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Abstract Enchondromas are a common tumor in bone that can occur as multiple lesions in enchondromatosis, which is associated with deformity of the affected bone. These lesions harbor somatic mutations in IDH and driving expression of a mutant Idh1 in Col2 expressing cells in mice causes an enchondromatosis phenotype. Here we compared growth plates from E18.5 mice expressing a mutant Idh1 with control littermates using single cell RNA sequencing. Data from Col2 expressing cells were analysed using UMAP and RNA pseudo-time analyses. A unique cluster of cells was identified in the mutant growth plates that expressed genes known to be upregulated in enchondromas. There was also a cluster of cells that was underrepresented in the mutant growth plates that expressed genes known to be important in longitudinal bone growth. Immunofluorescence showed that the genes from the unique cluster identified in the mutant growth plates were expressed in multiple growth plate anatomic zones, and pseudo-time analysis also suggested these cells could arise from multiple growth plate chondrocyte subpopulations. This data supports the notion that a subpopulation of chondrocytes become enchondromas at the expense of contributing to longitudinal growth.

Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their low bioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. This calls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybrid structures with bioactive components and stable fluffy topological morphology by cross-linking calcium and phosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequent grafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealed that these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecular mechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that small-dose AL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivo results restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as the consequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant with peculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well as bone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies for other bone diseases.

Abstract Background Obesity is a global health issue with detrimental effects on various human organs, including the reproductive system. Observational human data and several lines of animal experimental data suggest that maternal obesity impairs ovarian function and early embryo development, but the precise pathogenesis remains unclear. Methods We established a high-fat diet (HFD)-induced obese female mouse model to assess systemic metabolism, ovarian morphology, and oocyte function in mice. For the first time, this study employed single-cell RNA sequencing to explore the altered transcriptomic landscape of preimplantation embryos at different stages in HFD-induced obese mice. Differential gene expression analysis, enrichment analysis and protein-protein interactions network analysis were performed. Results HFD-induced obese female mice exhibited impaired glucolipid metabolism and insulin resistance. The ovaries of HFD mice had a reduced total follicle number, an increased proportion of atretic follicles, and irregular granulosa cell arrangement. Furthermore, the maturation rate of embryonic development by in vitro fertilization of oocytes was significantly decreased in HFD mice. Additionally, the transcriptional landscapes of preimplantation embryos at different stages in mice induced by different diets were significantly distinguished. The maternal-to-zygotic transition was also affected by the failure to remove maternal RNAs and to turn off zygotic genome expression. Conclusions HFD-induced obesity impaired ovarian morphology and oocyte function in female mice and further led to alterations in the transcriptional landscape of preimplantation embryos at different stages of HFD mice.

Abstract Inferior vena cava filter (IVCF) implantation is a common method of thrombus capture. By implanting a filter in the inferior vena cava (IVC), microemboli can be effectively blocked from entering the pulmonary circulation, thereby avoiding acute pulmonary embolism (PE). Inspired by the helical flow effect in the human arterial system, we propose a helical retrievable IVCF, which, due to the presence of a helical structure inducing a helical flow pattern of blood in the region near the IVCF, can effectively avoid the deposition of microemboli in the vicinity of the IVCF while promoting the cleavage of the captured thrombus clot. It also reduces the risk of IVCF dislodging and slipping in the vessel because its shape expands in the radial direction, allowing its distal end to fit closely to the IVC wall, and because its contact structure with the inner IVC wall is curved, increasing the contact area and reducing the risk of the vessel wall being punctured by the IVCF support structure. We used ANSYS 2023 software to conduct unidirectional fluid–structure coupling simulation of four different forms of IVCF, combined with microthrombus capture experiments in vitro, to explore the impact of these four forms of IVCF on blood flow patterns and to evaluate the risk of IVCF perforation and IVCF dislocation. It can be seen from the numerical simulation results that the helical structure does have the function of inducing blood flow to undergo helical flow dynamics, and the increase in wall shear stress (WSS) brought about by this function can improve the situation of thrombosis accumulation to a certain extent. Meanwhile, the placement of IVCF will change the flow state of blood flow and lead to the deformation of blood vessels. In in vitro experiments, we found that the density of the helical support rod is a key factor affecting the thrombus trapping efficiency, and in addition, the contact area between the IVCF and the vessel wall has a major influence on the risk of IVCF displacement.

The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.

Abstract The rete ovarii (RO) is an epithelial structure that arises during development in close proximity to the ovary and persists throughout adulthood. However, the functional significance of the RO remains elusive, and it is absent from recent discussions of female reproductive anatomy. The RO comprises three regions: the intraovarian rete within the ovary, the extraovarian rete in the periovarian tissue, and the connecting rete linking the two. We hypothesize that the RO plays a pivotal role in ovarian homeostasis and responses to physiological changes. To begin to uncover the nature and function of RO cells, we conducted transcriptomic profiling of the RO. This study presents three datasets, and reports our analysis and quality control approaches for bulk, single-cell, and nucleus-level transcriptomics of the fetal and adult RO tissues using the Pax8-rtTA; Tre-H2B-GFP mouse line, where all RO regions express nuclear GFP. The integration and rigorous validation of these datasets will advance our understanding of the RO’s roles in ovarian development, female maturation, and adult female fertility.

Objective: Banana flower polysaccharide was used as raw materials to analyze the antioxidant activity and stability. Methods: Bioactive polysaccharide from banana flower was extracted using hot-water extraction method combining with alcohol-precipitation method. Initially, the chemical composition of banana flower polysaccharide was detected and analyzed. Then, the total antioxidant capacity (T-AOC), as well as DPPH, hydroxyl and superoxide anion radicals scavenging activities were utilized to analyze the antioxidant activity of banana flower polysaccharide in vitro. On this basis, the antioxidant stability of banana flower polysaccharide was evaluated further by simulating different food processing conditions, including light, pH value, temperature, metal ions, common food ingredients, as well as sterilization methods, using the hydroxyl radical scavenging activity as the evaluation index. Results: The extraction yield of banana flower polysaccharide was about 14.56%, and the total sugar content, uronic acid content, protein content, phenolic content and flavonoid content of banana flower polysaccharide were 515.61, 287.88, 53.46, 2.23 and 7.94 mg/g, respectively. The result in this paper showed that polysaccharide obtained from banana flower possessed good reducing power, as well as DPPH and hydroxyl radicals scavenging capacities. The antioxidant property of banana flower polysaccharide was degraded by lighting, but remained stable under strong acidic as well as alkaline conditions. Banana flower polysaccharide had good heat resistance, specially under heating 60~80 ℃ from 2 to 3.5 h, its antioxidant stability was strong. Then, the good antioxidant stability of banana flower polysaccharide was observed in the presence of Na+ metal ion, whereas the antioxidant activity of banana flower polysaccharide was decreased with the increasing in the concentration of K+, Fe3+ and Cu2+ metal ions. Additionally, the antioxidant activity of banana flower polysaccharide was improved within the common food ingredients such as citric acid and sodium benzoate, but was decreased under sucrose and glucose as common food ingredients. The sterilization methods had different degrees of adverse effect on the antioxidant activity of banana flower polysaccharide, hence, high pressure sterilization could be used for sterilizing banana flower processing products. Conclusion: Banana flower polysaccharide had good antioxidant activity. The environmental factors including continuous light, Fe3+ and Cu2+ metal ions, as well as sucrose and glucose as common food ingredients might have the great influence on the antioxidant activity of banana flower polysaccharide. Hence, the direct contact with these environmental factors should be avoided during the processing and storage of banana flower.

Pesticides and their transformation products are found in raw agricultural and processed food products, posing risks to human health. Therefore, a thorough investigation of dimethachlon’s dissipation, metabolites, residue levels in crops, and changes during food processing is essential for an accurate dietary risk assessment. This study identified two metabolites, 4-(3,5-dichloroanilino)-4- oxobutanoic acid (DCBAA) and 3,5-dichloroaniline (3,5-DCA), formed from dimethachlon in crops under field conditions. A precise and sensitive analytical method was developed to detect dimethachlon, DCBAA, and 3,5-DCA in rapeseed pods, seeds, and oil. The half-lives of dimethachlon in rapeseed pods at two sites ranged from 1.61 to 1.67 days. During degradation, the maximum residue levels of DCBAA and 3,5-DCA in rapeseed pods reached 38.59 % and 3.47 % of the initial parent compound concentration, respectively. At harvest (day 10), final dimethachlon residues in rapeseed were 0.11 mg/kg and 0.27 mg/kg. Processing rapeseed into oil through sun-drying and stir-frying reduced dimethachlon residues, with processing factors (PF) of 0.69 and 0.64, respectively. However, pressing the seeds concentrated dimethachlon in the oil, with a PF of 1.92. Notably, DCBAA tended to concentrate during sun-drying but decreased during stir-frying and pressing. Supervised trials indicated that dimethachlon residues in rapeseed posed no long-term dietary risks.

Objectives To observe the CISD2 expression among PCOS patients and to explore its profound impact on the follicular microenvironment. Moreover, we want to elucidate the intricate mechanistic contribution of CISD2 to the onset and progression of PCOS.Methods Oxidase NOX2, mitophagy-related proteins, and CISD2 were detected by WB. The changes in mitochondrial structure and quantity were observed by transmission electron microscopy. Mitochondrial and lysosome colocalization was used to detect the changes of mitophagy. MDA kit, GSH and GSSG Assay kit and ROS probe were used to detect oxidative stress damage.Results We found that CISD2, mitophagy and oxidase in the GCs of PCOS patients were significantly increased. Testosterone stimulation leads to the increase of oxidase, mitophagy, and CISD2 in KGN cells. CISD2 inhibition promoted the increase of mitophagy, and the activation of mitochondria-lysosome binding, while alleviating the oxidative stress.Conclusions Inhibition of CISD2 can improve the occurrence of oxidative stress by increasing the level of mitophagy, thus affecting the occurrence and development of PCOS diseases.

ObjectiveOsteoarticular tuberculosis (OATB) is one of the most common forms of extrapulmonary tuberculosis; however, limited epidemiological data are available on this public health concern worldwide, especially in developing countries. This study aimed to analyze the clinical epidemiology and drug resistance characteristics of OATB cases in Hunan province which located in South-central China.MethodsWe retrospectively enrolled OATB patients with Mycobacterium tuberculosis culture positive at Hunan Chest Hospital from January 2013 through March 31, 2022. The multiple demographic, clinical variables and drug susceptibility data of the patients were collected from the hospital’s electronic patient records. Descriptive statistical methods, Chi-square test and logistic regression analysis were employed as statistical methods.ResultsOf the 269 OATB cases, 197 (73.23%) were males, 206 (76.85%) were farmers; patients’ ages ranged from 5 to 85 years, 57 (21.19%) aged at 20–29 years old and 52 (19.33%) aged at 60–69 years old. In terms of the disease, 177 (65.80%) had spinal TB with most occurrence in lumbar vertebrae (26.02%, 70/269), multiple spinal sites (18.96%, 51/269) and thoracic vertebrae (15.24%, 41/269). Outside of the spine, OATB mainly occurred in the lower limb (13.38%, 36/269). In terms of drug resistance, 40 (14.87%) and 72 (26.77%) were resistant to rifampicin (RFP) and isoniazid (INH) respectively; 38 (14.13%) were multi-drug resistant (MDR), and a total of 78 (29.00%) isolates were drug resistant. OATB patients aged 40–49 years old (compared to those aged ≥70 years) and from the west of Hunan province, China (compared to those from the center of Hunan) were at risk for developing RR/MDR (ORs were 5.057 and 4.942, respectively; 95% CIs were 1.009–25.342 and 1.458–16.750, respectively).ConclusionIn South-central China, OATB mainly affected males, farmers and those aged 20–29 and 60–69 years old. Spinal TB is prone to occur in the lumbar and multiple spinal sites. The resistance situation of OATB was serious, and people aged 40–49 years old and patients from the west of Hunan were risk factors of RR/MDR. All these findings will help to improve the prevention, diagnosis and treatment strategies of OATB.

ObjectivesThis study aimed to investigate the epidemiological and drug resistance (DR) characteristics of extrapulmonary tuberculosis (EPTB) in South-Central China.MethodsEPTB inpatients who were culture-positive for Mycobacterium tuberculosis were retrospectively included in a study at a provincial TB hospital in Hunan, a province in South-Central China, from January 2013 to December 2021. Demographic, clinical, and drug susceptibility data were retrieved from TB treatment records. Descriptive statistical methods and a Chi-squared test were used to analyze the epidemiological and DR characteristics of EPTB patients. A logistic regression model was used to explore the risk factors of rifampicin-resistant/multidrug-resistant (RR/MDR)-EPTB.ResultsA total of 1,324 cases were included. The majority of EPTB patients were in the age range of 20–29 years, were predominantly men (male-to-female ratio: 2.03), and were farmers (65.63%). Most EPTB cases were found in 2013 and 2017 from 2013 to 2021. The most prevalent subtypes of EPTB were lymphatic TB (29.83%, 395/1,324), multiple EPTB (20.85%, 276/1,324), and musculoskeletal TB (14.65%, 194/1,324). Musculoskeletal TB and genitourinary TB predominantly presented as exclusive EPTB forms, while lymphatic TB and pharyngeal/laryngeal TB often co-occurred with pulmonary TB (PTB). Drug susceptibility testing results showed that total DR rates (resistance to any of RFP, isoniazid [INH], streptomycin [STR], and/or ethambutol [EMB]) and RR/MDR rates in EPTB were 25.23% and 12.39%, respectively. Musculoskeletal TB exhibited the highest rates of total DR (31.40%), INH resistance (28.90%), STR resistance (20.10%), EMB resistance (6.20%), MDR (13.90%), and poly-DR (6.70%). The multivariable logistic regression model showed that patients aged from 20 to 59 years (compared to those aged 10 years), workers (compared to retirees), and EPTB patients from the south and west of Hunan (compared to those from the east of Hunan) were at an increased risk of developing RR/MDR EPTB (all OR values > 1).ConclusionOur study provided a detailed account of the epidemiological and DR characteristics of EPTB in Hunan province, China. The significant DR rates, particularly in musculoskeletal TB cases, highlight the need for timely diagnosis, effective drug susceptibility testing, and the development of more effective treatment regimens for EPTB, especially targeting musculoskeletal TB treatments.

ObjectivesTo investigate the clinical epidemiological and drug resistance (DR) characteristics of lymph node tuberculosis (LNTB) in Hunan Province which locates in South-central China, and to provide scientific clues for effective prevention and treatment of LNTB.MethodsWe retrospectively collected LNTB patients with Mycobacterium tuberculosis culture positive at Hunan Chest Hospital, the biggest TB reference hospital in South-central China, from January 2013 to December 2021. The multiple demographic, clinical and drug susceptibility data of patients were collected from the hospital’s electronic patient records. Descriptive statistical methods, Chi-square test and logistic regression analysis were employed as statistical methods.ResultsOf the 577 LNTB cases, 373 (64.64%) were males, 352 (61.01%) were farmers; majority (161, 33.10%) aged at 20–29 years old; 147 (25.48%) had simple LNTB, 350 (60.66%) had LNTB combined with pulmonary TB (PTB) (defined as LNTB-PTB), and 80 (13.86%) had LNTB combined with other extrapulmonary TB (EPTB) (defined as LNTB-EPTB). A total of 345 (59.79%, 345/577) LNTB patients had cervical node infection, and the simple LNTB patients (81.63%, 120/147) had higher proportion of this infection than LNTB-PTB (51.71%, 181/350) and LNTB-EPTB (55.00%, 44/80) (both p values

Summary: Intratumoral heterogeneity is common in cancer, particularly in sarcomas like undifferentiated pleomorphic sarcoma (UPS), where individual cells demonstrate a high degree of cytogenic diversity. Previous studies showed that a small subset of cells within UPS, known as the metastatic clone (MC), as responsible for metastasis. Using a CRISPR-based genomic screen in-vivo, we identified the COMPASS complex member Setd1a as a key regulator maintaining the metastatic phenotype of the MC in murine UPS. Depletion of Setd1a inhibited metastasis development in the MC. Transcriptome and chromatin sequencing revealed COMPASS complex target genes in UPS, such as Cxcl10, downregulated in the MC. Deleting Cxcl10 in non-MC cells increased their metastatic potential. Treating mice with human UPS xenografts with a COMPASS complex inhibitor suppressed metastasis without affecting tumor growth in the primary tumor. Our data identified an epigenetic program in a subpopulation of sarcoma cells that maintains metastatic potential.

Addressing the scarcity of research on the residual expansion deformation of steam-cured concrete and its underlying factors, this study introduces a testing apparatus to characterize the internal stress in fresh concrete during the thermal treatment. It explores the impact of water-to-cement ratio (w/c) and paste-to-aggregate ratio (p/a) on internal stress and elucidates the developmental patterns of internal stress in concrete throughout the thermal treatment phase. The key findings are as follows: (i) During the thermal treatment, the internal stress in concrete under constraint is predominantly compressive, exhibiting a rapid increase in the heating stage, followed by a gradual decline in the constant temperature treatment stage, and a continued decrease with a decelerating trend during the cooling stage. (ii) Both w/c and p/c significantly influence internal stress in concrete, and this stress can be enhanced by reducing the initial free water content and augmenting the initial structural strength of the concrete. This paper serves as a valuable foundation and reference for further investigations into the residual expansion deformation of steam-cured concrete.

Objective To investigate the value of Hounsfield units (HUs) as an independent predictor of failed percutaneous drainage of spinal tuberculosis paraspinal abscess under computed tomography (CT) guidance. Methods A retrospective analysis was conducted on 61 patients who underwent CT-guided percutaneous drainage for spinal tuberculosis paraspinal abscess between October 2017 and October 2020. Preoperative CT scans were used to measure the HUs of the abscess. Patients were categorized into successful drainage (n = 49) and failed drainage (n = 12) groups. Statistical analysis involved independent sample t-tests and chi-square tests to compare between the 2 groups. Binary logistic regression was performed to identify independent predictive factors for drainage failure. Receiver operating characteristic (ROC) curves were employed to ascertain risk factor thresholds and diagnostic performance. Results Among the patients, 49 experienced successful drainage while 12 faced drainage failure. The mean HUs of abscesses in the failed drainage group were significantly higher than those in the successful drainage group (p < 0.001). ROC analysis revealed an area under the curve of 0.897 (95% confidence interval, 0.808–0.986) for predicting drainage failure based on HUs. The optimal HU cutoff value for predicting drainage failure was 22.3, with a sensitivity of 91.7% and specificity of 69.4%. Conclusion HUs are an independent predictor of failed percutaneous drainage of spinal tuberculosis paraspinal abscess under CT guidance. The HU value of 22.3 can be used as an initial screening threshold for predicting the success or failure of drainage.

Live streaming is revolutionizing the landscape of e-commerce, creating new opportunities for platforms and e-tailers to improve their performance. However, little is known about the underlying mechanisms that shape consumer behavior in this burgeoning business phenomenon. This study aims to shed light on the relationships between environmental cues generated by live streaming and online impulse buying. Drawing upon the Stimulus-Organism-Response framework, a comprehensive model was formulated to explore how social cues (streamer interaction, peer interaction) and media cues (vividness, realness) impact pleasure, arousal, perceived uncertainty, and subsequently induce consumers’ urge to buy impulsively. The model was tested by survey data from 403 consumers. SPSS and PLS are employed to verify the model. The findings revealed that realness and streamer interaction can reduce perceived uncertainty and foster a pleasant consumer experience, while vividness and peer interaction serve to awaken and delight consumers. Pleasure, arousal, and perceived uncertainty mediate antecedent variables’ effects on urge to buy impulsively in a parallel and reverse way, and emotions exert a more powerful influence. This study enriched the research on the influence mechanisms of impulse buying driven by live streaming and provided suggestions for platforms and streamers to optimize product display and guide interaction, which is conducive to leveraging the advantages of live streaming and creating greater commercial value.

Mixup is an effective data augmentation method that generates new augmented samples by aggregating linear combinations of different original samples. However, if there are noises or aberrant features in the original samples, mixup may propagate them to the augmented samples, leading to over-sensitivity of the model to these outliers. To solve this problem, this paper proposes a new mixup method called AMPLIFY. This method uses the attention mechanism of Transformer itself to reduce the influence of noises and aberrant values in the original samples on the prediction results, without increasing additional trainable parameters, and the computational cost is very low, thereby avoiding the problem of high resource consumption in common mixup methods such as Sentence Mixup. The experimental results show that, under a smaller computational resource cost, AMPLIFY outperforms other mixup methods in text classification tasks on seven benchmark datasets, providing new ideas and new ways to further improve the performance of pre-trained models based on the attention mechanism, such as BERT, ALBERT, RoBERTa, and GPT. Our code can be obtained at https://github.com/kiwi-lilo/AMPLIFY.

BackgroundTuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), remains a serious public health problem. Increasing evidence supports that selective evolution is an important force affecting genomic determinants of Mtb phenotypes. It is necessary to further understand the Mtb selective evolution and identify the positively selected genes that probably drive the phenotype of Mtb.MethodsThis study mainly focused on the positive selection of 807 Mtb strains from Southern Xinjiang of China using whole genome sequencing (WGS). PAML software was used for identifying the genes and sites under positive selection in 807 Mtb strains.ResultsLineage 2 (62.70%) strains were the dominant strains in this area, followed by lineage 3 (19.45%) and lineage 4 (17.84%) strains. There were 239 codons in 47 genes under positive selection, and the genes were majorly associated with the functions of transcription, defense mechanisms, and cell wall/membrane/envelope biogenesis. There were 28 codons (43 mutations) in eight genes (gyrA, rpoB, rpoC, katG, pncA, embB, gid, and cut1) under positive selection in multi-drug resistance (MDR) strains but not in drug-susceptible (DS) strains, in which 27 mutations were drug-resistant loci, 9 mutations were non-drug-resistant loci but were in drug-resistant genes, 2 mutations were compensatory mutations, and 5 mutations were in unknown drug-resistant gene of cut1. There was a codon in Rv0336 under positive selection in L3 strains but not in L2 and L4 strains. The epitopes of T and B cells were both hyper-conserved, particularly in the T-cell epitopes.ConclusionThis study revealed the ongoing selective evolution of Mtb. We found some special genes and sites under positive selection which may contribute to the advantage of MDR and L3 strains. It is necessary to further study these mutations to understand their impact on phenotypes for providing more useful information to develop new TB interventions.

In the last decade, ferroptosis has received much attention from the scientific research community. It differs from other modes of cell death at the morphological, biochemical, and genetic levels. Ferroptosis is mainly characterized by non-apoptotic iron-dependent cell death caused by iron-dependent lipid peroxide excess and is accompanied by abnormal iron metabolism and oxidative stress. In recent years, more and more studies have shown that ferroptosis is closely related to the occurrence and development of lung diseases. COPD, asthma, lung injury, lung fibrosis, lung cancer, lung infection and other respiratory diseases have become the third most common chronic diseases worldwide, bringing serious economic and psychological burden to people around the world. However, the exact mechanism by which ferroptosis is involved in the development and progression of lung diseases has not been fully revealed. In this manuscript, we describe the mechanism of ferroptosis, targeting of ferroptosis related signaling pathways and proteins, summarize the relationship between ferroptosis and respiratory diseases, and explore the intervention and targeted therapy of ferroptosis for respiratory diseases.

Abstract Background Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15–20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell–cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI. Methods We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell–cell signaling interactions and differentiation trajectories. Results Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries. Conclusions Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

Abstract N 6 -methyladenosine (m6A) maintains maternal RNA stability in oocytes. One regulator of m6A, ALKBH5, reverses m6A deposition and is essential in RNA metabolism. However, the specific role of ALKBH5 in oocyte maturation remains elusive. Here, we show that Alkbh5 depletion causes a wide range of defects in oocyte meiosis and results in female infertility. Temporal profiling of the maternal transcriptomes revealed striking RNA accumulation in Alkbh5 −/− oocytes during meiotic maturation. Analysis of m6A dynamics demonstrated that ALKBH5-mediated m6A demethylation ensures the timely degradation of maternal RNAs, which is severely disrupted following Alkbh5 −/− depletion. A distinct subset of transcripts with persistent m6A peaks are recognized by the m6A reader IGF2BP2 and thus remain stabilized, resulting in impaired RNA clearance. Additionally, reducing IGF2BP2 in Alkbh5-depleted oocytes partially rescued these defects. Overall, this work identifies ALKBH5 as a key determinant of oocyte quality and unveil the facilitating role of ALKBH5-mediated m6A removal in maternal RNA decay.

Abstract Background Targeting EBV-proteins with mRNA vaccines is a promising way to treat EBV-related tumors like nasopharyngeal carcinoma (NPC). We assume that it may sensitize tumors to immune checkpoint inhibitors. Results We developed an LMP2-mRNA lipid nanoparticle (C2@mLMP2) that can be delivered to tumor-draining lymph nodes. C2@mLMP2 exhibited high transfection efficiency and lysosomal escape ability and induced an increased proportion of CD8 + central memory T cells and CD8 + effective memory T cells in the spleen of the mice model. A strong synergistic anti-tumor effect of C2@mLMP2 in combination with αPD-1 was observed in tumor-bearing mice. The mechanism was identified to be associated with a reverse of CD8 + T cell exhaustion in the tumor microenvironment. The pathological analysis further proved the safety of the vaccine and the combined therapy. Conclusions This is the first study proving the synergistic effect of the EBV-mRNA vaccine and PD-1 inhibitors for EBV-related tumors. This study provides theoretical evidence for further clinical trials that may expand the application scenario and efficacy of immunotherapy in NPC. Graphical Abstract

Abstract Purpose To advance a modified oblique lumbar interbody fusion (M-OLIF) achieving anterior debridement and posterior freehand instrumentation simultaneously in circumferential approach via dynamic position and compare with traditional combined anterior–posterior surgery (CAPS) in clinical and radiological evaluation. Patients and methods Innovative freehand instrumentation in floating position was described. Consecutive patients having undergone surgeries for lumbar tuberculosis from 2017 January to 2019 December had been retrospectively reviewed. Patients with follow-ups for at least 36 months were included and divided into M-OLIF or CAPS group according to surgical methods applied. Outcomes included operation time, estimated blood loss, complication profile for safety evaluation; Vascular Analogue Scale (VAS) and Oswestry Disability Index (ODI) for efficacy evaluation; C-reactive protein and Erythrocyte Sedimentation Rate for tuberculosis activity and recurrence evaluation; X-ray and CT scan for radiological evaluation. Results Totally 56 patients had been enrolled in the study (26 for M-OLIF and 30 for CAPS). Compared with CAPS group, M-OLIF group illustrated significantly decreased estimated blood loss, operation time, hospital stay, and less postoperative morbidities. Meanwhile, M-OLIF group showed earlier improvement in VAS in 3 days and ODI in the first month postoperatively, without obvious discrepancy in further follow-ups. The overall screw accuracy in M-OLIF and CAPS group was 93.8% and 92.3% respectively, without significant difference in perforation distribution. Conclusion M-OLIF was efficient for lumbar tuberculosis requiring multilevel fixation, with reduced operation time and iatrogenic trauma, earlier clinical improvement compared with traditional combined surgery.

Abstract In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of anti‐tumor drugs. Drug carriers can be utilised in various forms, including magnetotactic bacteria, bacterial biohybrids, minicells, bacterial ghosts and bacterial spores. Additionally, functionalised and engineered bacteria obtained through gene engineering and surface modification could provide enhanced capabilities for drug delivery. This review summarises the current studies on bacteria‐based drug delivery systems for anti‐tumor therapy and discusses the prospects and challenges of bacteria as drug carriers. Furthermore, our findings aim to provide new directions and guidance for the research on bacteria‐based drug systems.

Test-time augmentation (TTA) is a well-established technique that involves aggregating transformed examples of test inputs during the inference stage. The goal is to enhance model performance and reduce the uncertainty of predictions. Despite its advantages of not requiring additional training or hyperparameter tuning, and being applicable to any existing model, TTA is still in its early stages in the field of NLP. This is partly due to the difficulty of discerning the contribution of different transformed samples, which can negatively impact predictions. In order to address these issues, we propose Selective Test-Time Augmentation, called STTA, which aims to select the most beneficial transformed samples for aggregation by identifying reliable samples. Furthermore, we analyze and empirically verify why TTA is sensitive to some text data augmentation methods and reveal why some data augmentation methods lead to erroneous predictions. Through extensive experiments, we demonstrate that STTA is a simple and effective method that can produce promising results in various text classification tasks.

Simultaneous nitrification and denitrification (SND) is effective and energy-saving for wastewater treatment. As an inevitable intermediate product in the SND process, nitrite affects the efficiency of ammonia oxidation and the composition of nitrifiers. To investigate the impact of nitrite on ammonia oxidation efficiency, two reactors performing SND were respectively operated without nitrite (R1 as control) and with 20 mg N/L nitrite addition (R2 as experimental). The total nitrogen removal efficiency was 74.5% in R1 while 99.0% in R2. With nitrite addition (i.e., 20 mg N/L), the ammonia removal rate in R2 increased to 4.5 times of that in R1. The ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) contributed to respective around 46.9% and 41.8% ammonia removal in R2 based on the results of experiments with specific inhibitors. The number of respective AOA and AOB ammonia monooxygenase gene (amoA) copies increased by 280 and 30 times due to nitrite addition, according to the qPCR results. The high-throughput sequencing results illustrated the increase of dominant AOB species from 0.40% in R1 to 1.59% in R2 and the phylogenetic tree analysis revealed a close link to Nitrosospira multiformis. These results indicated that the ammonia removal efficiency was improved and AOA/AOB were enriched by nitrite addition. The specific nitrite reductases in AOA and AOB boosted the adaptation of nitrite addition. This study demonstrated the positive impacts of nitrite addition on the ammonia removal efficiency and rate in the SND process.

Baked foods with a huge market scale play an important part in people's daily diet, and the market scale maintains a trend of rapid growth. The quality of baked foods is affected by many factors, such as raw material composition and processing conditions, so understanding the factors affecting the quality of baked foods is of great significance to process and produce high-quality baked foods. This paper reviewed the effects of fermentation conditions, processing conditions, and raw material composition on the quality of baked foods, and it also involved research on functional baked foods with the addition of special nutritional ingredients or low / no sugar content. These new types of baked foods are more in line with the current people's pursuit of the concept of nutritious and healthy diet. This paper could provide the reference for the design and production of high-quality baked foods, and promote the development and upgrading of the baked food industry.

In view of the problems in transmission capacity of illumination guidance system, this paper presents a high speed of 2.5 Gbit/s optical system based on gigabit transceiver. The system takes gigabit transceiver as the core device. It is used to achieve a series of processing with multiple data types and multiple interface in optical fiber transmission and Field Programmable Gate Array (FPGA). It ultimately achieves the high-speed optical fiber transmission of serial data. The results show that the system can increase the processing rate of the data from guidance array to ground console. It also reduces the number of equipment in illumination guidance system, which breaks through the limit of transmission distance between guidance array and ground console.

Relying on the Mawan undersea large-diameter, dual-line, mud–water-balanced shield tunnel project and focusing on the characteristics of the tunnel, such as the complex geological conditions at the expected intersection location and the existence of a superimposed perturbation or secondary perturbation effect, theoretical calculations and three-dimensional numerical simulations were used to reveal the ground disturbance situation of the large-diameter, two-lane mud–water shield when it is propelled under various working conditions. The working conditions were set for the dynamic intersection of the left and right lines, with stopping and moving as the two modes, and a traversing simulation was carried out under three conditions related to the strata. The results show that the surface settlement curve for the two-lane construction became a “W”-shaped bimodal curve due to the superposition effect; the dynamic intersection construction greatly disturbed the ground layer and there was a plastic zone expanding outward at a small angle above the tunnel, with shear damage in the soil layer and tensile damage in the rock layer. A “one line stops, and another advances” intersection can reduce the impact of disturbance; the surface settlement value after the completion of the advancement was smaller than the dual-line intersection. The surrounding rock stress and displacement under the advancement of a single shield machine did not change to a great degree, there was no obvious change in the surface settlement above the tunnel, and the effect of the secondary disturbance was small.

Under the premise of using the solid-phase method to pre-sinter Bi2O3 and Sb2O3 into BiSbO4 as a substitute for equal amounts of Bi2O3 and Sb2O3 in the formula, the effects of co-doping with In(NO3)3, Al(NO3)3, and Y(NO3)3 on the microstructure and electrical properties of ZnO varistors were studied. The experimental results show that with an increase in In3+-doped molar concentration, the leakage current of the ZnO varistor shows a rapid decrease and then a slow increase trend. However, the nonlinear coefficient is the opposite of it. With the combined effect of the rare earth element Y3+, the average grain size is significantly reduced, which leads to an increase in the voltage gradient. At the same time, a certain amount of doped In3+ and Al3+ is dissolved into the grains, resulting in a decrease in grain resistance and thus a low level of residual voltage. The varistor with 0.6 mol% In3+, 0.1 mol% Al3+, and 0.9 mol% Y3+ doping ratios exhibits excellent overall performance. The nonlinear coefficient is 62.2, with the leakage current being 1.46 µA/cm2 and the voltage gradient being 558 V/mm, and the residual voltage ratio is 1.73. The prepared co-doped ZnO varistors will provide better protection for metal oxide surge arresters.

Developmental engineering (DE) involves culturing various cells on modular scaffolds (MSs), yielding modular tissues (MTs) assembled into three-dimensional (3D) tissues, mimicking developmental biology. This study employs an integrated approach, merging experimental and mathematical methods to investigate the biological processes in MT cultivation and assembly. Human dermal fibroblasts (HDFs) were cultured on tissue culture plastics, poly(lactic acid) (PLA) discs with regular open structures, or spherical poly(methyl methacrylate) (PMMA) MSs, respectively. Notably, HDFs exhibited flattened spindle shapes when adhered to solid surfaces, and complex 3D structures when migrating into the structured voids of PLA discs or interstitial spaces between aggregated PMMA MSs, showcasing coordinated colonization of porous scaffolds. Empirical investigations led to power law models simulating density-dependent cell growth on solid surfaces or voids. Concurrently, a modified diffusion model was applied to simulate oxygen diffusion within tissues cultured on solid surfaces or porous structures. These mathematical models were subsequently combined to explore the influences of initial cell seeding density, culture duration, and oxygen diffusion on MT cultivation and assembly. The findings underscored the intricate interplay of factors influencing MT design for tissue assembly. The integrated approach provides insights into mechanistic aspects, informing bioprocess design for manufacturing MTs and 3D tissues in DE.

Autoimmune diseases (AIDs) are immune disorders whose incidence and prevalence are increasing year by year. AIDs are produced by the immune system’s misidentification of self-antigens, seemingly caused by excessive immune function, but in fact they are the result of reduced accuracy due to the decline in immune system function, which cannot clearly identify foreign invaders and self-antigens, thus issuing false attacks, and eventually leading to disease. The occurrence of AIDs is often accompanied by the emergence of inflammation, and inflammatory mediators (inflammatory factors, inflammasomes) play an important role in the pathogenesis of AIDs, which mediate the immune process by affecting innate cells (such as macrophages) and adaptive cells (such as T and B cells), and ultimately promote the occurrence of autoimmune responses, so targeting inflammatory mediators/pathways is one of emerging the treatment strategies of AIDs. This review will briefly describe the role of inflammation in the pathogenesis of different AIDs, and give a rough introduction to inhibitors targeting inflammatory factors, hoping to have reference significance for subsequent treatment options for AIDs.

Abstract Background Leaves of tobacco (Nicotiana tabacum L.) are flue-cured to use as a key industrial supply in various parts of the world. The quality of tobacco leaves is dependent on chemical components and their proportions. Generally, the stem attached to tobacco leaf is detached before curing. However, the leaf stem remains green for an extended period of time (as compared to leaf) during flue-curing. Hence, it is expected to affect the quality of tobacco's final product. Results To understand the impact of the green stem of leaf on the metabolome of flue-cured tobacco, we employed a broad targeted metabolomics approach. We selected two tobacco cultivars (Yun87 and K326) and cultivated them in five geographic locations in China. For flue-curing, leaves were harvested without a stem (L) or with an attached stem (SPL). After metabolome analysis, a total of 1027 metabolites were annotated in these samples. A variable number of metabolites were differentially accumulated between both types of leaves (depending on geographic location or cultivar) representing an influence of environment or genotype. Interestingly, only 68 metabolites were differentially accumulated between L and SPL samples irrespective of the cultivar or geographic location. These differentially accumulated metabolites belonged to major groups of primary and secondary metabolites. We have discussed the importance of identified metabolites in terms of carbon, nitrogen, and polyphenolic metabolism. Conclusion The present research is the first comprehensive description of several metabolites in tobacco leaves related to the contribution of leaf stem. The current study opens novel prospects for investigating the potential of such metabolites in improving the quality of flue-cured tobacco.

The AC filter protection devices used in the Longquan-Zhengping HVDC transmission project are non-standardized products supplied by ABB in 2003. The AC filter overload protection for the project must be standardized through renovation. Through analysis of the protection architectures， protection principles， and protection settings of the unrenovated AC filter overload protection and the standardized AC filter overload protection， the differences between them in the protection architectures， implementation methods of skin effect coefficients， implementation methods of protection principle， and the expression form of protection settings are expounded. Moreover， the renovation method for standardizing AC filter overload protection is proposed. Finally， it is verified that the standardized AC filter overload protection can meet the demands of the project.

This network meta-analysis (NMA) aims to investigate the efficacy and safety of different pharmacological treatments for idiopathic membranous nephropathy (IMN). Thirty-four relevant studies were extracted from PubMed, Embase, Cochrane database, and MEDLINE. Treatment with tacrolimus (TAC), cyclophosphamide (CTX), mycophenolate mofetil, chlorambucil (CHL), cyclosporin A (CSA), steroids, rituximab (RTX), and conservative therapy were compared. Outcomes were measured using remission rate and incidence of side effects. Summary estimates were expressed as the odds ratio (OR) and 95% confidence intervals (CIs). The quality of findings was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. In the direct meta-analysis for comparison of complete remission (CR) rate, the curative effect of RTX is inferior to CTX (OR 0.37; CI 0.18, 0.75). In the NMA of CR rate, the results showed that the curative effects of CTX, CHL, and TAC were significantly higher than those of the control group. The efficacy of RTX is not inferior to the CTX (OR 0.81; CI 0.32, 2.01), and the level of evidence was moderate; CSA was not as effective as RTX, and the difference was statistically significant with moderate evidence (OR 2.98, CI 1.00, 8.91). In summary, we recommend CTX and RTX as the first-line drug for IMN treatment.

Abstract Characterization and categorization of quantum correlations are both fundamentally and practically important in quantum information science. Although quantum correlations such as non-separability, steerability, and non-locality can be characterized by different theoretical models in different scenarios with either known (trusted) or unknown (untrusted) knowledge of the associated systems, such characterization sometimes lacks unambiguous to experimentalist. In this work, we propose the physical interpretation of nonlocal quantum correlation between two systems. In the absence of complete local description of one of the subsystems quantified by the local uncertainty relation, the correlation between subsystems becomes nonlocal. Remarkably, different nonlocal quantum correlations can be discriminated from a single uncertainty relation derived under local hidden state (LHS)–LHS model only. We experimentally characterize the two-qubit Werner state in different scenarios.

IntroductionHemiplegic migraine (HM) is a rare subtype of migraine. HM in children may be atypical in the initial stage of the disease, which could easily lead to misdiagnosis.MethodsWe report two cases of atypical hemiplegic migraine that onset as an acute encephalopathy. And a comprehensive search was performed using PubMed, Web of Science, and Scopus. We selected only papers that reported complete clinical information about the patients with CACNA1A or ATP1A2 gene mutation.ResultsPatient #1 showed a de novo mutation, c.674C>A (p. Pro225His), in exon 5 of the CACNA1A gene. And patient #2 showed a missense mutation (c.2143G>A, p. Gly715Arg) in exon 16 of the ATP1A2. Together with our two cases, a total of 160 patients (73 CACNA1A and 87 ATP1A2) were collected and summarized finally.DiscussionAcute encephalopathy is the main manifestation of severe attacks of HM in children, which adds to the difficulty of diagnosis. Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation. When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment. Early recognition and treatment of the disease can help improve the prognosis.

Ultra-high-performance concrete (UHPC) is a promising cementitious composite to produce lightweight and high-performance structures. Steel fibres are an essential constituting material of UHPC to prevent the brittle failure of UHPC, but the high cost steel fibres impedes the wider application of UHPC to some extent. This paper proposes a concept to produce UHPC reinforced with macro fibres processed from waste glass-fibre-reinforced polymer (GFRP) composites, therefore addressing two issues of the high cost of UHPC as well as the difficulty in disposal of waste GFRP simultaneously. A series of tests have been carried out to investigate the effect of adding macro fibres on the properties of UHPC. The test results show that the incorporation of macro fibres leads to a loss of the workability and a reduction of up to 21.8 % in the compressive strength, but improves the flexural strength and flexural toughness greatly by up to 27.9 % and 46.9 times, respectively. The tensile constitutive relationship has been converted from the results of the bending tests through inverse analyses. The proposed concept of producing UHPC with recycled macro fibres contributes to lowering the price of UHPC, whose properties are comparable to that of UHPC with steel fibres, and establishing an effective routine to valorise the waste GFRP.

Objective: This study aimed to investigate the residues and risk assessment of pesticides in peach gum. Methods: The quantitative analysis of 44 pesticide residues in peach gum was established based on liquid chromatography tandem-mass spectrometry （LC-MS/MS）, and the pesticide residues in 173 peach gum samples were detected as well as the risk assessment of pesticide residues. Results: The limits of detection （LOD） and the limits of quantification （LOQ） of 44 kinds of pesticides in this quantitative method were between 0.05~1.80 μg/kg and 0.20~2.42 μg/kg, respectively. Recoveries of these pesticides ranged from 61.77%~119.48%. In 173 peach gum samples, 22 out of 44 pesticides were detected and the total detection rate of pesticides in peach gum was 98.8%. The detection rate of difenoconazole was the highest （95%）, followed by chlorpyrifos （54%）, carbendazim （34%）, furamethoxam （32%） and pyraclostrobin （19%）. The average residue of difenoconazole in different peach gum samples was the highest （0.332 mg/kg）, followed by furamethoxam （0.093 mg/kg）, carbendazim （0.061 mg/kg） and chlorpyrifos （0.033 mg/kg）. Conclusion: Pesticide residues in peach gum were related to the usage of pesticides in peach production and were at a low risk level. It is recommended to pick peach gum from August to October.

The increased cultivation of Cannabis sativa L. in North America, represented by high Δ9-tetrahydrocannabinol-containing (high-THC) cannabis genotypes and low-THC-containing hemp genotypes, has been impacted by an increasing number of plant pathogens. These include fungi which destroy roots, stems, and leaves, in some cases causing a build-up of populations and mycotoxins in the inflorescences that can negatively impact quality. Viroids and viruses have also increased in prevalence and severity and can reduce plant growth and product quality. Rapid diagnosis of the occurrence and spread of these pathogens is critical. Techniques in the area of molecular diagnostics have been applied to study these pathogens in both cannabis and hemp. These include polymerase chain reaction (PCR)-based technologies, including RT-PCR, multiplex RT-PCR, RT-qPCR, and ddPCR, as well as whole-genome sequencing (NGS) and bioinformatics. In this study, examples of how these technologies have enhanced the rapidity and sensitivity of pathogen diagnosis on cannabis and hemp will be illustrated. These molecular tools have also enabled studies on the diversity and origins of specific pathogens, specifically viruses and viroids, and these will be illustrated. Comparative studies on the genomics and metabolomics of healthy and diseased plants are urgently needed to provide insight into their impact on the quality and composition of cannabis and hemp-derived products. Management of these pathogens will require monitoring of their spread and survival using the appropriate technologies to allow accurate detection, followed by appropriate implementation of disease control measures.

Abstract Background The correlation between nontraditional lipids and ischemic stroke (IS) is inconsistent and controversial. This study aimed to examine the association of four nontraditional lipids with IS risk in Chinese adults. Methods This prospective community-based cohort study was performed in Songjiang District, Shanghai, China. The study began in 2016 and included 34,294 participants without stroke before the investigation. The association between nontraditional lipids (nonhigh-density lipoprotein cholesterol [non-HDL-C], total cholesterol/high-density lipoprotein cholesterol [TC/HDL-C], triglyceride [TG]/HDL-C, and low-density lipoprotein cholesterol [LDL-C]/HDL-C) and IS was studied with multivariate Cox regression models. The dose–response associations between these four serum lipids and IS were explored using restricted cubic spline (RCS) analysis. Results There were a total of 458 IS cases with 166,380 person-years of follow-up. Compared with the lowest tertiles, the highest tertiles of the nontraditional blood lipids showed greater IS risk after controlling for potential confounders. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were as follows: TC/HDL-C, 1.63 (1.28–2.07); TG/HDL-C, 1.65 (1.28–2.13); LDL-C/HDL-C, 1.51 (1.18–1.92); and non-HDL-C, 1.43 (1.13–1.81). The fully adjusted RCS curves presented a nonlinear relationship, and the risk increased when the TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C levels were > 3.47, > 0.92, and > 1.98, respectively. Conclusions This community-based cohort study presents a positive association between the four nontraditional lipids and IS incidence. Maintaining relatively low lipid ratios can be beneficial for preventing stroke. Nontraditional lipids can be considered targets for managing blood lipids.

Curcumenol, an effective ingredient of Wenyujin, has been reported that exerted its antitumor potential in a few cancer types. However, the effect and molecular mechanism of curcumenol in lung cancer are largely unknown. Here, we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells. Next, we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time. Subsequently, using RNA sequencing, we found that the long non-coding RNA H19 (lncRNA H19) was significantly downregulated in lung cancer cells treated with curcumenol, when compared to untreated controls. Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol, while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis. In conclusion, our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Therefore, our findings will hopefully provide a valuable drug for treating lung cancer patients.

Abstract Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor–host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.

The existing research on the failure characteristics of coal samples has some problems, such as single mechanical parameter test and large limitation of stress loading direction. The numerical simulation effect has deviation in the inversion of real geological conditions, and the determination of coal and rock dynamic disaster and bursting liability is based on the macro-research of field experiments. There are few studies on the failure mechanism of coal samples under different unloading stress paths in true triaxial. In order to solve the above problems, taking the engineering geology of Hujiahe Coal Mine in Binchang, Shaanxi Province as the research background, the true triaxial test of coal samples under three different unloading stress paths is designed by using the triaxial dynamic and static load test system of high-frequency vibration acquisition and borehole imaging. And the failure characteristics, peak strength characteristics, acoustic emission response characteristics and fractal law of coal samples are studied. ① The results show that the failure modes of coal samples under three different unloading stress paths are tensile-shear composite failure, and the initiation failure of macro-cracks mostly occurs in the coal samples with relatively low strength. The axial stress of each coal sample increases continuously, and each horizontal stress provides tensile stress in the process of gradually decreasing, resulting in significantly different surface failure forms of coal samples under different unloading stress paths. ② There are obvious differences in the stress of the three different unloading stress paths at the peak failure stage, and the standard deviation reaches 4.35 MPa, accounting for 29.25% of the average peak strength. When the stress load exceeds the average peak strength of the three stress paths by 14.87 MPa, the coal samples are damaged. ③ Under the action of high static load, the pores of the coal samples are compacted after initial loading. The internal structure is relatively uniform, and no fracture expands. The damage variable value is 0 in the initial stage. In the stable development stage of damage, the internal pores of the coal samples reach the limit state and break to form micro-fracture, and the damage variable value is 0.04-0.17. During the loading process, the micro-fracture develop rapidly, expand and converge into the fracture network, and the coal sample is macroscopically damaged. The bearing capacity of the coal sample decreases rapidly, the damage variable value increases sharply first and then stabilizes, and the maximum damage variable value reaches 1.0 in the stage of accelerated damage development. The acoustic emission(AE) energy value increases suddenly when the coal sample is damaged by stress instability and tensile-shear failure. When the AE energy intersects with the damage variable curve, the coal sample begins to break, and the AE energy has a good coupling with the coal sample failure. ④ Under different unloading stress paths, the larger the fractal dimension of coal sample, the higher the degree of fragmentation.

Abstract Wigner negativity, as a well-known indicator of nonclassicality, plays an essential role in quantum computing and simulation using continuous-variable systems. The conditional preparation of Wigner-negative states through appropriate non-Gaussian operations on an auxiliary mode is common procedure in quantum optics experiments. Motivated by the demand of real-world quantum network, here we investigate the remote creation and distribution of Wigner negativity in the multipartite scenario from a quantitative perspective. By establishing a monogamy relation akin to the generalized Coffman-Kundu-Wootters inequality, we show that the amount of Wigner negativity cannot be freely distributed among different modes. Moreover, for photon subtraction—one of the main experimentally realized non-Gaussian operations—we provide an intuitive method to quantify remotely generated Wigner negativity. Our results pave the way for exploiting Wigner negativity as a valuable resource for numerous quantum information protocols based on non-Gaussian scenario.

IntroductionColorectal cancer (CRC) ranks second for mortality and third for morbidity among the most commonly diagnosed cancers worldwide. We aimed to investigate the heterogeneity and convergence of tumor microenvironment (TME) in CRC.MethodsWe analyzed the single-cell RNA sequencing data obtained from the Gene Expression Omnibus (GEO) database and identified 8 major cell types and 25 subgroups derived from tumor, para-tumor and peripheral blood.ResultsIn this study, we found that there were significant differences in metabolic patterns, immunophenotypes and transcription factor (TF) regulatory patterns among different subgroups of each major cell type. However, subgroups manifested similar lipid metabolic patterns, immunosuppressive functions and TFs module at the end of the differentiation trajectory in CD8+ T cells, myeloid cells and Fibroblasts. Meanwhile, TFs regulated lipid metabolism and immunosuppressive ligand-receptor pairs were detected by tracing the differentiation trajectory. Based on the cell subgroup fractions calculated by CIBERSORTx and bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA), we constructed an immune risk model and clinical risk model of CRC which presented excellent prognostic value.ConclusionThis study identified that the differentiation was accompanied by remodeling of lipid metabolism and suppression of immune function, which suggest that lipid remodeling may be an important trigger of immunosuppression. More importantly, our work provides a new perspective for understanding the heterogeneity and convergence of the TME and will aid the development of prognosis and immunotherapies of CRC patients.

Unexplained recurrent spontaneous abortion (URSA) is one of the most intractable clinical challenges in reproduction. As a specific type of endogenous non-coding RNA, circular RNAs (circRNAs) have great pre-clinical diagnostic and therapeutic values in diseases. Recently, thousands of circRNAs were detected in human pre-implantation embryos, indicating that circRNAs potentially have important regulatory functions. However, the roles of circRNAs in URSA remain largely unknown. In this study, we elucidated deregulated circRNA expression and distinct competing endogenous RNA (ceRNA) networks by comparing URSA placental villus with that of patients with normal pregnancy using microarrays. We characterized a distinct circRNA, circRNA-0050703, which is downregulated in URSA placental villus (thus we named it circRNA-DURSA). Silencing of circRNA-DURSA results in trophoblast cell apoptosis in vitro. Furthermore, mechanistic dissection revealed that circRNA-DURSA exerts its effects by competitively binding to miR-760, which post-transcriptionally targets HIST1H2BE. Additionally, after circRNA-DURSA silencing in vivo, the numbers of implanted embryos decreased significantly. These results reveal the regulatory roles of circRNA-DURSA in trophoblasts and identified a distinct circRNA-DURSA/miR-760/HIST1H2BE axis as potentially important diagnostic and therapeutic targets for URSA treatment.

Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.