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Abstract Backgrounds Currently, family with sequence similarity 65 member A (FAM65A) is reported as a pivotal regulator in various cancers. However, the effect of FAM65A in lung squamous cell carcinoma (LSCC) is still unclear, the prime objective of this research is to explore the role of FAM65A in LSCC. Methods Gene expression data and correlated clinical information were downloaded from the public database and the expression of FAM65A was detected. The expression of FAM65A was also detected in our collected clinical samples and LSCC cell lines. Survival package of R language was used to determine the survival significance of FAM65A. Proteins expression level was determined via western blot assay. Cell function experiments and in vivo experiments were performed to explore the effect of FAM65A on LSCC cell biological behaviors. Results FAM65A expression was significantly increased in LSCC clinical samples and cell lines. High FAM65A expression predicted poor prognosis in LSCC patients. After silencing FAM65A, the ability of LSCC cell proliferation, invasion and migration was decreased, and LSCC cell cycle was blocked. Moreover, in vivo experiments revealed that silencing FAM65A could inhibit LSCC cell proliferation. Conclusions High FAM65A expression could enhance proliferative, invasive and migratory abilities of LSCC. FAM65A might be a novel biomarker of LSCC.

Abstract With the continuous advancement of virtualization technology and the widespread adoption of 5G networks, the application of the Network Function Virtualization (NFV) architecture has become increasingly popular and prevalent. While the NFV architecture brings a lot of advantages, it also introduces security challenges, including the effective and efficient verification of the integrity of deployed Virtual Network Functions (VNFs) and ensuring the secure operation of VNFs. To address the challenge of efficiently conducting virtual remote attestation for VNFs and establishing trust in virtualized environments like NFV architecture, we propose TVRAVNF, which is a highly efficient and low-cost TEE-based virtual remote attestation scheme for VNFs. The scheme we proposed ensures the security and effectiveness of the virtual remote attestation process by leveraging TEE. Furthermore, we introduces a novel local attestation mechanism, which not only reduces the overall overhead of the virtual remote attestation process but also shortens the attestation interval to mitigate Time-Of-Check-Time-Of-Use attacks, thereby enhancing overall security. We conduct experiments to validate the overhead of the TVRAVNF scheme and compare its performance with that of a typical remote attestation process within a maximum unattested time interval. The experimental results demonstrate that, by employing the local attestation mechanism, our solution achieves nearly an 80% significant performance improvement with a relatively small time overhead for small to medium-sized files. This further substantiates the significant advantages of our approach in both security and efficiency.

Abstract Background Acute exacerbation (AE) of interstitial lung disease (ILD) is one of the most serious complications during perioperative period of lung cancer resection. This study aimed to investigate the correlation between preoperative 2- deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/CT findings and AE in lung cancer patients with ILD. Methods We retrospectively reviewed the data of 210 patients who underwent lung resection for non-small cell lung cancer. Relationships between clinical data and PET images and AE were evaluated. The patients were divided into an AE(+) and an AE(-) group for multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was conducted and the area under curve (AUC) was used to assess the predictive values. Results Among 210 patients, 48 (22.8%) were diagnosed with ILD based on chest CT. Among them, 9 patients (18.75%) developed AE after lung resection and were defined as AE(+) group. The course of ILD was longer in AE(+) group compared to AE(-) group. More patients in AE(+) group had a history of AE and chronic obstructive pulmonary disease (COPD) than in AE(-) group. The maximum standardized uptake value (SUVmax) of the noncancerous interstitial pneumonia (IP) area and cancers in AE(+) group was significantly higher compared to AE(-) group. Univariate logistic regression analysis showed that AE, COPD, SUVmax of the noncancerous IP area, SUVmax of cancer, surgical method were significantly correlated with AE. The course of ILD[OR(95%CI) 2.919; P = 0.032], SUVmax of the noncancerous IP area[OR(95%CI) 7.630;P = 0.012] and D-Dimer level[OR(95%CI) 38.39;P = 0.041] were identified as independent predictors for AE in patients with ILD after lung cancer surgery. When the three indicators were combined, we found significantly better predictive performance for postoperative AE than that of SUVmax of the noncancerous IP area alone [0.963 (95% CI 0.914-1.00); sensitivity, 100%, specificity 87.2%, P

Abstract Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation.

To explore the differences in the composition, content and comprehensive quality of free amino acids (FAA) in millet from Longzhong area in Gansu Province，12 different cultivars of millet were used as research objects, the types and contents of FAA were determined by liquid chromatography-tandem mass spectrometry. Comprehensive evaluation of FAA quality was performed by principal component analysis (PCA) and hierarchical cluster analysis (HCA). The results showed that 19~20 kinds of FAA were detected in all kinds of millet, and the total content of FAA ranged from 1046.80~1773.85 mg/kg, asparagine (Asn), aspartic acid (Asp), glutamic acid (Glu) and glycine (Gly) were the four main FAA in millet. There were significant differences in the contents of FAA (Pbitter amino acids>sweet amino acids>aromatic amino acids. 9 Medicinal amino acids and 3 branched chain amino acids were found in millet, the average content of medicinal amino acids was 706.34 mg/kg, the percentages of medicinal amino acids to total FAA was 53.63%, so millet had many potential medicinal values. There was a significant relation with FAA in different cultivars of millet, five principal components were extracted after PCA, and the cumulative contribution ratio of the five components was 86.20%, the FAA comprehensive scores of LG-23、LG-11 and YG-18 were ranked as the top three. The 12 different cultivars millet were divided into four groups by HCA, FAA comprehensive quality performances of groups Ⅰ (LG-23) and Ⅲ (LG-11 and YG-18) were optimal, the content of total FAA was significantly higher than the other two groups (P

Abstract Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome‐wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment‐resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation‐relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein‐coding region of HLA‐DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA‐DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin‐6 (IL‐6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA‐DRB1 polymorphism, and enhanced IL‐6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Abstract Background Surgery is the primary treatment for benign breast disease and causes some disruption to the normal physiology of the breast, even when this disruption is localised, it remains unclear whether it affects women’s ability to breastfeed. There are only a few studies describing the experience of breastfeeding in women who have undergone benign breast disease (BBD) surgery. Methods We retrospectively analysed data from patients aged 20–40 years in Guangdong, China, who underwent breast lumpectomy for BBD in our department between 01 January 2013 and 30 June 2019, with a follow-up date of 01 February 2022. Patients were included who had a history of childbirth between the time of surgery and the follow-up date. By collecting general information about this group of patients and information about breastfeeding after surgery, we described the breastfeeding outcomes of women of a fertile age who had previously undergone surgery for benign breast disease. Results With a median follow-up of 5.9 years, a total of 333 patients met the inclusion criteria. From the breastfeeding data of the first child born postoperatively, the mean duration of ‘exclusive breastfeeding’ was 5.1 months, and the mean duration of ‘any breastfeeding’ was 8.8 months. The rate of ‘ever breastfeeding’ is 91.0%, which is lower than the national average of 93.7%, while the exclusive breastfeeding rate at six months was 40.8%, was higher than the 29.2% national average. The any breastfeeding rate at 12 months was 30.0%, which was well below the 66.5% national average. The common reason for early breastfeeding cessation was insufficient breast milk. A total of 29.0% of patients who had ever breastfed after surgery voluntarily reduced the frequency and duration of breastfeeding on the operated breast because of the surgery. Conclusions There are some impacts of BBD surgery on breastfeeding and some may be psychological. Institutions should provide more facilities for mothers who have undergone breast surgery to help them breastfeed, such as conducting community education on breastfeeding after breast surgery, training professional postoperative lactation consultants in hospitals, and extending maternity leave. Families should encourage mothers to breastfeed with both breasts instead of only the non-operated breast.

Although characterized by high reactive oxygen species (ROS) generation, cancer cells maintain redox homeostasis to avoid severe damage (e.g., DNA, protein, and plasma membrane dysfunction) and facilitate cancer progression. Emerging evidence has indicated that targeting the regulation of redox homeostasis to amplify oxidative stress is of value in cancer therapy. However, therapeutic agents like nucleic acids, small molecular inhibitors, and chemotherapeutic drugs fail to exert effective cancer inhibition due to their low bioavailability, susceptibility to serum enzymes, and inefficiency in cell membrane penetrating. Therefore, specific delivery vectors are required to facilitate the intracellular delivery of anti-tumor drugs. In the past few decades, various engineered nanomaterials have been designed and developed for drug delivery. In particular, rational nanoparticles (NPs) have garnered more attention due to their splendid long circulation ability, modification capacity, and stimulation-responded release. In this review, the methods of ROS generation and ROS-regulated signaling in cancer development were firstly briefly introduced. The anti-oxidant system, including the metabolism shifting and anti-oxidant genes, were next reviewed, and the strategies of NPs-mediated targeted regulation of redox homeostasis were emphatically discussed. The main strategies include NPs-induced delivery of nucleic acids, small molecule inhibitors, chemotherapeutic agents, radiosensitizers, and NPs-induced ROS generation and GSH depletion. The future development of NP-mediated redox dyshomeostasis in cancer therapy and their challenges in clinical translation were finally discussed.

Oxide particles with suitable size can refine the microstructure and improve the strength and toughness of steel. In this study, the particles containing Al2O3 were successfully introduced into H13 steel by vacuum casting. The micro-sized Al2O3-containg particles were randomly distributed in the dendritic structure and their number was increased by almost a factor of one. The secondary dendritic arm spacing of the ingot was decreased, which might be attributed to the heterogeneous nucleation of these oxides during solidification. Meanwhile, the alloying element segregation of the ingot was also alleviated. The micro-sized primary carbides were refined as the oxide particles were introduced to H13 steel, especially for V-rich carbides. After hot rolling and heat treatment, the size of austenitic grain was reduced by up to 75% (7.2 ± 1.8 μm), which was due to the particle stimulated nucleation and Zener pinning of micro- and nanoscale oxides in the oxide-added steel. The mechanical properties were obviously modified with the ultimate tensile strength of 1835 MPa, yield strength of 1479 MPa, tensile elongation of 13.4% and impact toughness of 24 J/cm2 after the introduction of oxide particles. It is expected that the introduction of oxide particles by vacuum casting can be applied widely in other die steel for superior performance.

Abstract Molecular computing is an emerging paradigm that plays an essential role in data storage, bio-computation, and clinical diagnosis with the future trends of more efficient computing scheme, higher modularity with scaled-up circuity and stronger tolerance of corrupted inputs in a complex environment. Towards these goals, we construct a spatially localized, DNA integrated circuits-based classifier (DNA IC-CLA) that can perform neuromorphic architecture-based computation at a molecular level for medical diagnosis. The DNA-based classifier employs a two-dimensional DNA origami as the framework and localized processing modules as the in-frame computing core to execute arithmetic operations (e.g. multiplication, addition, subtraction) for efficient linear classification of complex patterns of miRNA inputs. We demonstrate that the DNA IC-CLA enables accurate cancer diagnosis in a faster (about 3 h) and more effective manner in synthetic and clinical samples compared to those of the traditional freely diffusible DNA circuits. We believe that this all-in-one DNA-based classifier can exhibit more applications in biocomputing in cells and medical diagnostics.

Abstract Background Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy. Methods We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno‐collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in‐house samples. Additionally, novel therapeutic targets were identified based on these established immuno‐collagenic subtypes. Results Our categorization divided tumors into three subtypes: “soft & hot” (low collagen activity and high immune infiltration), “armored & cold” (high collagen activity and low immune infiltration), and “quiescent” (low collagen activity and immune infiltration). Notably, “soft & hot” tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7‐H3), an available drug target, as strongly expressed in “armored & cold” tumors, relating with poor prognosis. Conclusion This study introduces histopathology‐based universal immuno‐collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Abstract Brain tumour segmentation (BTS) is crucial for diagnosis and treatment planning by delineating tumour boundaries and subregions in multi‐modality bio‐imaging data. Several BTS models have been proposed to address specific technical challenges encountered in this field. However, accurately capturing intricate tumour structures and boundaries remains a difficult task. To overcome this challenge, HAB‐Net, a model that combines the strengths of convolutional neural networks and transformer architectures, is presented. HAB‐Net incorporates a custom‐designed hierarchical and pseudo‐convolutional module called hierarchical asymmetric convolutions (HAC). In the encoder, a coordinate attention is included to extract feature maps. Additionally, swin transformer, which has a self‐attention mechanism, is integrated to effectively capture long‐range relationships. Moreover, the decoder is enhanced with a boundary attention module (BAM) to improve boundary information and overall segmentation performance. Extensive evaluations conducted on the BraTS2018 and BraTS2021 datasets demonstrate significant improvements in segmentation accuracy for tumour regions.

Abstract Background Sleep loss is a common public health problem that causes hyperalgesia, especially that after surgery, which reduces the quality of life seriously. Methods The 48-h sleep restriction (SR) mouse model was created using restriction chambers. In vivo imaging, transmission electron microscopy (TEM), immunofluorescence staining and Western blot were performed to detect the status of the blood-spinal cord barrier (BSCB). Paw withdrawal mechanical threshold (PWMT) was measured to track mouse pain behavior. The role of infiltrating regulatory T cells (Tregs) and endothelial cells (ECs) in mouse glycolysis and BSCB damage were analyzed using flow cytometry, Western blot, CCK-8 assay, colorimetric method and lactate administration. Results The 48-h SR made mice in sleep disruption status and caused an acute damage to the BSCB, resulting in hyperalgesia and neuroinflammation in the spinal cord. In SR mice, the levels of glycolysis and glycolysis enzymes of ECs in the BSCB were found significantly decreased [CON group vs. SR group: CD31+Glut1+ cells: p < 0.001], which could cause dysfunction of ECs and this was confirmed in vitro. Increased numbers of infiltrating T cells [p < 0.0001] and Treg population [p < 0.05] were detected in the mouse spinal cord after 48-h SR. In the co-cultured system of ECs and Tregs in vitro, the competition of Tregs for glucose resulted in the glycolysis disorder of ECs [Glut1: p < 0.01, ENO1: p < 0.05, LDHα: p < 0.05; complete tubular structures formed: p < 0.0001; CCK8 assay: p < 0.001 on 24h, p < 0.0001 on 48h; glycolysis level: p < 0.0001]. An administration of sodium lactate partially rescued the function of ECs and relieved SR-induced hyperalgesia. Furthermore, the mTOR signaling pathway was excessively activated in ECs after SR in vivo and those under the inhibition of glycolysis or co-cultured with Tregs in vitro. Conclusions Affected by glycolysis disorders of ECs due to glucose competition with infiltrating Tregs through regulating the mTOR signaling pathway, hyperalgesia induced by 48-h SR is attributed to neuroinflammation and damages to the barriers, which can be relieved by lactate supplementation.

Abstract Background Chemoimmunotherapy has shown promising advantages of eliciting immunogenic cell death and activating anti-tumor immune responses. However, the systemic toxicity of chemotherapy and tumor immunosuppressive microenvironment limit the clinical application. Methods Here, an injectable sodium alginate hydrogel (ALG) loaded with nanoparticle albumin-bound-paclitaxel (Nab-PTX) and an immunostimulating agent R837 was developed for local administration. Two murine hepatocellular carcinoma and breast cancer models were established. The tumor-bearing mice received the peritumoral injection of R837/Nab-PTX/ALG once a week for two weeks. The antitumor efficacy, the immune response, and the tumor microenvironment were investigated. Results This chemoimmunotherapy hydrogel with sustained-release character was proven to have significant effects on killing tumor cells and inhibiting tumor growth. Peritumoral injection of our hydrogel caused little harm to normal organs and triggered a potent antitumor immune response against both hepatocellular carcinoma and breast cancer. In the tumor microenvironment, enhanced immunogenic cell death induced by the combination of Nab-PTX and R837 resulted in 3.30-fold infiltration of effector memory T cells and upregulation of 20 biological processes related to immune responses. Conclusions Our strategy provides a novel insight into the combination of chemotherapy and immunotherapy and has the potential for clinical translation.

Dolomite formation is a crucial aspect of natural gas reservoirs in the marine strata of the Sichuan Basin, particularly in the exploration of deep carbonate reserved oil and gas resources. Understanding the genetic mechanism of dolomite is essential for predicting the distribution of favorable dolomite reservoirs in deep formations. Taking the third member of the Maokou Formation in the southeastern Sichuan Basin as an example, present work systematically investigates the genetic mechanism of dolomite by analyzing geochemical characteristics such as carbon and oxygen isotopes, strontium isotopes and rare earth elements. The analysis is based on data from outcrops, core samples and thin sections. The results reveal that the dolomites of the third member of the Maokou Formation in the southeastern Sichuan Basin can be categorized into laminated fine-crystalline dolomite, laminated fine to medium-crystalline dolomite, and saddle dolomite cement. Among these, the laminated fine to medium-crystalline dolomite is the most common type. The δ18O values of this dolomite type (-7.04‰ to -6.08‰) appeared unaffected by hydrothermal fluids, and are similar to those of mud-crystal limestone. Additionally, the 87Sr/86Sr ratio (0.707 550 to 0.707 740) locate within the range of contemporaneous seawater, indicating a diagenesis process of quasi-syngenetic to burial-induced restricted marine water infiltration dolomitization. The δ18O values of hydrothermally influenced dolomite range from -7.33‰ to -7.11‰, showing slightly negative compared to those of mud-crystal limestone. These dolomites also showed relatively higher 87Sr/86Sr ratios (0.707 950 to 0.708 171) than those of contemporaneous seawater. The laminated fine-crystalline dolomite, which was not affected by hydrothermal fluids, shares a common genetic mechanism with the previously mentioned laminated fine to medium-crystalline dolomite. Saddle dolomite cement found in caves and fractures is either directly precipitated or recrystallized from hydrothermal fluids. This type of dolomite is characterized by higher 87Sr/86Sr ratios (with a mean value of 0.707 970), significantly negative δ18O values (with a mean value of -7.32‰), and positive Eu anomalies. A gradient change from laminated fine-crystalline dolomite to laminated fine to medium-crystalline dolomite and finally to saddle dolomite cement is observed, controlled by a transition from marine water to hydrothermal fluids. The dolomite in the study area is proposed to be the product of multi-stage fluid-induced diagenesis.

Abstract Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer (LARC) patients with microsatellite stable (MSS) / mismatch repair-proficient (pMMR) tumors is an attractive, but debatable strategy. This phase 2, multicenter, prospective, single-arm study enrolled patients from 6 centers from June 2021 to November 2022. Locally advanced rectal cancer (LARC, cT3-4aN0M0 and cT1-4aN1-2M0) patients aged ≥18 years with the distance from distal border of tumor to anal verge ≤10 cm (identified by Magnetic Resonance Imaging) were qualified for inclusion. The patients received long-course radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week) and three 21-day cycles capecitabine (850–1000 mg/m2, bid, po, day1–14) and three 21-day cycles tislelizumab (200 mg, iv.gtt, day8) as neoadjuvant. Total mesorectal excision (TME) was 6–12 weeks after the end of radiotherapy to achieve radical resection. A total of 50 patients were enrolled in this study. The pathological complete response rate was 40.0% [20/50, 95% confidence interval (CI): 27.61–53.82%], while 15 (30.0%, 95% CI: 19.1–43.75%), 9 (18.0%, 95% CI: 9.77–30.8%), 2 (4.0%, 95% CI: 1.10–13.46%) patients respectively achieved grade 1, 2, and 3 tumor regression. Treatment-related adverse events (TRAEs) occurred in 28 (56.0%) LARC patients, including 26(52.0%) with grade I-II and 2 (4.0%) with grade III (1 with grade 3 immune-related colitis and 1 with grade 3 rash). PD-1 blockade plus long-course chemoradiotherapy (CRT) showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients. A larger randomized controlled study is desired to further validate the above findings.

BackgroundRecent epidemiological studies have indicated a correlation between platelet indices and pulmonary arterial hypertension (PAH), yet the causality between them remains unclear. To explore the causal relationship between four platelet indices and PAH, with the aim of providing a theoretical basis for clinical prevention and treatment.MethodsSingle-nucleotide polymorphisms (SNPs) associated with platelet-related traits were selected as exposure factors from published genome-wide association studies (GWAS), including: platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). Summary-level data for PAH were obtained from the FinnGen study (248 cases and 289,117 controls). Two-sample and multivariable Mendelian randomization (MR) analyses were conducted to assess the causal relationship between exposure factors and the risk of outcomes. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach, supplemented by weighted median, mode-based estimation, MR-Egger regression, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to detect and adjust for pleiotropy, ensuring the reliability of the results through sensitivity analysis.Results(1) The IVW results from the two-sample MR analysis showed a positive causal association between PLT and the risk of developing PAH [(OR = 1.649, 95%CI: 1.206–2.256, P = 0.0017)], with the sensitivity analysis confirming the robustness of the causal relationship. The MR-Egger intercept analysis did not detect potential pleiotropy (P = 0.879). (2) The MVMR results showed no statistically significant causal relationship between these four markers and the risk of developing PAH. After adjusting for collinearity, a direct positive causal association was observed between PLT and the risk of developing PAH (OR = 1.525, 95%CI: 1.063–2.189, P = 0.022).ConclusionThe positive correlation between PLT and the risk of PAH suggests that correcting elevated platelet levels may reduce the risk of developing PAH.

BackgroundBreast cancer, one of the most prevalent malignancies among women worldwide, has rising incidence rates. Physical activity, particularly exercise, has emerged as a significant modifier of cancer prognosis, influencing both tumor biology and patient outcomes.MethodsIn this study, we utilized a murine breast cancer model, dividing mice into a control group and an exercise group; the latter underwent 21 days of voluntary running. We conducted RNA sequencing, bioinformatics analysis, pan-cancer analysis, and cellular experiments to investigate the underlying mechanisms influenced by exercise.ResultsExercise led to a significant reduction in tumor size and weight. Post-exercise mRNA sequencing indicated a notable upregulation of THSD7B in the exercised mice, with significant alterations observed in pathways such as MicroRNAs in cancers and the Calcium signaling pathway. In a broader cancer context, THSD7B showed considerable expression variability, being significantly downregulated in several cancers, correlating with positive prognostic outcomes in PRAD, LAML, KIRC, and GBM and highlighting its potential role as a prognostic marker and therapeutic target. THSD7B expression was also negatively associated with processes of breast cancer cell proliferation, migration, and invasion.ConclusionThis study underscores the dual role of exercise in modulating gene expression relevant to tumor growth and highlights the potential of THSD7B as a therapeutic target in cancer. Future research should further explore the specific mechanisms by which exercise and THSD7B influence cancer progression and develop immunotherapy-enhanced strategies to change patient outcomes in clinical settings.

BackgroundBreast cancer ranks as one of the most prevalent malignancies among women globally, with increasing incidence rates. Physical activity, particularly exercise, has emerged as a potentially significant modifier of cancer prognosis, influencing tumor biology and patient outcomes.MethodsUsing a murine breast cancer model, we established a control and an exercise group, where the latter was subjected to 21 days of voluntary running. RNA Sequencing, bioinformatics analysis, pan-cancer analysis, and cell experiments were performed to validate the underlying mechanisms.ResultsWe observed that exercise significantly reduced tumor size and weight, without notable changes in body weight, suggesting that physical activity can modulate tumor dynamics. mRNA sequencing post-exercise revealed substantial downregulation of CD300E in the exercise group, accompanied by alterations in critical pathways such as MicroRNAs in cancers and the Calcium signaling pathway. Expanding our analysis to a broader cancer spectrum, CD300E demonstrated significant expression variability across multiple cancer types, with pronounced upregulation in myeloma, ovarian, lung, and colorectal cancers. This upregulation was correlated with poorer prognostic outcomes, emphasizing CD300E’s potential role as a prognostic marker and therapeutic target. Moreover, CD300E expression was associated with cancer cell proliferation and apoptosis.ConclusionThe study highlights the dual role of exercise in modulating gene expression relevant to tumor growth and the potential of CD300E as a target in cancer therapeutics. Further research is encouraged to explore the mechanisms by which exercise and CD300E influence cancer progression and to develop targeted strategies that could enhance patient outcomes in clinical settings.

Platinum-based chemotherapy has been widely used for clinical cancer treatment, but drug resistance is the main barrier to induce the poor prognosis of cancer patients. Long non-coding RNAs (lncRNAs) have been recognized as a type of new cancer therapeutic targets due to their important role in regulating cancer progression such as drug resistance. However, it is still challenged to effectively intervene the expression of lncRNAs as they are usually located at various subcellular organelles (e.g., nucleus, mitochondrion, and endoplasmic reticulum). We herein developed an endosomal pH-responsive nanoparticle (NP) platform for small interfering RNA (siRNA) and cisplatin prodrug co-delivery and effective cisplatin-resistant hepatocellular carcinoma (HCC) therapy. This co-delivery nanoplatform is comprised of a hydrophilic polyethylene glycol (PEG) shell and a hydrophobic poly (2-(diisopropylamino)ethyl methacrylate) (PDPA) core, in which cisplatin prodrug and electrostatic complexes of nucleus-targeting amphiphilic peptide (NTPA) and siRNA are encapsulated. After intravenous injection and then uptake by tumor cells, the endosomal pH could trigger the dissociation of nanoplatform and enhance the endosomal escape of loaded cisplatin prodrug and NTPA/siRNA complexes via the “proton sponge” effect. Subsequently, the NTPA/siRNA complexes could specifically transport siRNA into the nucleus and efficiently reverse cisplatin resistance via silencing the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncMALAT1) mainly localized in the nucleus, ultimately inhibiting the growth of cisplatin-resistant HCC tumor.

Summary: Despite the success of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition in tumor therapy, many patients do not benefit. This failure may be attributed to the intrinsic functions of PD-L1. We perform a genome-wide CRISPR synthetic lethality screen to systematically explore the intrinsic functions of PD-L1 in head and neck squamous cell carcinoma (HNSCC) cells, identifying ferroptosis-related genes as essential for the viability of PD-L1-deficient cells. Genetic and pharmacological induction of ferroptosis accelerates cell death in PD-L1 knockout cells, which are also more susceptible to immunogenic ferroptosis. Mechanistically, nuclear PD-L1 transcriptionally activates SOD2 to maintain redox homeostasis. Lower reactive oxygen species (ROS) and ferroptosis are observed in patients with HNSCC who have higher PD-L1 expression. Our study illustrates that PD-L1 confers ferroptosis resistance in HNSCC cells by activating the SOD2-mediated antioxidant pathway, suggesting that targeting the intrinsic functions of PD-L1 could enhance therapeutic efficacy.

Microseismic monitoring is pivotal for mine safety, offering early warnings for coal mining operations. By introducing the MTfit and MSATSI inversion methods to study the focal mechanisms of microseismic events and the stress field in coal mines, we applied these techniques for the first time to the 63upper06 working face in the Dongtan Coal Mine. We selected 107 high-quality microseismic events during the mining process and used MTfit to invert their focal mechanisms. Moreover, we used MSATSI to determine the direction of the maximum horizontal principal compressive stress in the region. This allowed us to establish a connection between mining activities, focal mechanisms, and rock strata fractures. Results show the predominance of normal and reverse faulting with significant CLVD components, underlining tensile and compressive failures as dominant in the mine’s seismicity. Further, the study subdivides the research area into three subregions for detailed stress analysis: Subregion 1 is located below the working face with a maximum principal stress of 20.3 MPa, oriented between N60°E and N75°E; Subregion 2 is above the working face and exhibits more complex stress conditions with a maximum principal stress of 30.1 MPa; and Subregion 3 is situated at the roof’s right side of the working face, with a maximum principal stress of 20.3 MPa, oriented at 30°northwest. It provides an important reference for seismic risk assessment and disaster prevention and control during mining.

Seismic landslide susceptibility evaluation models are usually built on the basis of historical sample data; however, the evaluation results are often unsatisfactory when the environmental settings differ between the historical sample data region and application region. Therefore, similarity between the environmental settings is important for the application of such models. In this paper, a seismic landslide susceptibility evaluation model was first built using data from the 2008 Ms 8.0 Wenchuan earthquake-induced landslide, and the model was then used to evaluate the 2022 Ms 6.8 Luding earthquake area. In addition, the grade of susceptibility is typically represented by the landslide density, which is insufficient for capturing the details of landslides, such as their sizes, frequencies, and spatial distribution patterns. The authors therefore use a large and concentrated landslide as the susceptibility grade for the Luding earthquake area. The test results demonstrate that these two areas have similar background environments. The area under the curve (AUC) value of the receiver operating characteristics (ROC) curve of the evaluation accuracy for the model applied to the Luding earthquake area is 0.889, which indicates relatively high accuracy. Besides, the results also demonstrate that the evaluations are consistent with the disaster situation of the Moxi Platform, Wandong Village, as well as the Dagangshan Hydropower Station area. Therefore, it is reliable to apply the susceptibility evaluation model based on the Wenchuan earthquake data to the Luding earthquake area. These results show that better evaluations can be obtained based on environmental similarity tests between the areas used for historical data modeling and areas to which the models are applied.

The Sichuan basin (SCB) is situated at the southeastern edge of the Tibetan Plateau where widespread seismicity has occurred. In the past decades, seismic events occurred in and around SCB have been responsible for more than 100 thousand casualties. To quantify the present-day seismic hazard of this region, especially the densely populated Chengdu-Chongqing economic zone (CCEZ), we develop a probabilistic earthquake forecast model using strain rates derived from 187 Global Navigation Satellite System (GNSS) horizontal velocities, of which 102 velocity vectors are first released. The second invariant of the strain rate tensor suggests that the Shimian County and its surroundings are exposed to the highest seismic hazard in and around SCB. The second most dangerous area is located between 103–105°E. The Chongqing area is the least dangerous. The principal strain rate axes interior of the Sichuan basin suggest that this region is experiencing broad-scale extension, which according to our knowledge, is first revealed by our dense GNSS network. The comparison between the cumulative histograms of the second invariant of geodetic strain rate and earthquake count indicates that the geodetic strain rates in this region can serve as a reliable predictor of M≥6 earthquake locations. Thus, we proceed to calculate the total seismic moment anticipated for the entire area within the next 30 years.

Introduction: The emergence and application of generative artificial intelligence/large language models (hereafter GenAI LLMs) have the potential for significant impact on the healthcare industry. However, there is currently a lack of systematic research on GenAI LLMs in healthcare based on reliable data. This article aims to conduct an exploratory study of the application of GenAI LLMs (i.e., ChatGPT) in healthcare from the perspective of digital media (i.e., online news), including the application scenarios, potential opportunities, and challenges. Methods: This research used thematic qualitative text analysis in five steps: firstly, developing main topical categories based on relevant articles; secondly, encoding the search keywords using these categories; thirdly, conducting searches for news articles via Google ; fourthly, encoding the sub-categories using the elaborate category system; and finally, conducting category-based analysis and presenting the results. Natural language processing techniques, including the TermRaider and AntConc tool, were applied in the aforementioned steps to assist in text qualitative analysis. Additionally, this study built a framework, using for analyzing the above three topics, from the perspective of five different stakeholders, including healthcare demanders and providers. Results: This study summarizes 26 applications (e.g., provide medical advice, provide diagnosis and triage recommendations, provide mental health support, etc.), 21 opportunities (e.g., make healthcare more accessible, reduce healthcare costs, improve patients care, etc.), and 17 challenges (e.g., generate inaccurate/misleading/wrong answers, raise privacy concerns, lack of transparency, etc.), and analyzes the reasons for the formation of these key items and the links between the three research topics. Conclusions: The application of GenAI LLMs in healthcare is primarily focused on transforming the way healthcare demanders access medical services (i.e., making it more intelligent, refined, and humane) and optimizing the processes through which healthcare providers offer medical services (i.e., simplifying, ensuring timeliness, and reducing errors). As the application becomes more widespread and deepens, GenAI LLMs is expected to have a revolutionary impact on traditional healthcare service models, but it also inevitably raises ethical and security concerns. Furthermore, GenAI LLMs applied in healthcare is still in the initial stage, which can be accelerated from a specific healthcare field (e.g., mental health) or a specific mechanism (e.g., GenAI LLMs’ economic benefits allocation mechanism applied to healthcare) with empirical or clinical research.

As seismology has evolved, scientists have developed various earthquake magnitude scales tailored for specific scenarios, including Richter magnitude (ML) for local, moderate quakes, moment magnitude (Mw) for large-scale seismic events, energy magnitude (Me), which correlates directly with the total energy released, and duration magnitude (MD) for quickly assessing shallow or nearby seismic activities. Despite these advances, these scales were not specifically designed to address the unique challenges posed by mine earthquakes, particularly in coal mine environments where seismic events are typically of lower energy and lower perceptibility but have potentially significant impacts. This study applies the K-class magnitude system for the first time to address significant discrepancies in magnitude values for the same seismic events in mine earthquakes, particularly in coal mines when different formulas are used. However, because current seismic monitoring systems in domestic coal mines continue to employ a variety of magnitude scales, we have developed a corrected Richter scale (MLc) specifically tailored to the geological conditions of coal mines. This adaptation facilitates the conversion to and from the K class, enhancing the accuracy and relevance of seismic assessments in these environments. Therefore, we conducted continuous blasting experiments at the Dongtan Coal Mine and derived the corrected Richter magnitude MLc. Based on data analysis, we fitted the energy attenuation coefficient and compared the K values with four types of traditional magnitude results. Finally, we derived the conversion relationship between the K class and the corrected Richter magnitude MLc, establishing a mine earthquake measurement system. The successful application of the K class in coal mines suggests its potential to be extended to the entire field of induced microseismicity, including mining-induced microseismicity, shale gas extraction-induced microseismicity, and oil extraction-induced microseismicity, providing valuable insights and tools for a broader range of geophysical research and industry practices.

1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer's disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved Aβ1–42-induced paralysis and exhibited remarkable antioxidant and anti-Aβ1–42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-Aβ aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer's disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer's disease.

Traditional CNNs struggle with SAR and optical image fusion cloud removal due to SAR image noise, feature space differences and random cloud distribution. This often leads to blurred results with less texture information. This paper proposes a synergistic convolution-transformer cloud removal method (SCT-CR), which is based on a specially designed synergistic convolution module that enables the synergistic fusion of SAR and optical imagery. The proposed network employs a transformer module in the high-dimensional section to better perceive the contextual information of the image and achieve intelligent extraction of global image features. The proposed SCT-CR network successfully addresses the problem of image blur in generated images and makes full use of the texture information present in SAR images. The SCT-CR model is tested on the spectral properties and recovery of visual effects. The experimental results on public datasets SEN12MS-CR and LuojiaSET-OSFCR show that the proposed model has stable and optimal performance. On the SEN12MS-CR dataset, the proposed model improves the SSIM metrics by 15.7 %, 10.2 %, 4.9 %, and 0.5 % compared to the SAR2OPT, SarOptcAGN, DSen2-CR, and GLF-CR models, respectively. On the LuojiaSET-OSFCR dataset, it was improved by 20.0 %, 10.0 %, 6.6 %, and 1.9 %, respectively.

Abstract Background This study aimed to assess the clinical application of the Artery Occlusion Image Score (AOIS), a new metric based on computed tomographic angiography (CTA) that reflects the severity of occlusive changes in the main intracranial arteries. Materials and Methods Patients diagnosed with acute ischemic stroke (AIS) were divided into three groups: anterior circulation infarcts (ACI group), posterior circulation infarcts (PCI group), and both anterior and posterior circulation infarcts (ACI + PCI group). The sensitivity and specificity of AOIS were evaluated using the Basilar Artery on Computed Tomography Angiography (BATMAN) score, the Clot Burden Score (CBS), and the National Institutes of Health Stroke Scale (NIHSS) as comparators through receiver-operating characteristic (ROC) curve analysis. Results The final analysis included 439 consecutive patients. In the ACI group, AOIS demonstrated high sensitivity (86.3%) and specificity (85.0%) and outperformed CBS in predicting patient prognosis. In the PCI group, AOIS also showed high sensitivity (88.9%) and specificity (90.0%) and outperformed BATMAN in predicting patient prognosis. In the ACI + PCI group, AOIS positively correlated with the NIHSS score (Spearman’s ρ = 0.602, P

Automatic test paper design is critical in education to reduce workloads for educators and facilitate an efficient teaching process. However, current designs fail to satisfy the realistic teaching requirements of educators, including the consideration of both test quality and efficiency. This is the main reason why teachers still manually construct tests in most teaching environments. In this paper, the quality of tests is quantitatively defined while considering multiple objectives, including a flexible coverage of knowledge points, cognitive levels, and question difficulty. Then, a model based on the technique of linear programming is delicately designed to explore the optimal results for this newly defined problem. However, this technique is not efficient enough, which cannot obtain results in polynomial time. With the consideration of both test quality and generation efficiency, this paper proposes a genetic algorithm (GA) based method, named dynamic programming guided genetic algorithm with adaptive selection (DPGA-AS). In this method, a dynamic programming method is proposed in the population initialization part to improve the efficiency of the genetic algorithm. An adaptive selection method for the GA is designed to avoid prematurely falling into the local optimal for better test quality. The question bank used in our experiments is assembled based on college-level calculus questions from well-known textbooks. The experimental results show that the proposed techniques can construct test papers with both high effectiveness and efficiency. The computation time of the test assembly problem is reduced from 3 hours to 2 seconds for a 5000-size question bank as compared to a linear programming model with similar test quality. The test quality of the proposed method is better than the other baselines.

Abstract Airway mucous cell metaplasia and mucous hypersecretion is one of the key characteristic pathophysiological status of chronic obstructive pulmonary disease (COPD). micro(mi)RNAs are acknowledged as non‐encoding RNA molecules playing important roles in gene expression regulation. In this study, we searched the Gene Expression Omnibus (GEO) database for the differentially expressed miRNAs between COPD and non‐COPD controls with bioinformatics analysis. Finally, we focused on miR‐513a‐5p and investigated the potential mechanism by which miR‐513a‐5p regulates airway mucous hypersecretion and goblet cell metaplasia. A dual‐luciferase reporter assay was then showing that miR‐513a‐5p targeted the 3′‐UTR of TFR1 and inhibited its expression in vitro. In vivo transfection demonstrated that TFR1 downregulation partially blocked MUC5AC hypersecretion and goblet cell hyperplasia in COPD model rats. In vitro study, CSE increased the intracellular expression and secretion of MUC5AC by BEAS‐2B branchial epithelial cells in the BEAS‐2B cell and THP‐1 cell coculture system. Coculture with either miR‐513a‐5p mimic‐pretreated or TFR1‐deficient THP‐1 cells attenuated intracellular MUC5AC expression in BEAS‐2B cells exposed to CSE. ELISA demonstrated that transfection of TFR1 siRNA or pretreatment with miR‐513a‐5p mimic reduced the secretion of inflammatory factors that are responsible for airway goblet cell hyperplasia, such as IL‐1β, IL‐13, and IL‐17, by THP‐1 cells after CSE stimulation. Our findings supported that miR‐513a‐5p/TFR1 signaling axis might activate macrophages as well as promote airway inflammation and airway mucous cell hyperplasia in COPD.

Recently, hyperbolic media (HM) has attracted considerable interest due to their open isofrequency contour (IFC) and high-k modes, while their numerical computational methods in infinite space are challenging. Although the uniaxial perfectly matched layer (UPML) has been successfully utilized, its failure in absorbing electromagnetic waves with HM has been shown in recent research. In this work, the reason for the failure is thoroughly analyzed, and an improved UPML is proposed based on the frequency domain finite element method (FEM) to truncate the unbound hyperbolic computational domain. Finally, the excellent absorption effect of the improved UPML is verified by representative examples such as an infinite HM, a linear-crossing metamaterial, and a Bessel beam.

With the continuous evolution of novel network attacks, traditional Intrusion Detection Systems (IDSs) have commonly employed Deep Neural Networks (DNNs) for intrusion detection. However, the effectiveness of a DNN in this respect is closely related to the quality of the training data set, and large-scale network traffic data are difficult to label accurately. Therefore, some challenges still need to be addressed to detect network attacks. In this paper, we introduce a Time-Space Separable Attention Network (TSSAN) for intrusion detection. TSSAN utilizes depth wise separable convolution and a time-space self-attention mechanism to effectively extract temporal and spatial features. By extracting the common features from the unlabeled data, TSSAN significantly enhanced the detection performance for rare attack types. Experimental evaluations were conducted using UNSW-NB15 and CICIDS-2017 datasets. Meticulous experiments for evaluating the individual components of the model were rigorously carried out using the CICIDS-2017 dataset. In the unsupervised learning experiment, our method achieved 0.86 and 0.92 f1score in the two datasets. In semi-supervised learning, the experiment showed that our method performed significantly better than the traditional deep learning method when the labelled data were gradually reduced.

Objective The red-bed soft rocks is easy to disintegrate and weaken its strength when it encounters water, which is easy to cause poor stability and economic loss or even casualties in slope construction. It is of great significance to reveal the variation characteristics of cohesion and internal friction angle of red-bed soft rocks under the action of dry and wet cycling for the design of slope treatment measures. Methods Investigating the three groups of red-bed soft rock formations within the Lower Cretaceous Chaochuan Formation situated in the Shengzhou-Xinchang region of Zhejiang Province, this study delves into the disintegration and strength attention tendencies inherent in these formations. This exploration unfolds through a comprehensive suite of method ologies, including dry-wet cycle tests, point load strength tests of disintegrated rock blocks and direct shear tests of disintegrated particles. Results The results reveal that the sample undergoes disintegrates, in the form of fragments, particle slag, and mud paste due to successive dry-wet cycles. The main disintegration process can be divided into four distinct stages: Initial disintegration, rapid disintegration, fine reconfiguration, and eventual stabilization. The point load strength of the sample decreases with the increase as the number of dry-wet cycles increases, while the disintegration resistance index Idn shows a positive exponential relationship with the point load strength Is(50). Notably, the point load strength Is(50) of the sample experiences rapid weakening between 80% to 100% and 50% to 80% of the disintegration resistance index Idn, demonstrating gradual attenuation characteristics. The peak shear strength of the sample ranges between 1.219 MPa and 0.567 MPa, which mostly occurs before and after the shear displacement of 3 mm. Under the consistent axial pressure, the peak shear strength of the same group decreases with an increasing number of cycles. Additionally, the internal friction angle of disintegrated particles of the sample ranges from 22.28° to 33.03°, while the cohesion is between 0.46 MPa and 0.74 MPa. Both the friction angle and cohesion of the sample show a negative exponential relationship with the number of dry-wet cycles. Conclusion The test results indicate that siliceous cementation exhibits better disintegration resistance compared to argillaceous cementation, and the rock with high clay minerals more easily disintegrates. Additionally, the water absorption and expansion capacity of "white mineral" albite significantly lag behind that of clay minerals, with a lesser variance in its content compared to clay minerals.

Abstract 5-methylcytosine (m5C) is a post-transcriptional RNA modification identified, m5C readers can specifically identify and bind to m5C. ALYREF and YBX1 as members of m5C readers that have garnered increasing attention in cancer research. However, comprehensive analysis of their molecular functions across pancancer are lacking. Using the TCGA and GTEx databases, we investigated the expression levels and prognostic values of ALYREF and YBX1. Additionally, we assessed the tumor microenvironment, immune checkpoint-related genes, immunomodulators, Tumor Immune Dysfunction and Exclusion (TIDE) score and drug resistance of ALYREF and YBX1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses were performed to investigate the potential functions associated with m5C readers and coexpressed genes. Aberrant expression of ALYREF and YBX1 was observed and positively associated with prognosis in KIRP, LGG and LIHC. Furthermore, the expression levels of ALYREF and YBX1 were significantly correlated with immune infiltration of the tumor microenvironment and immune-related modulators. Last, our analysis revealed significant correlations between ALYREF, YBX1 and eIFs. Our study provides a substantial understanding of m5C readers and the intricate relationship between ALYREF, YBX1, eIFs, and mRNA dynamics. Through multidimensional analysis of immune infiltration and drug sensitivity/resistance in ALYREF and YBX1, we propose a possibility for combined modality therapy utilizing m5C readers.

Abstract Cryptosporidium parvum is an obligate intracellular parasite with a highly reduced mitochondrion that lacks the tricarboxylic acid cycle and the ability to generate ATP, making the parasite reliant on glycolysis. Genetic ablation experiments demonstrated that neither of the two putative glucose transporters CpGT1 and CpGT2 were essential for growth. Surprisingly, hexokinase was also dispensable for parasite growth while the downstream enzyme aldolase was required, suggesting the parasite has an alternative way of obtaining phosphorylated hexose. Complementation studies in E. coli support a role for direct transport of glucose-6-phosphate from the host cell by the parasite transporters CpGT1 and CpGT2, thus bypassing a requirement for hexokinase. Additionally, the parasite obtains phosphorylated glucose from amylopectin stores that are released by the action of the essential enzyme glycogen phosphorylase. Collectively, these findings reveal that C. parvum relies on multiple pathways to obtain phosphorylated glucose both for glycolysis and to restore carbohydrate reserves.

Extracting building from high-resolution (HR) remote sensing imagery (RSI) serves a variety of areas, such as smart city, environment management, and emergency disaster services. Previous building extraction methods primarily focus on pixel-level and superpixel-level features, which do not fully utilize the superpixel-level spatial context, leaving room for performance improvement. To bridge the gap, this study incorporates spatial context of both pixels and superpixels for building extraction of HR RSI. Specifically, the proposed method develops a trainable superpixel segmentation module to segment HR RSI into superpixels by fusing pixel features and pixel-level context. And a superpixel-level context aggregation module is devised to incorporate the multiple-scale spatial context of superpixels to extract buildings. Experiments on public challenging datasets show that our method is superior to the state-of-the-art baselines in accuracy, with better building boundaries and higher integrity. This study explores a new approach for HR RSI building extraction by introducing spatial context of superpixels, and a methodological reference for the HR RSI interpretation tasks.

Lithium metal anode (LMA) is a promising candidate for achieving next-generation high-energy-density batteries due to its ultrahigh theoretical capacity and most negative electrochemical potential. However, the practical application of lithium metal battery (LMB) is largely retarded by the instable interfaces, uncontrolled dendrites, and rapid capacity deterioration. Herein, we present a comprehensive overview towards the working principles and inherent challenges of LMAs. Firstly, we diligently summarize the intrinsic mechanism of Li stripping and plating process. The recent advances in atomic and mesoscale simulations which are crucial in guiding mechanism study and material design are also summarized. Furthermore, the advanced engineering strategies which have been proved effective in protecting LMAs are systematically reviewed, including electrolyte optimization, artificial interface, composite/alloy anodes and so on. Finally, we highlight the current limitations and promising research directions of LMAs. This review sheds new lights on deeply understanding the intrinsic mechanism of LMAs, and calls for more endeavors to realize practical Li metal batteries.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

Seven different substrates were prepared by mixing red soil, humus and river sand in different volume ratios and the growth and yield of Amorphophallus muelleri bulbils in different substrates was investigated. The growth of A. muelleri seedlings were tracked during the reproductive period, with measurements taken of indicators such as petiole length, petiole basal diameter and leaf size during the late period of leaf expansion. Number of surviving plants, weights and sizes of corms, and leaf bulbils were recorded after lodging. The results showed that there were differences in the physical and chemical properties of the seven substrates, but all met the growth requirements of A. muelleri. T1 (river sand), T2 (river sand: humus 1:1), T3 (humus), and T7 (river sand: humus: red soil 1:1:1) had higher emergence rates, reaching 95 %. T4 (humus: red soil 1:1) and T7 had better growth, with larger petiole and leaf sizes than other substrates. T3, T4, and T7 had higher yields, with a bulbil yield of 0.30 t hm−2 and a corm yield of 22.06 t hm−2. Compared to the use of a single substrate, whether river sand, humus, or red soil, the proportional mixture of the three test materials improved the physical structure and chemical composition of the substrate, contributing to the growth of A. muelleri. T7 (river sand: humus: red soil 1:1:1) was was found to be the best nursery substrate for A. muelleri.

Abstract Aims The adverse effects of sedentary behavior on obesity and chronic diseases are well established. However, the prevalence of sedentary behavior has increased, with only a minority of individuals meeting the recommended physical activity guidelines. This study aimed to investigate whether habitual leg shaking, a behavior traditionally considered unfavorable, could serve as an effective strategy to improve energy metabolism. Materials and Methods A randomized crossover study was conducted, involving 15 participants (mean [SD] age, 25.4 [3.6]; mean [SD] body mass index, 22 [3]; 7 women [46.7%]). The study design involved a randomized sequence of sitting and leg shaking conditions, with each condition lasting for 20 min. Energy expenditure, respiratory rate, oxygen saturation, and other relevant variables were measured during each condition. Results Compared to sitting, leg shaking significantly increased total energy expenditure [1.088 kj/min, 95% confidence interval, 0.69–1.487 kj/min], primarily through elevated carbohydrate oxidation. The average metabolic equivalent during leg shaking exhibited a significant increase from 1.5 to 1.8. Leg shaking also raised respiratory rate, minute ventilation, and blood oxygen saturation levels, while having no obvious impact on heart rate or blood pressure. Electromyography data confirmed predominant activation of lower leg muscles and without increased muscle fatigue. Intriguingly, a significant correlation was observed between the increased energy expenditure and both the frequency of leg shaking and the muscle mass of the legs. Conclusions Our study provides evidence that habitual leg shaking can boost overall energy expenditure by approximately 16.3%. This simple and feasible approach offers a convenient way to enhance physical activity levels.

[This corrects the article DOI: 10.1371/journal.ppat.1008437.].

ObjectiveThe aims of this survey were to investigate the public awareness of drug clinical trials (DCTs) and willingness to participate the DCTs, and provide references for propaganda and science popularization of DCTs.MethodsA self-designed questionnaire named “an online survey questionnaire on public awareness of DCTs” was used to conduct an online survey from January to March 2022. The demographic characteristics and the response of participants to the awareness and willingness to participate the DCTs were collected. The factors affecting the public awareness of DCTs were analyzed by single factor and binary logistic regression analysis.ResultsOne thousand three hundred eighty valid questionnaires were collected, and the respondents’ awareness rate of DCTs was 61.1%. Thirteen demographic characteristics including age, gender, education, occupation, work fields, household type, marital status, city type, income, medical insurance, medical expenditure, pressure to seek medical care, financial pressure, both significantly affected the qualified rate of participants’ awareness of DCTs (p

The recycling of industrial solid by-products such as red mud (RM) has become an urgent priority, due to their large quantities and lack of reutilization methods can lead to resource wastage. In this work, RM was employed to fabricate green hydrochar (HC) to prepare zero-valent iron (ZVI) modified carbonous materials, and conventional iron salts (IS, FeCl3) was applied as comparison, fabricated HC labeled as RM/HC and IS/HC, respectively. The physicochemical properties of these HC were comprehensively characterized. Further, hexavalent chromium (Cr(VI)) removal performance was assessed (375.66 and 337.19 mg/g for RM/HC and IS/HC, respectively). The influence of dosage and initial pH were evaluated, while isotherms, kinetics, and thermodynamics analysis were also conducted, to mimic the surface interactions. The stability and recyclability of adsorbents also verified, while the practical feasibility was assessed by bok choy-planting experiment. This work revealed that RM can be used as a high value and green fabricant for HC the effective removal of chromium contaminants from the wastewater.

IntroductionThe single and combined association between brominated flame retardants (BFRs) and cardiovascular diseases (CVD) has remained unelucidated. This research aimed at exploring the associations between mixture of BFRs and CVD.MethodsThis research encompassed adult participants from the National Health and Nutrition Examination Survey in 2005–2016. The weighted quantile sum (WQS) model and quantile g-computation (QGC) model were applied to examine the combined effects of BFRs mixture on CVD.ResultsIn this research, overall 7,032 individuals were included. In comparison with the lowest quartile, the highest quartile of PBB153 showed a positive association with CVD, with odds ratio (OR) values and 95% confidence intervals (CI) of 19.2 (10.9, 34.0). Furthermore, the acquired data indicated that PBB153 (OR: 1.23; 95% CI: 1.02, 1.49), PBB99 (OR: 1.29; 95% CI: 1.06, 1.58), and PBB154 (OR: 1.29; 95% CI: 1.02, 1.63) were linked to congestive heart failure. PBB153 was also related to coronary heart disease (OR: 1.29; 95% CI: 1.06, 1.56). Additionally, a positive correlation between the BFRs mixture and CVD (positive model: OR: 1.23; 95% CI: 1.03, 1.47) was observed in the weighted quantile sum (WQS) model and the quantile g-computation (QGC) model.DiscussionTherefore, exposure to BFRs has been observed to heighten the risk of cardiovascular disease in US adults, particularly in the case of PBB153. Further investigation is warranted through a large-scale cohort study to validate and strengthen these findings.

ObjectiveTo establish a radiomics model based on intratumoral and peritumoral features extracted from pre-treatment CT to predict the major pathological response (MPR) in patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant immunochemotherapy.MethodsA total of 148 NSCLC patients who underwent neoadjuvant immunochemotherapy from two centers (SRRSH and ZCH) were retrospectively included. The SRRSH dataset (n=105) was used as the training and internal validation cohort. Radiomics features of intratumoral (T) and peritumoral regions (P1 = 0-5mm, P2 = 5-10mm, and P3 = 10-15mm) were extracted from pre-treatment CT. Intra- and inter- class correlation coefficients and least absolute shrinkage and selection operator were used to feature selection. Four single ROI models mentioned above and a combined radiomics (CR: T+P1+P2+P3) model were established by using machine learning algorithms. Clinical factors were selected to construct the combined radiomics-clinical (CRC) model, which was validated in the external center ZCH (n=43). The performance of the models was assessed by DeLong test, calibration curve and decision curve analysis.ResultsHistopathological type was the only independent clinical risk factor. The model CR with eight selected radiomics features demonstrated a good predictive performance in the internal validation (AUC=0.810) and significantly improved than the model T (AUC=0.810 vs 0.619, p

IntroductionMatrine (MT) is a potential resistance reversal agent. However, it remains unclear whether MT can reverse the resistance of Haemophilus parasuis (H. parasuis) to β-lactams, and, if so, by what mechanism MT works.MethodsWe screened one cefaclor (CEC)-resistant strain (clinical strain C7) from eight clinical (H. parasuis) strains and determined the underlying resistance mechanism. Then, we investigated the reversal effect of MTon the resistance of this strain to CEC.Results and DiscussionThe production of β-lactamase, overexpression of AcrAB-TolC system, and formation of biofilm might not be responsible for the resistance of clinical strain C7 to CEC. Fourteen mutation sites were found in four PBP genes (ftsI, pbp1B, mrcA, and prcS) of clinical strain C7, among which the mutation sites located in ftsI (Y103D and L517R) and mrcA (A639V) genes triggered the resistance to CEC. The minimum inhibitory concentration (MIC) of CEC against clinical strain C7 was reduced by two to eight folds after MT treatment, accompanied by the significant down-regulated expression of mutated ftsI and mrcA genes. Based on such results, we believed that MT could reverse the resistance of H. parasuis to CEC by inhibiting the mutations in ftsI and mrcA genes. Our research would provide useful information for restoring the antimicrobial activity of β-lactams and improving the therapeutic efficacy of Glässer’s disease.