance, prevention, and treatment strategies.

Abstract T cell is an indispensable component of the immune system and its multifaceted functions are shaped by the distinct T cell types and their various states. Although multiple computational models exist for predicting the abundance of diverse T cell types, tools for assessing their states to characterize their degree of resting, activation, and suppression are lacking. To address this gap, a robust and nuanced scoring tool called T cell state identifier (TCellSI) leveraging Mann–Whitney U statistics is established. The TCellSI methodology enables the evaluation of eight distinct T cell states—Quiescence, Regulating, Proliferation, Helper, Cytotoxicity, Progenitor exhaustion, Terminal exhaustion, and Senescence—from transcriptome data, providing T cell state scores (TCSS) for samples through specific marker gene sets and a compiled reference spectrum. Validated against sizeable pseudo‐bulk and actual bulk RNA‐seq data across a range of T cell types, TCellSI not only accurately characterizes T cell states but also surpasses existing well‐discovered signatures in reflecting the nature of T cells. Significantly, the tool demonstrates predictive value in the immune environment, correlating T cell states with patient prognosis and responses to immunotherapy. For better utilization, the TCellSI is readily accessible through user‐friendly R package and web server (https://guolab.wchscu.cn/TCellSI/). By offering insights into personalized cancer therapies, TCellSI has the potential to improve treatment outcomes and efficacy.

Abstract Developing advanced engineering polymers that combine high strength and toughness represents not only a necessary path to excellence but also a major technical challenge. Here for the first time a rigid‐flexible interlocking polymer (RFIP) is reported featuring remarkable mechanical properties, consisting of flexible polyurethane (PU) and rigid polyimide (PI) chains cleverly woven together around the copper(I) ions center. By rationally weaving PI, PU chains, and copper(I) ions, RFIP exhibits ultra‐high strength (twice that of unwoven polymers, 91.4 ± 3.3 MPa), toughness (448.0 ± 14.2 MJ m−3), fatigue resistance (recoverable after 10 000 cyclic stretches), and shape memory properties. Simulation results and characterization analysis together support the correlation between microstructure and macroscopic features, confirming the greater cohesive energy of the interwoven network and providing insights into strengthening toughening mechanisms. The essence of weaving on the atomic and molecular levels is fused to obtain brilliant and valuable mechanical properties, opening new perspectives in designing robust and stable polymers.

Background Osteoporosis (OP) is a chronic disease characterized by decreased bone mass, loss of skeletal structural integrity and increased susceptibility to fracture. Available studies have shown that the pyruvate dehydrogenase kinase (PDK) family is associated with osteoclastogenesis and bone loss, but the specific role of Pdk3 in bone pathology has not been systematically investigated. Methods A cell OP model was established in receptor activator for nuclear factor-κB Ligand (RANKL)-induced bone marrow macrophages (BMMs). Hereafter, the expression levels of Pdk3 and osteoclastogenesis feature genes including nuclear factor of activated T cells 1 (Nfatc1), Cathepsin K (Ctsk), osteoclast associated Ig-like receptor (Oscar) in BMMs-derived osteoclasts were examined based on real-time quantitative PCR and western blotting methods. Further, the phosphorylation of ERK, P65 and JAK/STAT and their correlation was Pdk3 was gauged. In particular, changes in the activity of these signaling pathways were observed by silencing experiments of the Pdk3 gene (using small interfering RNA). Finally, the effects of Pdk3 gene silencing on signaling pathway activity, osteoclastogenesis, and related inflammatory and apoptotic indicators were observed by transfection with PDK3-specific siRNA. Results Following RANKL exposure, the levels of Pdk3 and osteoclastogenesis feature genes were all elevated, and a positive correlation between Pdk3 and osteoclastogenesis feature genes was seen. Meanwhile, ERK, P65 and JAK/STAT phosphorylation was increased by RANKL, and Pdk3 was confirmed to be positively correlated with the phosphorylation of ERK, P65 and JAK/STAT. Additionally, in RANKL-exposed osteoclasts, Pdk3 knockdown diminished the phosphorylation of ERK, P65 and JAK/STAT, reduced the expressions of osteoclastogenesis feature genes. Importantly, knockdown of Pdk3 also reduced the expression of inflammatory cytokines and resulted in elevated levels of Bax and Casp3 expression, as well as downregulation of Bcl2 expression. Conclusion This study reveals for the first time the role of Pdk3 in RANKL-induced osteoclastogenesis and OP. These findings provide a foundation for future studies on the role of Pdk3 in other bone diseases and provide new ideas for the development of OP therapeutics targeting Pdk3.

IntroductionAtherosclerosis (AS) is considered the underlying cause of many diseases, particularly cardiovascular and cerebrovascular diseases. Inulin, a type of fructan, has shown potential in improving atherosclerosis, although there are conflicting findings. It is hypothesized that the polymerization degree of inulin may largely influence its therapeutic effectiveness. Therefore, this study aimed to investigate the effects and mechanisms of short-chain and long-chain inulin in AS.MethodsApoE−/− mice fed a high fat diet (HFD) were used to establish an atherosclerosis model. These mice received daily oral administration of either short-chain or long-chain inulin for 12 weeks. Plasma lipid metabolism-related indices were measured using biochemical analysis, and plasma immunological indices were analyzed via ELISA. The aorta, aortic root regions, liver tissue, adipose tissue, and colon tissue were examined through various staining techniques, including ORO staining, hematoxylin and eosin staining, Alcian blue staining, and immunofluorescent or immunohistochemical assays. Microbiome analysis was conducted in the cecal content.ResultsThe results indicated that both short-chain and long-chain inulin substantially reduced the formation of atherosclerotic plaques. Inulin also improved plasma lipid concentrations and hepatic lipid metabolism, and partially alleviated both localized (atherosclerotic lesions) and systemic inflammation. Short-chain inulin was more effective than long-chain inulin in reducing atherosclerotic plaques formation, enhancing lipid metabolism and reducing inflammation. Additionally, both types of inulin showed similar effectiveness in enhancing intestinal epithelial barrier integrity, gut microbiota composition and functionality.ConclusionThese findings suggest that inulin has a protective role against atherosclerosis by enhancing lipid metabolism, reducing inflammation, and improving intestinal barrier and gut microbiota. As a dietary intervention, short-chain inulin is more effective than long-chain inulin, offering clinical implications for using inulin as a therapeutic agent for atherosclerosis.

Metamifop (MET) is a widely used pesticides in paddy field and it has good weed control effect. As a chiral pesticide that may be hazardous to human health through food chain transmission, there could be selective differences in the metabolism and toxicity of its enantiomers, so the study of chiral MET may offer an assessment of MET toxicity and stereoselectivity at the enantiomeric level. A total of 39, 43 and 31 differential metabolites were screened from the data sets of Rac-, R-(-)- and S-(+)-MET, respectively. Metabolic pathway analysis revealed that MET and its enantiomers primarily affected sphingolipid metabolism, glycerophospholipid metabolism, linoleic acid metabolism, α-linolenic acid metabolism and arachidonic acid metabolism. Rac- and S-(+)-MET affected the synthesis of glycosylphosphatidylinositol (GPI)-anchored biomolecules. R-(-)- and S-(+)-MET affected glutathione metabolism. R-(-)-MET affected vitamin B6 metabolism, selenium compound metabolism, and steroid biosynthesis. Pyrimidine metabolism was only affected by Rac-MET. The experimental results indicated that MET and its enantiomers may affect the nervous and immune systems in rats. Further inter-group difference analysis also demonstrated stereoselectivity of MET and its enantiomers on rat serum metabolism. These findings may provide more detailed information on the toxicity of Rac-, S-(+)- and R-(-)-MET in rat, as well as some context for assessing the environmental risk of the three agents to organisms.

Essential oils with β-caryophyllene, citral, and linalool as key compounds often exhibit some anti-anxiety like effects in aromatherapy. However, evidence of the effect of these three compounds through human inhalation remains limited. It is worth exploring their potential anxiolytic effect through the olfactory pathway, and finding out whether the three compounds lead to different physiological responses. A total of 48 subjects were randomly assigned to three odor (β-caryophyllene, citral, and linalool) inhalation groups and one control (odorless jojoba oil) group. Stress stimulation was induced using n-back and mental arithmetic tasks. The odor was administered before the task test session. Assessments including the State-Trait Anxiety Inventory (STAI), electroencephalogram (EEG) activities, facial expressions, several physiological indicators, and a self-report scale of subjective perception of the odor environments were carried out. The changes before and after inhalation, as well as the inter-group differences, were analyzed. Both β-caryophyllene and citral inhalation led to a significant decrease in anxiety levels, while only β-caryophyllene resulted in a notable reduction across both sub-scales of STAI. Following the odor inhalation, heart rate significantly decreased in all three groups, with the β-caryophyllene group exhibiting the most pronounced decline. While the systolic blood pressure of the linalool group demonstrated a statistically significant difference. Regarding facial expressions, β-caryophyllene significantly increased the ratio of 'Happiness' and decreased the ratio of ‘Fear'. In the non-task state, citral reduced the power of frontal alpha, delta, and theta waves while β-caryophyllene had a similar effect. All odor inhalation groups showed increased delta and theta waves after the task compared with the control group, with the β-caryophyllene group having notably lower frontal beta waves. β-Caryophyllene and citral exhibited good anti-anxiety effects. Subjects receiving different odors showed different EEG and physiological responses, indicating the differences in emotional regulation ways among the three compounds.