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Abstract Bladder cancer (BLCA) is a prevalent cancer with high case‐fatality rates and a substantial economic burden worldwide. Understanding its molecular underpinnings to guide clinical management is crucial. Ferroptosis, a recently described non‐apoptotic form of cell death, is initiated by the lethal accumulation of iron‐dependent lipid peroxidation products. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in BLCA remain unclear. Re‐analysis of single‐cell RNA data reveals a decrease in high‐ferroptosis cancer cells as BLCA advances. USP52/PAN2 is identified as a key regulator of ferroptosis in BLCA through an unbiased siRNA screen targeting 96 deubiquitylases (DUBs). Functionally, USP52 depletion impedes glutathione (GSH) synthesis by promoting xCT protein degradation, increasing lipid peroxidation and ferroptosis susceptibility, thus suppressing BLCA progression. Mechanistically, USP52 interacts with xCT and enzymatically cleaves the K48‐conjugated ubiquitin chains at K4 and K12, enhancing its protein stability. Clinical BLCA samples demonstrate a positive correlation between USP52 and xCT expression, with high USP52 levels associated with aggressive disease progression and poor prognosis. In vivo, USP52 depletion combined with ferroptosis triggers imidazole ketone Erastin (IKE) synergistically restrains BLCA progression by inducing ferroptosis. These findings elucidate the role of the USP52‐xCT axis in BLCA and highlight the therapeutic potential of targeting USP52 and ferroptosis inducers in BLCA.

IntroductionThis study presents a systematic literature review of career interventions for high school students, exploring the theoretical framework, intervention modality, evaluation and outcomes of the intervention.MethodsFive keywords, three databases and five inclusion criteria were defined. Of the 419 documents collected, 25 remained for meta-synthesis.ResultsThe results showed that (1) the theoretical framework mainly consisted of career construct theory, social cognitive career theory, and cognitive information processing theory. (2) The intervention modality was mainly group counseling (8 sessions, 45 min). (3) The evaluation system mainly consisted of a pre-and post-test for the experimental and control group, and (4) the intervention outcomes were mainly focused on the positive development of career adaptability and career decision-making.DiscussionThe discussion offers recommendations for future research and practice in high school career interventions. (1) Social cognitive career theory should be given attention. (2) A three-tiered high school career development guidance model of career curriculum, career group counseling and individual counseling could be developed. (3) Career interventions should be shifted to mixed quantitative and qualitative studies, tracer studies, and special groups. (4) Outcome expectations should be given equal attention.

Objectives: To explore the feasibility of different radiomics models for predicting the malignant potential of small intestinal stromal tumors (SISTs), and to select the best radiomics model. Methods: A retrospective analysis of 140 patients with SISTs was conducted. Radiomics features were extracted from CT-enhanced images. Support vector machine (SVM), Decision tree (DT), Conditional inference trees (CIT), Random Forest (RF), K-nearest neighbors (KNN), Back-propagation neural network (BPNet), and Bayes were used to construct different radiomics models. The clinical data and CT performance were selected using univariate analysis and to construct clinical model. Nomogram model was developed by combining clinical data and radiomics features. Model performances were assessed by using the area under the receiver operator characteristic (ROC) curve (AUC). The models’ clinical values were assessed by decision curve analysis (DCA). Results: A total of 1132 radiomics features were extracted. Among radiomics models, SVM was better than DT, CIT, RF, KNN, BPNet, Bayes because it had the highest AUC with a significant difference (P

Lack of biopsies after treatment, especially in solid tumors, restricts the understanding of chimeric antigen receptor (CAR)-T cells -related characteristic in vivo, thus hindering the development of strategies to improve CAR-T cells efficacy. Here, we applied nineteen individual single-cell RNA sequencing (scRNA-seq) data from clinical samples of digestive cancers to explore the characteristics of tumor-infiltrating T cells (TILs) to identify effective targets which might be benefit for enhancing the function of CAR-T cells. The data showed that natural killer cell granule protein 7 (NKG7) was overexpressed in TILs and positively associated with anti-PD1 or anti-CTLA4 therapy in digestive cancers. Subsequently, we found that ectopic expression of NKG7 significantly improved the cytotoxicity of B7H3-targeting CAR-T cells to B7H3-positive digestive cancer cells (MKN45, Huh7, HuCCT-1, SW620 and PANC-1 cells), as well as promoted the TNF-α and IL-2 expression. Furthermore, in a CD19-targeting CAR-T model, the therapeutic efficacy was also found increased after NKG7 overexpression. Mechanically, NKG7 preserved surface CAR expression and promoted CAR-T cell proliferation after exposing to relative tumor antigen. These results indicated that it may be feasible to explore single-cell sequencing data of clinical tumor samples to find strategies to improve CAR-T function, and that ectopic expression of NKG7 is an effective strategy to improve the therapeutic efficacy of CAR-T cells against tumors.

The poor soil structure caused by salinization is a major factor affecting crop growth and soil structure will further affect hydrological function. Biochar is widely used to improve soil physical structure because of its special porous material. However, the mechanism of soil pore structure on hydrological function (e.g., soil saturated hydraulic conductivity, plant available water, least limiting water range) after biochar incorporation in saline soil remains unclear. Therefore, the present study examined the response of soil structural properties of different biochar addition in saline clay loam, and subsequently assessed how the pore structure influence soil hydrological function. The study involved four treatments: CK (Control)、C1 (7.5 t ha−1 biochar)、C2 (15 t ha−1 biochar)、C3 (30 t ha−1 biochar). Soil aggregate stability increased from 15 % to 30 % when the amount of biochar addition increased from 7.5 t ha−1 to 30 t ha−1. The highest connectivity index (2.36) and the highest fractal dimension (2.56) were found at the biochar addition of 30 t ha−1. Biochar addition reduced the proportion of small pores (300 µm pore size). Biochar amendment reduced the soil penetration resistance, with the soil saturated hydraulic conductivity, plant available water and the least limiting water range were measured 46 %, 27 % and 40 % greater in rate of 30 t ha−1 biochar addition as compared with those of the CK, respectively. Pearson’s correlation analysis and redundancy analysis revealed that the soil saturated hydraulic conductivity was positively correlated with large pores (diameter >300 μm) and pore connectivity (p < 0.05). The lowest least limiting water range of the CK was primarily constrained by a relatively higher penetration resistance. The improved pore connectivity and elongated pore structures were the key responsible for the reduced penetration resistance in biochar-amended soil, which subsequently increased the least limiting water range. These quantitative estimates highlight the positive effects of biochar amendment-induced soil pore structure alternations towards improving soil hydrological functionalities. These findings are essential for devising effective strategies to enhance sustainable agriculture in saline soils.

Purpose This retrospective, single-center, case-control study evaluated the safety and efficacy of Computed tomography (CT)-guided microwave ablation (MWA) for pulmonary nodules located in the right middle lobe (RML), a challenging location associated with a high frequency of complications.Methods Between May 2020 and April 2022, 71 patients with 71 RML pulmonary nodules underwent 71 MWA sessions. To comparison, 142 patients with 142 pulmonary nodules in non-RML were selected using propensity score matching. The technical success, technique efficacy, complications, and associated factors were analyzed. The duration of the procedure and post-ablation hospital stay were also recorded.Results Technical success was achieved in 100% of all patients. There were no significant differences in technique efficacy rates between the RML and non-RML groups (97.2% vs. 95.1%, p = 0.721). However, both major (47.9% vs. 19.7%, p

Influenza D virus (IDV) plays an important role in the bovine respiratory disease (BRD) complex. Its potential for the zoonotic transmission is of particular concern. In China, IDV has previously been identified in agricultural animals by molecular surveys with no live virus isolates reported. In this study, live IDVs were successfully isolated from cattle in China, which prompted us to further investigate the national prevalence, antigenic property, and infection biology of the virus. IDV RNA was detected in 11.1% (51/460) of cattle throughout the country in 2022–2023. Moreover, we conducted the first IDV serosurveillance in China, revealing a high seroprevalence (91.4%, 393/430) of IDV in cattle during the 2022–2023 winter season. Notably, all the 16 provinces from which cattle originated possessed seropositive animals, and 3 of them displayed the 100% IDV-seropositivity rate. In contrast, a very low seroprevalence of IDV was observed in pigs (3%, 3/100) and goats (1%, 1/100) during the same period of investigation. Furthermore, besides D/Yama2019 lineage-like IDVs, we discovered the D/660 lineage-like IDV in Chinese cattle, which has not been detected to date in Asia. Finally, the Chinese IDVs replicated robustly in diverse cell lines but less efficiently in the swine cell line. Considering the nationwide distribution, high seroprevalence, and appreciably genetic diversity, further studies are required to fully evaluate the risk of Chinese IDVs for both animal and human health in China, which can be evidently facilitated by IDV isolates reported in this study.

ABSTRACTIn contrast to traditional intermetallics that are difficult to process and prone to cracking during additive manufacturing, our work demonstrates the successful fabrication of crack-free, high-performance CCIMAs via electron beam powder bed fusion (EBPBF). The microstructures of CCIMAs (NiCoFeAlTiB) fabricated by EBPBF are remarkably complex, exhibiting a multiphase composition where the disordered FCC phase forms the matrix interleaved with L12-ordered intermetallic phase. The unique combination of ordered lattices and high-entropy disordered phases, tuned by optimised EBPBF processing, imparts exceptional mechanical properties with a high tensile strength (∼1 GPa) and a sufficient ductility (∼11%). It is found that additional minor HCP and L21 precipitates can also effectively slow down and block the crack extension. This work demonstrates a pathway for crack-free fabrication of CCIMAs with tailored microstructures using EBPBF which may provide new insights and manufacturing strategies to unlock the potential of these advanced intermetallic alloys.

The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz (EFV)/nevirapine (NVP) for first-line ART. In this study, we assessed the prevalence of PDR among PLWH in Shanghai, China during 2017–2021, and to reveal PDR transmission between Shanghai and other regions of China. A total of 5050 PLWH not on ART during 2017–2021 were included. Partial HIV-1 pol sequences were amplified, sequenced, and analysed for drug-resistance mutations (DRMs). Besides, transmission network of PDR variants was inferred using HIV-TRACE. The overall prevalence of PDR was 4.8% (242/5050; 95% CI, 4.2–5.4). Prevalence of NNRTI-associated PDR was 3.9% (95% CI, 3.4–4.5), higher than those of NRTI-associated (0.8%; 95% CI, 0.5–1.1) and PI-associated PDR (0.9%; 95% CI, 0.6–1.2). High prevalence of PDR (especially high-level resistance) to EFV (132/5050, 2.6%) and NVP (137/5050, 2.7%) were found. CRF01_AE (46.0%) was the predominant HIV-1 genotype with any DRMs, followed by CRF55_01B (21.0%), and CRF07_BC (15.1%). Two NRTI-associated (S68G/N/R and T215A/N/S/Y), five NNRTI-associated (V179D/E/T/L, K103N/R/S/T, E138A/G/K, V106M/I/A and Y181C/I) and two PI-associated mutations (M46I/L/V and Q58E) were the most common observed DRMs in PDR patients in Shanghai. The vast majority of S68G occurred in CRF01_AE (45%). M46I/L/V and Q58E showed a relatively high prevalence in CRF01_AE (4.1%) and CRF07_BC (12.6%). Transmission network analyses demonstrated cross-regional transmission links of PDR variants between Shanghai and other regions of China, which was mainly driven by the potential low-level DRM V179D/E. These results provide crucial information for clinical decision making of first-line ART in PLWH with PDR.

Immunotherapy is a promising strategy for nasopharyngeal carcinoma (NPC), a common and aggressive malignancy with poor prognosis. However, the literature lacks a comprehensive and objective overview of the current research status and trends of immunotherapy-related fields in NPC. We performed a bibliometric analysis of 513 original articles and reviews in English on immunotherapy for NPC from the Web of Science Core Collection database, using CiteSpace and Bibliometrix software tools. We visualized the development trend of publications, the distribution of countries/regions, the co-occurrence of keywords, the collaboration and citation of authors, the citation of journals, the evolution of topics, and the thematic map. We found that the publication volume increased sharply after 2017, with China as the main contributor and leader, the US as an important partner, and the Netherlands as a potential innovator. The research focused on immune checkpoint inhibitors and cell therapy, which were also the hotspots of clinical trials. Tumor microenvironment, immune infiltration, multicenter studies, and novel immunotherapy were the frontier topics and the key challenges for future research. CD137l-DC, lymphoma, and chimeric antigen receptor were emerging topics with good prospects. Our study provides a valuable insight into the research status and trends of immunotherapy for NPC, which may guide future research directions and clinical applications.

Phase transformation is a crucial factor that determines the quality and deformation of components in laser-directed energy deposition (L-DED). Owing to the limitations of in situ observation methods, there is a lack of effective means to study the complete phase transformation and their impacts on deformation during the deposition process. In this study, multilayer heterogeneous deposition was investigated with the high-carbon high-speed steel by modelling the coupled phase transformation-thermomechanical physics. The methodology was proposed to identify the specific phase transformations by iteratively comparing the whole deformation history between digital image correlation (DIC) measurements and simulations. Besides the thermo-mechanical coupling effect and basic volumetric phase transformation, carbon partitioning between precipitated carbides and matrix was manifested, which also resulted in a rise of the Ms point by 208.4 °C and a reduction of the transformation rate by 73.2%. Additionally, an increase of 13.8% in energy absorption could be attributed to the surface oxidation of the deposited layer. The model predictions exhibited good consistency with the DIC in-situ measurement data, indicating that the deformation history contained sufficient information on the phase transformations. Based on the proposed transformation-thermomechanical coupling model, it helps to understand the complete phase transformation during deposition.

Erythropoietin-producing hepatocyte receptor A2 (EphA2) is an attractive target for immunotherapy due to its high expression in a variety of solid tumors including prostate cancer. Among various types of immunotherapeutics, chimeric antigen receptor T (CAR-T) cell therapy has made promising progress in hematological and solid tumors. Here, we detected the expression of EphA2 in prostate cancer cells and developed a second-generation CAR targeting EphA2 with CD28 as a co-stimulatory receptor to explore its tumor suppressive potential for prostate cancer in vitro and in vivo. EphA2 was highly expressed on the surface of PC3 and DU145 cells. EphA2 CART cells effectively inhibited prostate cancer growth in an antigen-dependent manner in vitro and in vivo. In addition, tumor cells could stimulate the proliferation of CAR-T cells and the release of cytokine IFN-γ in vitro. These findings shed light on EphA2 as a potential target for prostate cancer, promising EphA2 specific CAR-T cells for the treatment of prostate cancer.

Background: Sepsis is a disease associated with high morbidity and mortality rates, especially among the elderly and patients in intensive care units. Disulfidptosis, a newly identified form of cell death triggered by disulfide stress, is emerging as a significant factor in disease progression. This study aimed to explore the diagnostic and prognostic value of disulfidptosis-related genes in sepsis. Methods: We obtained two datasets from the Gene Expression Omnibus (GEO) database to conduct our analysis. Functional enrichment analysis was performed to identify relevant biological pathways. A protein-protein interaction network was constructed to identify hub genes critical to sepsis. Additionally, we analyzed the immune infiltration status in sepsis patients. The diagnostic value of these hub genes for sepsis was evaluated using nomograms, receiver operating characteristic (ROC) curves, and calibration curves in both training and validation datasets. Finally, a miRNA-immune-related hub genes (miRNA-IHGs) regulatory network was developed to elucidate the synergistic interactions between miRNAs and their target genes. Results: A total of 3,469 differentially expressed genes (DEGs) were identified, of which seven were related to disulfidptosis (DR-DEGs). Functional enrichment analysis showed that DR-DEGs were significantly enriched in pathways related to actin dynamics. Five hub genes (MYH10, ACTN4, MYH9, FLNA, and IQGAP1) were identified as central to these processes. The analysis of immune infiltration revealed significantly lower levels of 11 immune cell types, while macrophages and regulatory T cells were significantly elevated in sepsis patients. The area under the ROC curves (AUCs) of the IHGs risk prediction model were 0.917 and 0.894 for the training and validation sets, respectively. A miRNA-IHGs regulatory network, comprising 17 nodes and 27 edges, was constructed, with MYH9 being the most frequently regulated by miRNAs. Conclusion: The pathophysiological process of sepsis appears to involve disulfidptosis, highlighting it as a potential new therapeutic targets for sepsis management.

Amentoflavone (AME) is a flavonoid compound found in over 120 plants. Its extensive pharmacological activity for treating cardiocerebrovascular diseases and neurological disorders have attracted the attention of researchers in recent years. However, owing to the poor solubility and low bioavailability of AME, it has not been developed as a drug for treating these diseases. This review focuses on two aspects of AME: First, it provides a detailed summary and introduction to AME based on its chemical structure, physicochemical properties, plant sources, extraction and purification methods, administration systems, and pharmacokinetic properties. Second, it summarizes the effects of AME on cardiocerebrovascular diseases and neurological disorders, and its specific pharmacological mechanisms. This review aims to promote the use of AME for treating cardiocerebrovascular diseases and neurological disorders. AME exhibits multiple activities, indicating its potential as a natural drug for treating these diseases. Further studies on its pharmacokinetics and toxicology are required to ensure its safety and efficacy.

To address the problems of poor speed performance and the large influence of the distributed capacitance of traditional pilot differential protection, a pilot protection scheme based on the characteristics of the transient voltage waveform is proposed. First, the expression of the relationship between the fault voltage of the current-limiting reactor and the measuring point is derived. From the theoretical derivation, it can be inferred that for internal faults, the voltage ratio of the current-limiting reactor to the measuring point on both sides of the HVDC line is constant over a short period. For external faults, the voltage ratio of the current-limiting reactor to the measuring point varies exponentially on the fault side, while on the other side, it remains constant. Based on the above characteristics, the waveform characteristics of the voltage ratio of the current-limiting reactor to the measuring point are used to establish a protection criterion. A pilot protection scheme based on the standard deviation coefficient is proposed. The simulation results show that this method can reliably identify internal and external faults and has high sensitivity and selectivity. Moreover, this method is reliable for different types of faults and fault resistances. In addition, the proposed protection scheme can identify the type of fault in a short time window, requires a low sampling frequency, and does not require data synchronization.

This paper concentrates on the numerical investigation of slip-flow and heat transfer characteristics in the entry region of elliptical microchannels under isothermal or isoflux boundary conditions. Slip boundaries caused by rarefaction effect are implemented using user-defined functions. The impacts of Reynolds number (25≤ Re ≤ 1000), Knudsen number (0.01≤ Kn ≤ 0.1), Peclet number (17.5 ≤ Pe ≤ 700) and aspect ratio (0.2≤ ε ≤ 1) on the apparent friction factor Reynolds number product fappRe and local Nusselt number Nu(x) are discussed in detail. The results demonstrate that at the entrance region, fappRe decreases with increasing Re, especially for ε = 0.33, Kn = 0.01 and Re

Background Both depression and respiratory disease are common today in young populations. However, little is known about the relationship between them. Aims This study aims to explore the association between depression in childhood to early adulthood and respiratory health outcomes in early adulthood, and the potential underlying mechanisms. Method A prospective study was conducted based on the Swedish BAMSE (Barn, Allergi, Miljö, Stockholm, Epidemiologi [Children, Allergy, Milieu, Stockholm, Epidemiology]) birth cohort (n = 4089). We identified clinically diagnosed depression through the dispensation of antidepressants, using national register data confirmed by self-reported diagnosis. At the 24-year follow-up, respiratory health was assessed via questionnaires and clinical evaluation. Metabolic and inflammatory profiles were analysed to explore potential mechanisms. Results Among the 2994 participants who provided study data, 403 (13.5%) had depression at any time point from around age 10 to 25 years. Depression was associated with higher risks of any chronic bronchitis symptoms (odds ratio = 1.58, 95% CI 1.21–2.06) and respiratory symptoms (odds ratio = 1.41, 95% CI 1.11–1.80) in early adulthood, independent of body mass index (BMI) and smoking status. Compared to individuals without depression, those with depression had a higher fat mass index (FMI (β = 0.48, 95% CI 0.22–0.74)) and increased blood levels of fibroblast growth factor 21 and Interleukin-6 in early adulthood. These markers together with FMI were found to partly mediate the association between depression and respiratory symptoms (total mediation proportion: 19.8 and 15.4%, respectively, P < 0.01). Conclusions Depression in childhood to early adulthood was associated with an increased risk of respiratory ill-health in early adulthood, independently of smoking. Metabolic and inflammatory dysregulations may underlie this link.

Herein, a sequentially responsive peptide DNA bilingual nanobiosensor is developed, which allows integrated quantification of amyloid signaling pathway. In this system, upstream beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) protease and downstream Aβ oligomer (AβO) are designed as two inputs for the AND DNA logic gate. In the existence of both inputs, peptide substrate with aptamer can be sequentially cleaved, reporting electrochemical and fluorescence dual‐mode outputs. In comparison with conventional single protease activity assay based on peptide nanotechnology, this strategy permits accurate diagnosis of Alzheimer's disease (AD) from normal subjects. More importantly, it can achieve distinguished diagnosis between AD and type 2 diabetes mellitus patients. This bilingual nanobiosensor is successfully applied to detect BACE1 (1–100 U mL−1) and AβO (5–1000 pg mL−1) with limit of detections as low as 0.10 U mL−1 and 0.76 pg mL−1, respectively. Furthermore, this strategy inspires advanced nanobiosensors to target the activation of other signaling pathways, which are potential tools for future biology and medicine investigation.

ObjectivesThis work aimed to study the long-term outcome and function of a heterotopic replanted finger.MethodsRetrospective analysis of two cases of successful finger reconstruction after finger heterotopic replantation. One case was a severed thumb, and the other case was a severed finger. The average follow-up time was 10 years. The clinical outcome and function of the heterotopic replanted finger, including range of motion, grip strength, and sensory recovery, were analyzed,. A comparative analysis was conducted with patients who underwent thumb replantation in the same period.ResultsThe two heterotopically replanted fingers survived. Five months after the heterotopic replantation surgery, a new thumb was reconstructed using the heterotopically replanted thumb and the free tarsometatarsal joint from the foot. In the other case, the finger was reconstructed 1 year later with a free anterolateral thigh flap and the heterotopically replanted finger. The movement of the thumb, the pinching of the fingers, the clenching of the fist, and the feeling recovery were all good. The patient was capable of independently performing daily life and work activities such as eating, dressing, writing, and so on. There was no significant difference in hand function between the patients who received in situ finger replantation and heterotopic replantation during the same period.ConclusionFor severed fingers that cannot be replanted in situ in an emergency situation, heterotopic replantation and secondary reconstruction may be a feasible and practical surgical method.

Gut microbiome is indispensable for maintaining normal brain function. Specifically, gut microbiota plays a causal role in sleep deprivation (SD)-induced cognitive impairment. In this study, neurobehavioral effects of the Bifidobacterium breve strain (CCFM1025) were assessed in sleep-deprived mice. CCFM1025 improved the body weight and food and water intake of the mice. It also alleviated SD-induced cognitive behavioural abnormalities (in the novel object recognition test), but did not show beneficial effects on mood- and spatial memory-related behaviours. CCFM1025 significantly altered the gut microbial composition and genome function. Key microbial metabolites that may regulate sleep function were also identified, such as isovaleric acid and γ-aminobutyric acid in the gut and purine metabolites in the serum. Those metabolites may participate in gut-brain communication by acting on the striatal melatonin system, for example to increase melatonin levels, and by regulating the expression of circadian clock genes such as those encoding the adenosine A2A receptor and period circadian regulator 1. Collectively, administration of probiotics alleviated cognitive impairment and circadian rhythm disturbance induced by SD via modulation of gut microbiome and its metabolites. These findings may help guide the treatment of insomnia or other sleep disorders via dietary strategies.

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.

Abstract The early diagnosis and treatment of foreign body aspiration (FBA) can significantly improve the overall prognosis of children. There are significant differences in the epidemiology and clinical characteristics of FBA in different regions. Therefore, we conducted a real-world study in the western region of China with over 4000 patients. The aim of this study was to improve the understanding of FBA in terms of its types, the specific months of its occurrence, and the distribution of primary caregiver characteristics in western China. We collected the clinical and epidemiological data of children who were diagnosed with FBA in our hospital over the past 20 years through a big data centre. We matched the data of healthy children who underwent routine physical examinations at the paediatric health clinic during the same period to analyse the differences in the data of actual guardians. A total of 4227 patients from five provinces were included in this study. Foreign bodies were removed by rigid bronchoscopy in 99.4% (4202/4227) of patients, with a median age of 19 months and a median surgical duration 16 min. January was the most common month of onset for 1725 patients, followed by February, with 1027 patients. The most common types of foreign objects were melon peanuts, seeds and walnuts, accounting for 47.2%, 15.3%, and 10.2%, respectively. In the FBA group, the proportion of grandparents who were primary caregivers was 70.33% (2973/4227), which was significantly greater than the 63.05% in the healthy group (2665/4227) (P

Abstract Background Biochar, a carbon-rich source and natural growth stimulant, is usually produced by the pyrolysis of agricultural biomass. It is widely used to enhance plant growth, enzyme activity, and crop productivity. However, there are no conclusive studies on how different levels of biochar application influence these systems. Methods and results The present study elucidated the dose-dependent effects of biochar application on the physiological performance, enzyme activity, and dry matter accumulation of tobacco plants via field experiments. In addition, transcriptome analysis was performed on 60-day-old (early growth stage) and 100-day-old (late growth stage) tobacco leaves to determine the changes in transcript levels at the molecular level under various biochar application levels (0, 600, and 1800 kg/ha). The results demonstrated that optimum biochar application enhances plant growth, regulates enzymatic activity, and promotes biomass accumulation in tobacco plants, while higher biochar doses had adverse effects. Furthermore, transcriptome analysis revealed a total of 6561 differentially expressed genes (DEGs) that were up- or down-regulated in the groupwise comparison under different treatments. KEGG pathways analysis demonstrated that carbon fixation in photosynthetic organisms (ko00710), photosynthesis (ko00195), and starch and sucrose metabolism (ko00500) pathways were significantly up-regulated under the optimal biochar dosage (600 kg/ha) and down-regulated under the higher biochar dosage (1800 kg/ha). Conclusion Collectively, these results indicate that biochar application at an optimal rate (600 kg/ha) could positively affect photosynthesis and carbon fixation, which in turn increased the synthesis and accumulation of sucrose and starch, thus promoting the growth and dry matter accumulation of tobacco plants. However, a higher biochar dosage (1800 kg/ha) disturbs the crucial source-sink balance of organic compounds and inhibits the growth of tobacco plants.

Abstract The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell–cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.

Abstract Objective We aimed to compare the clinical efficacy of inverted triangular cannulated compression screws combined with Gotfried positive or negative buttress reduction in the healing of femoral neck fractures. Methods Between October 2017 and March 2021, 55 patients with femoral neck fractures underwent treatment using inverted triangular cannulated compression screws combined with Gotfried positive or negative buttress reduction. Among these patients, 29 received inverted triangular cannulated compression screws combined with Gotfried positive buttress reduction treatment. This group consisted of 16 males and 13 females, with an average age of 43.45 ± 8.23 years. Additionally, 26 patients received inverted triangular cannulated compression nails combined with Gotfried negative buttress reduction treatment. This group included 14 males and 12 females, with an average age of 41.96 ± 8.69 years. Postsurgery, various measurements were taken, including the degree of shortening of the femoral neck, degree of bone nonunion, degree of fixation failure, degree of ischemic necrosis of the femoral head, and Harris score of the hip joint. Results All patients were followed up for a minimum of 18 months. The group that underwent treatment with an inverted triangular cannulated compression screw combined with Gotfried positive buttress reduction did not experience any cases of bone nonunion, fixation failure, or ischemic necrosis of the femoral head. In the group that received treatment with inverted triangle cannulated compression screws combined with Gotfried negative buttress reduction, there was one case of bone nonunion, three cases of early fixation failure, and one case of ischemic necrosis. Ultimately, five patients (19.23% of the total) underwent joint replacement surgery. The average shortening lengths in the vertical plane were 4.07 ± 1.98 mm and 8.08 ± 3.54 mm, respectively. In the horizontal plane, the average shortening lengths were 3.90 ± 1.57 mm and 7.77 ± 3.31 mm, respectively. At the last follow-up, the group that received Gotfried positive buttress reduction had a greater Harris hip joint score. Conclusion The success rate of combining inverted triangular cannulated compression screws with Gotfried positive buttress reduction surgery is relatively high. This surgical approach effectively prevents femoral neck shortening and improves hip joint function. Moreover, it is crucial to avoid negative buttress reduction when managing femoral neck fractures.

Abstract Investigation of histopathology slides by pathologists is an indispensable component of the routine diagnosis of cancer. Artificial intelligence (AI) has the potential to enhance diagnostic accuracy, improve efficiency, and patient outcomes in clinical pathology. However, variations in tissue preparation, staining protocols, and histopathology slide digitization could result in over-fitting of deep learning models when trained on the data from only one center, thereby underscoring the necessity to generalize deep learning networks for multi-center use. Several techniques, including the use of grayscale images, color normalization techniques, and Adversarial Domain Adaptation (ADA) have been suggested to generalize deep learning algorithms, but there are limitations to their effectiveness and discriminability. Convolutional Neural Networks (CNNs) exhibit higher sensitivity to variations in the amplitude spectrum, whereas humans predominantly rely on phase-related components for object recognition. As such, we propose Adversarial fourIer-based Domain Adaptation (AIDA) which applies the advantages of a Fourier transform in adversarial domain adaptation. We conducted a comprehensive examination of subtype classification tasks in four cancers, incorporating cases from multiple medical centers. Specifically, the datasets included multi-center data for 1113 ovarian cancer cases, 247 pleural cancer cases, 422 bladder cancer cases, and 482 breast cancer cases. Our proposed approach significantly improved performance, achieving superior classification results in the target domain, surpassing the baseline, color augmentation and normalization techniques, and ADA. Furthermore, extensive pathologist reviews suggested that our proposed approach, AIDA, successfully identifies known histotype-specific features. This superior performance highlights AIDA’s potential in addressing generalization challenges in deep learning models for multi-center histopathology datasets.

Abstract The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P

Abstract Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.

Abstract. Background:. Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection on psoriasis patients. The objective of this study was to identify clinical factors associated with the prognosis of psoriasis following SARS-CoV-2 infection. Methods:. A retrospective, multicenter study was conducted between March and May 2023. Univariable and multivariable logistic regression analyses were employed to identify factors associated with coronavirus disease 2019 (COVID-19)-related psoriasis outcomes. The study included 2371 psoriasis patients from 12 clinical centers, with 2049 of them having been infected with SARS-CoV-2. Results:. Among the infected groups, lower exacerbation rates were observed in individuals treated with biologics compared to those receiving traditional systemic or nonsystemic treatments (22.3% [236/1058] vs. 39.8% [92/231] vs. 37.5% [140/373], P

Abstract Although Omicron RBD of SARS-CoV-2 accumulates many mutations, the backbone region (truncated RBD) of spike protein is highly conserved. Here, we designed several subunit vaccines by keeping the conserved spike backbone region of SARS-CoV-2 Omicron BA.1 subvariant (S-6P-no-RBD), or inserting the RBD of Delta variant (S-6P-Delta-RBD), Omicron (BA.5) variant (S-6P-BA5-RBD), or ancestral SARS-CoV-2 (S-6P-WT-RBD) to the above backbone construct, and evaluated their ability to induce immune responses and cross-protective efficacy against various SARS-CoV-2 variants and SARS-CoV. Among the four subunit vaccines, S-6P-Delta-RBD protein elicited broad and potent neutralizing antibodies against all SARS-CoV-2 variants tested, including Alpha, Beta, Gamma, and Delta variants, the BA.1, BA.2, BA.2.75, BA.4.6, and BA.5 Omicron subvariants, and the ancestral strain of SARS-CoV-2. This vaccine prevented infection and replication of SARS-CoV-2 Omicron, and completely protected immunized mice against lethal challenge with the SARS-CoV-2 Delta variant and SARS-CoV. Sera from S-6P-Delta-RBD-immunized mice protected naive mice against challenge with the Delta variant, with significantly reduced viral titers and without pathological effects. Protection correlated positively with the serum neutralizing antibody titer. Overall, the designed vaccine has potential for development as a universal COVID-19 vaccine and/or a pan-sarbecovirus subunit vaccine that will prevent current and future outbreaks caused by SARS-CoV-2 variants and SARS-related CoVs.

Abstract The traceability of groundwater nitrate pollution is crucial for controlling and managing polluted groundwater. This study integrates hydrochemistry, nitrate isotope (δ15N-NO3 − and δ18O-NO3 −), and self-organizing map (SOM) and end-member mixing (EMMTE) models to identify the sources and quantify the contributions of nitrate pollution to groundwater in an intensive agricultural region in the Sha River Basin in southwestern Henan Province. The results indicate that the NO3 −-N concentration in 74% (n = 39) of the groundwater samples exceeded the WHO standard of 10 mg/L. According to the results of EMMTE modeling, soil nitrogen (68.4%) was the main source of nitrate in Cluster-1, followed by manure and sewage (16.5%), chemical fertilizer (11.9%) and atmospheric deposition (3.3%). In Cluster-2, soil nitrogen (60.1%) was the main source of nitrate, with a significant increase in the contribution of manure and sewage (35.5%). The considerable contributions of soil nitrogen may be attributed to the high nitrogen fertilizer usage that accumulated in the soil in this traditional agricultural area. Moreover, it is apparent that most Cluster-2 sampling sites with high contributions of manure and sewage are located around residential land. Therefore, the arbitrary discharge and leaching of domestic sewage may be responsible for these results. Therefore, this study provides useful assistance for the continuous management and pollution control of groundwater in the Sha River Basin.

316L stainless steel is used in a wide variety of corrosion-prone locations. However, its low hardness and poor tribological properties limit its application under heavy wear conditions. In this study, 316L Fe-based composite coatings co-doped with TB2 hard phases and rare-earth CeO2 exhibited excellent wear and corrosion resistance. Firstly, 316L-TiB2 cermet powder and (316L-TiB2)/CeO2 composite powder with high sphericity and density were prepared by high energy ball milling (HEBM), spraying drying granulation (SD), plasma spheroidization (PS) process. Then, 316L coatings, 316L-TiB2 and (316L-TiB2)/CeO2 cermet coatings were deposited by high velocity air fuel (HVAF) spraying. Finally, the effects of TiB2 and CeO2 additions on the microstructure, wear and corrosion behavior of the coatings were investigated. The results showed that TiB2 hard particles and CeO2 were uniformly distributed in the HVAF sprayed 316L-TiB2 and (316L-TiB2)/CeO2 coatings. The wear resistance of the coating prepared by 316L Fe-based composite powder with TiB2 and CeO2 is significantly improved. The hardness of the (316L-TiB2)/CeO2 composite coating was increased from 269 Hv0.3 to 826 Hv0.3 for the pure 316L coating, while the volumetric wear rate was only 3.6 % of that of the pure 316L coating (110 × 10−5 down to 4 × 10−5 mm3/N). Electrochemical tests show that the corrosion resistance of the coating decreases with the addition of TiB2 alone, but it can be improved by doping CeO2. The 316L Fe-based coating prepared by adding TiB2 and CeO2 can significantly improve the wear resistance of the coating, while the corrosion resistance decreases only slightly.

Abstract Breast cancer (BRCA) has become the most common type of cancer in women. Improving the therapeutic response remains a challenge. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a classic tumour suppressor with emerging new functions discovered in recent years, and myeloid PTEN loss has been reported to impair antitumour immunity. In this study, we revealed a novel mechanism by which myeloid PTEN potentially affects antitumour immunity in BRCA. We detected accelerated stress granule (SG) assembly under oxidative stress in PTEN-deficient bone marrow-derived macrophages (BMDMs) through the EGR1-promoted upregulation of TIAL1 transcription. PI3K/AKT/mTOR (PAM) pathway activation also promoted SG formation. ATP consumption during SG assembly in BMDMs impaired the phagocytic ability of 4T1 cells, potentially contributing to the disruption of antitumour immunity. In a BRCA neoadjuvant cohort, we observed a poorer response in myeloid PTENlow patients with G3BP1 aggregating as SGs in CD68+ cells, a finding that was consistent with the observation in our study that PTEN-deficient macrophages tended to more readily assemble SGs with impaired phagocytosis. Our results revealed the unconventional impact of SGs on BMDMs and might provide new perspectives on drug resistance and therapeutic strategies for the treatment of BRCA patients.

Abstract Background The different symptoms of major depressive disorder (MDD) in adolescents compared to adults suggested there may be differences in the pathophysiology between adolescents and adults with MDD. However, despite the amygdala being considered critical in the pathophysiology, there was limited knowledge about the commonalities and differences in the resting-state functional connectivity (rsFC) of amygdala subregions in MDD patients of different age groups. Methods In the current study, 65 adolescents (46 with MDD and 19 controls) and 91 adults (35 with MDD and 56 controls) were included. A seed-based functional connectivity analysis was performed for each of the amygdala subregions. A 2 × 2 ANOVA was used to analyze the main effect of age, diagnosis, and their interaction on the rsFC of each subregion. Results A significant main effect of age was revealed in the rsFC of bilateral centromedial (CM) subregions and right laterobasal (LB) subregion with several brain regions in the limbic system and frontoparietal network. The significant main effect of diagnosis showed MDD patients of different ages showed higher connectivity than controls between the right LB and left middle frontal gyrus (MFG). Conclusions The rsFC of specific amygdala subregions with brain regions in the limbic system and frontoparietal network is affected by age, indicating a distinct amygdala connectivity profile in adolescents. The decreased rsFC between the right LB and the left MFG in adolescents and adults with MDD could serve as a diagnostic biomarker and a target of nonpharmacological treatment for MDD.

Background: The effect of transcranial alternating current stimulation (tACS) on major depressive disorder (MDD) was not confirmed. Objective: To evaluate the feasibility, safety, and efficacy of tACS as an add-on treatment for the symptoms of depression and to understand how tACS affects brain activity. Methods: The 4-week, double-blind, randomized, sham-controlled trial was performed from January 29, 2023 to December 22, 2023. Sixty-six participants were recruited and randomly assigned to receive 20 40-min sessions of either active (77.5Hz, 15 mA) or sham stimulation, with one electrode on the forehead and two on the mastoid, each day (n = 33 for each group) for four weeks (till Week 4). The participants were followed for 4 more weeks (till Week 8) without stimulation for efficacy/safety assessment. During the 4-week trial, all participants were required to take 10–20 mg of escitalopram daily. The primary efficacy endpoint was the change in HAMD-17 scores from baseline to Week 4 (with 20 treatment sessions completed). Resting-state electroencephalography (EEG) was collected with a 64-channel EEG system (Brain Products, Germany) at baseline and the Week 4 follow-up. The chi-square test, Fisher's exact test, independent-sample t-test, or Wilcoxon rank-sum test were used, as appropriate, to compare the differences in variables between groups. The effect of the intervention on the HAMD-17 score was also evaluated with linear mixed modeling (LMM) as sensitivity analysis. The correlation between the mean reduction in EEG and the mean reduction in the HAMD-17 total score was evaluated using Spearman correlation analysis. Results: A total of 66 patients (mean [SD] age, 28.4 [8.18] years; 52 [78.8 %] female) were randomized, and 57 patients completed the study. Significant differences were found in the reductions in the HAMD-17 scores at Week 4 (t = 3.44, P = 0.001). Response rates at Week 4 were significantly higher in the active tACS group than in the sham tACS group (22 out of 33 patients [66.7 %] versus 11 out of 33 [33.3 %], P = 0.007). In the active tACS group, a correlation between the mean change in alpha power and HAMD-17 scores at Week 4 was found (r = 2.38, P = 0.024), and the mean change in alpha power was significantly bigger for responders (Z = 2.46, P = 0.014). No serious adverse events were observed in this trial. Conclusion: The additional antidepressant effect of tACS is significant, and the combination of tACS with antidepressants is a feasible and effective approach for the treatment of MDD. The antidepressant mechanism of tACS may be the reduction in alpha power in the left frontal lobe. Future research directions may include exploring more appropriate treatment parameters of tACS.

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). Previous studies have indicated that SFTS patients have a high mortality rate, which may be related to cytokine storm and immune dysfunction. In our study, we analyzed differences in cytokines and lymphocyte subsets between severe and non-severe SFTS patients, with the aim of identifying predictors of severity. Methods We retrospectively analyzed demographic characteristics, clinical data, cytokine profiles, and lymphocyte subsets from 96 laboratory confirmed SFTS patients between April 2021 and August 2023. Results A total of 96 SFTS patients were enrolled, with a mean age of 65.05 (± 7.92) years old. According to our grouping criteria, 35 (36.5%) of these patients were classified as severe group, while 61 (63.5%) were classified as non-severe group. Univariate analysis revealed that age, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interferon-α (IFN-α), CD4 + T cell, and CD8 + T cell counts were risk predictors for the severity of SFTS. Further multivariable logistic regression analysis confirmed age, IL-6 levels, and CD4 + T cell counts as independent predictors of SFTS severity. Conclusions Severe SFTS patients may experience cytokine storms and immune dysfunction. Aging, elevated levels of IL-6, and decreased CD4 + T cell count may serve as independent predictors for the severity of SFTS.

Abstract Objective Our study aimed to determine whether there exists an association between low-grade systemic inflammation, as measured by serum C-reactive protein (CRP), and the risk of lower-extremity deep venous thrombosis (LEDVT) in patients with primary intracerebral hemorrhage (ICH). Methods This observational study was retrospectively conducted on patients with primary ICH who were presented to two tertiary medical centers between January 2021 and August 2022. The primary outcome was detecting LEDVT occurrence within 14 days from the onset of the acute ICH episode. Weighted logistic regression and restricted cubic spline models were employed to estimate the association between CRP and LEDVT following 1:1 propensity score matching (PSM). Results Of the 538 patients with primary ICH who met the inclusion criteria, 76 (14.13%) experienced LEDVT. Based on the cut-off levels of CRP measured upon admission from the receiver operating characteristic (ROC) curve, patients with primary ICH were categorized into two groups: (i) CRP

The micaceous weathered granitic soil (WGS) is frequently encountered in civil engineering worldwide, unfortunately little information is available regarding how mica affects the physico-mechanical behaviors of WGS. This study prepares reconstituted WGS with different mica contents by removing natural mica in the WGS, and then mixes it with commercial mica powders. The geotechnical behavior as well as the microstructures of the mixtures are characterized. The addition of mica enables the physical indices of WGS to be specific combinations of coarser gradation and high permeability but high Atterberg limits. However, high mica content in WGS was found to be associated with undesirable mechanical properties, including increased compressibility, disintegration, and swelling potential, as well as poor compactability and low effective frictional angle. Microstructural analysis indicates that the influence of mica on the responses of mixtures originates from the intrinsic nature of mica as well as the particle packing being formed within WGS. Mica exists in the mixture as stacks of plates that form a spongy structure with high compressibility and swelling potential. Pores among the plates give the soil high water retention and high Atterberg limits. Large pores are also generated by soil particles with bridging packing, which enhances the permeability and water-soil interactions upon immersion. This study provides a micro-level understanding of how mica dominates the behavior of WGS and provides new insights into the effective stabilization and improvement of micaceous soils.

Abstract Background Q fever, caused by the zoonotic pathogen Coxiella burnetii, exhibits a worldwide prevalence. In China, Q fever is not recognized as a notifiable disease, and the disease is overlooked and underestimated in clinical practice, leading to diagnostic challenges. Case presentation We present a case series of three patients diagnosed with persistent Q fever between 2022 and 2023. The average age of our three cases was 63.33 years old, consisting of two males and one female. The medical history of the individuals included previous valve replacement, aneurysm followed by aortic stent-graft placement and prosthetic hip joint replacement. At the onset of the disease, only one case exhibited acute fever, while the remaining two cases were devoid of any acute symptoms. The etiology was initially overlooked until metagenomic next-generation sequencing test identified Coxiella burnetii from the blood or biopsy samples. Delayed diagnosis was noted, with a duration ranging from three months to one year between the onset of the disease and its confirmation. The epidemiological history uncovered that none of the three cases had direct exposure to domestic animals or consumption of unpasteurized dairy products. Case 1 and 2 resided in urban areas, while Case 3 was a rural resident engaged in farming. All patients received combination therapy of doxycycline and hydroxychloroquine, and no recurrence of the disease was observed during the follow-up period. Conclusion Q fever is rarely diagnosed and reported in clinical practice in our country. We should be aware of persistent Q fever in high-risk population, even with unremarkable exposure history. Metagenomic next-generation sequencing holds great potential as a diagnostic tool for identifying rare and fastidious pathogens such as Coxiella burnetii.

Abstract Backgrounds A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. Methods Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the “TwoSampleMR” R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. Results Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001–1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P

Abstract Phage predation is generally assumed to reduce microbial proliferation while not contributing to the spread of antibiotic resistance. However, this assumption does not consider the effect of phage predation on the spatial organization of different microbial populations. Here, we show that phage predation can increase the spread of plasmid-encoded antibiotic resistance during surface-associated microbial growth by reshaping spatial organization. Using two strains of the bacterium Escherichia coli, we demonstrate that phage predation slows the spatial segregation of the strains during growth. This increases the number of cell-cell contacts and the extent of conjugation-mediated plasmid transfer between them. The underlying mechanism is that phage predation shifts the location of fastest growth from the biomass periphery to the interior where cells are densely packed and aligned closer to parallel with each other. This creates straighter interfaces between the strains that are less likely to merge together during growth, consequently slowing the spatial segregation of the strains and enhancing plasmid transfer between them. Our results have implications for the design and application of phage therapy and reveal a mechanism for how microbial functions that are deleterious to human and environmental health can proliferate in the absence of positive selection.

Abstract CD8+ T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8+ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8+ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8+ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8+ T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8+ T cells. Intriguingly, inhibition of ADAM17 in CD8+ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8+ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

Abstract Background and aims The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. Methods The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. Results Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). Conclusion Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

There are numerous instabilities present in charged particle beams that undergo exponential growth and reach saturation. In various applications, such as free-electron lasers or micro-bunching light sources, achieving saturation is desirable. Conversely, there are applications where these instabilities are utilized as linear broad-band amplifiers for signals embedded in the charged beam. In the latter scenario, the saturation of an instability induces non-linear distortions in the imprinted signal, thereby limiting the useful range of such amplifiers. Accurate evaluation of these instabilities necessitates a complete and comprehensive modeling approach that includes shot noise within the beam. Unfortunately, such modeling is not always feasible or practical. In this paper, we introduce a methodology utilizing the frequency and bandwidth of the instability as key parameters. Through this, we derive an estimation for the range of linear instability growth. Our derivation is conducted in a model-independent manner, making it applicable to a broad spectrum of instabilities. To validate our approach, we employ established and thoroughly benchmarked simulations with a free electron laser (FEL) code as well as self-consistent 3-dimensional simulation of plasma-cascade instability using code SPACE.

Abstract This study aims to establish a rapid diagnostic method for Streptococcus agalactiae (GBS) based on recombinase polymerase amplification (RPA) and lateral flow strips (LFS). The best primer pairs designed by SIP gene were screened according to the basic RPA reaction, then the probe was designed. The reaction condition was optimized based on the color development of the LFS detection line. To ascertain the reaction specificity, 10 common clinical pathogens and 10 clinical specimens of GBS were tested. Furthermore, the reaction sensitivity was assessed by utilizing a tenfold gradient dilution of GBS genomic DNA as templates. RPA–LFS method was compared to the qPCR assay and biochemical culture method for the Kappa consistency test. The RPA–LFS technique was able to complete the amplification process within 30 min and the results were observed on lateral flow strips. The method is highly sensitive, with a minimum detection limit of 1.31 ng for GBS. The RPA–LFS method showed consistent accuracy of results compared to qPCR and the culture–biochemical method. The establishment of this method is conducive to the development of on-site immediate detection, which can provide information for the timely development of a reasonable antimicrobial treatment plan, and has a greater potential for clinical application.

This study investigated the effects of different dilution concentrations of azoxystrobin and thiophanate-methyl on the preservation of postharvest litchi fruit at ambient temperature. By analyzing the physiological indicators of litchi fruit during storage, the optimal fungicide formulation was selected, verified, and dietary exposure assessed thus the preservation method of extending shelf life for litchi at ambient temperature was obtained. The results showed that the litchi fruit treated with a 1600-fold dilution of 25% azoxystrobin (M1600), or a 1600-fold dilution of 25% azoxystrobin mixed with a 700-fold dilution of 70% thiophanate-methyl (M1600+J700) significantly inhibited the respiratory rate of litchi fruit, decreased the relative conductivity of pericarp and decay rate of litchi fruit (P

Abstract The increasing incidence of autism spectrum disorder (ASD) worldwide poses serious social and family problems. Various risk factors for ASD are gradually being recognized, and there are also various options for the treatment of ASD. It is worth noting that dietary interventions have been shown to have a positive effect in terms of mitigating and preventing some psychiatric disorders, such as epilepsy, Parkinson's disease, and ASD, and they are gradually receiving attention as a safe adjuvant treatment. In this review, based on the current understanding of the pathogenic factors and intervention strategies for ASD, different dietary patterns that can be selected for children with ASD are discussed in depth. Moreover, a review was conducted on the use of dietary factors, such as natural products from food sources, prebiotics, and probiotics, as effective supplements to existing dietary patterns. As increasing evidence shows that maternal risk factors, such as obesity, diabetes, and hypertension, are associated with an increased risk of ASD in offspring, dietary suggestions are also made for pregnant woman with ASD‐related risk factors to counteract the impact of these risk factors. With compensation from food‐derived natural products, prebiotics, and probiotics, suitable dietary patterns can further enhance the effectiveness of dietary interventions for ASD. In addition, dietary recommendations for pregnant woman may reduce the potential impact of obesity, diabetes, and hypertension and may help to prevent the occurrence of ASD to the maximum extent possible.

Abstract The viscosity of fracturing fluid and in-situ stress difference are the two important factors that affect the hydraulic fracturing pressure and propagation morphology. In this study, raw coal was used to prepare coal samples for experiments, and clean fracturing fluid samples were prepared using CTAB surfactant. A series of hydraulic fracturing tests were conducted with an in-house developed triaxial hydraulic fracturing simulator and the fracturing process was monitored with an acoustic emission instrument to analyze the influences of fracturing fluid viscosity and horizontal in-situ stress difference on coal fracture propagation. The results show that the number of branched fractures decreased, the fracture pattern became simpler, the fractures width increased obviously, and the distribution of AE event points was concentrated with the increase of the fracturing fluid viscosity or the horizontal in-situ stress difference. The acoustic emission energy decreases with the increase of fracturing fluid viscosity and increases with the increase of horizontal in situ stress difference. The low viscosity clean fracturing fluid has strong elasticity and is easy to be compressed into the tip of fractures, resulting in complex fractures. The high viscosity clean fracturing fluids are the opposite. Our experimental results provide a reference and scientific basis for the design and optimization of field hydraulic fracturing parameters.