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Abstract Background Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. However, the optimal injection timing of PEG-rhG-CSF after chemotherapy is obscure. The trial was designed to explore the best administration timing of PEG-rhG-CSF when breast cancer patients could benefit most. Methods Patients with early breast cancer were randomly assigned to receive a preventive injection on the 7th or 3rd day following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n = 80) received it on day 3. The occurrence of grades 3–4 neutropenia and FN in the first cycle was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction. Results In comparison to the control group, the experimental group exhibited higher white blood cell count (WBC) and absolute neutrophil count (ANC) on the 9th and 13th days following chemotherapy (P

To determine the quality changes and shelf life of grass carp fillets with sizing (GCFS), the aerobic bacterial count, microbial succession, water holding capacity (WHC), total volatile basic nitrogen (TVB-N), thiobarbituric acid reactive substances (TBARS), biogenic amines, ATP-related compounds and K value of GCFS were analyzed during storage at 4 ℃ and 10 ℃. Results showed that the aerobic bacterial count of GCFS stored at 4 ℃ and 10 ℃ approached or exceeded the limit on 7 d and 3 d, respectively, suggesting that low temperature significantly affects microbial amplification and microflora composition in GCFS, especially retarding the growth of Acinetobacter, Shewanella and Aeromonas. During storage, no significant difference (P>0.05) of WHC in samples was observed. The pH of GCFS reached the lowest level on 3 d, and the contents of TBARS, TVB-N and the specific biogenic amines (cadaverine, putrescine, histamine and tyramine) increased continuously. Furthermore, the changes in nucleotide degradation were greatly affected by storage temperature. The K value of GCFS exceeded the recommended limit value (60%) after 7 d of storage at 4 ℃ or 3 d of storage at 10 ℃, meaning that the samples entered the stale state. The results of sensory evaluation showed a negative correlation between the quality and storage time, with the phenomena of textural softening, flesh discoloration and fishy-smell aggravation in raw/cooked GCFS stored at 10 ℃ for 3 d and 4 ℃ for 5 d. Considering the results of various indicators and the pursuit of high edible quality, the suggested shelf life of GCFS at 4 ℃ and 10 ℃ was 3 d and 1 d, respectively.

Abstract Background We explored the potential novel anticancer mechanisms of 25‐hydroxyvitamin D (25(OH)D), a vitamin D metabolite with antitumour effects in breast cancer. It is stable in serum and is used to assess vitamin D levels in clinical practice. Transfer RNA‐derived small RNAs are small noncoding RNAs that generate various distinct biological functions, but more research is needed on their role in breast cancer. Methods Small RNA microarrays were used to explore the novel regulatory mechanism of 25(OH)D. High‐throughput RNA‐sequencing technology was used to detect transcriptome changes after 25(OH)D treatment and tRF‐1‐Ser knockdown. RNA pull‐down and high‐performance liquid chromatography–mass spectrometry/mass spectrometry were used to explore the proteins bound to tRF‐1‐Ser. In vitro and in vivo functional experiments were conducted to assess the influence of 25(OH)D and tRF‐1‐Ser on breast cancer. Semi‐quantitative PCR was performed to detect alternative splicing events. Western blot assay and qPCR were used to assess protein and mRNA expression. Results The expression of tRF‐1‐Ser is negatively regulated by 25(OH)D. In our breast cancer (BRCA) clinical samples, we found that the expression of tRF‐1‐Ser was higher in cancer tissues than in paired normal tissues, and was significantly associated with tumour invasion. Moreover, tRF‐1‐Ser inhibits the function of MBNL1 by hindering its nuclear translocation. Functional experiments and transcriptome data revealed that the downregulation of tRF‐1‐Ser plays a vital role in the anticancer effect of 25(OH)D. Conclusions In brief, our research revealed a novel anticancer mechanism of 25(OH)D, unveiled the vital function of tRF‐1‐Ser in BRCA progression, and suggested that tRF‐1‐Ser could emerge as a new therapeutic target for BRCA.

Abstract Background Patients who do not achieve a pathological complete response (pCR) after neoadjuvant systemic treatment (NST) have a significantly worse prognosis. A reliable predictor of prognosis is required to further subdivide non‐pCR patients. To date, the prognostic role in terms of disease‐free survival (DFS) between the terminal index of Ki‐67 after surgery (Ki‐67T) and the combination of the baseline Ki‐67 at biopsy before NST (Ki‐67B) and the percentage change in Ki‐67 before and after NST (Ki‐67C) has not been compared. Aim This study aimed to explore the most useful form or combination of Ki‐67 that can provide prognostic information to non‐pCR patients. Patients and Methods We retrospectively reviewed 499 patients who were diagnosed with inoperable breast cancer between August 2013 and December 2020 and received NST with anthracycline plus taxane. Results Among all the patients, 335 did not achieve pCR (with a follow‐up period of ≥1 year). The median follow‐up duration was 36 months. The optimal cutoff value of Ki‐67C to predict a DFS was 30%. A significantly worse DFS was observed in patients with a low Ki‐67C (p

Abstract Background CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1). Methods In this study, we recruited five patients who relapsed after CD19-targeted CAR-T. CD19- and CD22-CAR lentivirus-transfected T cells were cultured separately and mixed before infusion in an approximate ratio of 1:1. The total dose range of CD19 and CD22 CAR-T was 4.3 × 106–1.5 × 107/kg. Throughout the trial, we evaluated the patients’ clinical responses, side effects, and the expansion and persistence of CAR-T cells. Results After CART2, all five patients had minimal residual disease (MRD)-negative complete remission (CR). The 6- and 12-month overall survival (OS) rates were 100%. The median follow-up time was 26.3 months. Three of the five patients bridged to consolidated allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CART2 and remained in MRD-negative CR at the cut-off time. In patient No. 3 (pt03), CAR-T cells were still detected in the peripheral blood (PB) at 347 days post-CART2. Cytokine release syndrome (CRS) only occurred with a grade of ≤ 2, and no patients experienced symptoms of neurologic toxicity during CART2. Conclusions Mixed infusion of CD19- and CD22-targeted CAR-T cells is a safe and effective regimen for children with B-ALL who relapse after prior CD19-targeted CAR-T therapy. Salvage CART2 provides an opportunity for bridging to transplantation and long-term survival. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032211. Retrospectively registered: April 23, 2020.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Purpose: Triple-negative apocrine carcinoma (TNAC) is a sort of triple-negative breast cancer (TNBC) that is rare and prognosis of these patients is unclear. The present study constructed an effective nomogram to assist in predicting TNAC patients overall survival (OS). Methods: A total of 373 TNAC patients from the surveillance, epidemiology, and end results (SEER) got extracted from 2010 to 2016 and were divided into training (n = 261) and external validation (n = 112) groups (split ratio, 7:3) randomly. A Cox regression model was utilized to creating a nomogram according to the risk factors affecting prognosis. The predictive capability of the nomogram was estimated with receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Multivariate Cox regression analysis revealed age, surgery, chemotherapy, stage, and first malignant primary as independent predictors of OS. A prediction model was constructed and virtualized using the nomogram. The time-dependent area under the curve (AUC) showed satisfactory discrimination of the nomogram. Good consistency was shown on the calibration curves in OS between actual observations and the nomogram prediction. What's more, DCA showed that the nomogram had incredible clinical utility. Through separating the patients into groups of low and high risk group that connects with the risk system that shows a huge difference between the low-risk and high risk OS (P

Multi-objective genetic algorithms (MOGAs) are widely used for multi-reservoir systems’ optimization due to their high efficiency and fast convergence. However, the computational cost grows exponentially with the expansion of multi-reservoir systems and the increased dimensions of optimization problems, posing a great challenge to multi-reservoir operations. Therefore, it is important to find a suitable and efficient multi-objective algorithm for multi-reservoir system optimization. In this study, three representative MOGAs were selected, namely the Non-dominated Sorting Genetic Algorithm II (NSGA-II), Non-Dominated Sorting Genetic Algorithm III (NSGA-III), and Reference Vector Guided Evolutionary Algorithm (RVEA), and three multi-objective optimization models were then developed accordingly. Numerical experiments were conducted to evaluate the performance of these three algorithms for the optimization of a cascaded reservoir system. The results show that for the two-objective model, the non-dominant size generation rate (NDSGR) of NSGA-II is 1.66 and 4.01 times that of NSGA-III and RVEA, respectively. NSGA-II is more suitable for solving the optimization operation problem with two objectives. Based on the comprehensive evaluation, NSGA-III seems to be more appropriate for more than two objectives. These results emphasize the importance of using appropriate algorithms and provide further insights into the choice of algorithms for the optimization of hydropower systems. HIGHLIGHTS Development of MOGAs was reviewed.; Three representative MOGAs were selected, namely NSGA-II, NSGA-III, and RVEA, and three multi-objective optimization models were then developed accordingly for comparison.; Numerical experiments were conducted to evaluate the performance of representative MOGAs for optimization of a cascaded reservoir system.;

Neoadjuvant systemic therapy (NST) is widely applied in breast cancer treatment, but individuals respond differently to the same NST regimen. It is unclear which patients should adjust their NST regimen and what such an adjustment should be, especially for patients with radiologically partial response (PR). This study aimed to identify a quantitative efficacy evaluation index to evaluate the therapeutic effect of NST. 164 patients were enrolled in this study received four cycles of epirubicin and cyclophosphamide (EC), followed by four cycles of taxanes with trastuzumab [T(H)], if needed. Of patients with a volume change rate of EC treatment (δV1) below 0.80, more than half benefited from subsequent T(H) treatment compared with EC treatment. Importantly, for δV1 of 0.80 and higher, patients’ subsequent T(H) treatment was not as efficient as previous EC treatment and they have a lower pathological complete response (pCR) rate. Across all patients, nanoparticle albumin-bound paclitaxel had a numerically higher pCR rate over other taxanes in patients with triple-negative breast cancer. This study showed that the volume change rate is better than the diameter change rate in monitoring the therapeutic effect of NST. Furthermore, δV1 is a good quantitative efficacy evaluation index to distinguish patients resistant to EC treatment and predict the pCR rate and guide the adjustment of individualized NST regimens.

BackgroundNeoadjuvant systemic therapy (NST) could make some clinically node-positive (cN+) breast cancer patients achieve axillary pathologic complete response (pCR). This study aimed to identify the patients who are likely to achieve axillary pCR and help surgeons make surgical decisions on the axilla.MethodsThe cN+ breast cancer patients who received NST from 2015 to 2021 at The First Affiliated Hospital of Nanjing Medical University were enrolled. Univariate and multivariate logistic regression analyses were performed, and a nomogram was constructed based on the results of multivariate logistic regression analysis to predict the probability of axillary pCR and validated.ResultsThe axillary pCR was achieved in 208 (38.7%) patients. Patients who had a higher radiological response rate of breast tumor (P = 0.039), smaller longest diameter of positive node after NST (P = 0.028), ER-negative status (P = 0.006), HER2-positive status (P = 0.048) and breast pCR (P < 0.001) were more likely to achieve axillary pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.792 (95% CI: 0.744–0.839), and the calibration curve showed good agreement.ConclusionA nomogram was constructed to predict the axillary pCR of cN+ patients receiving NST based on baseline and efficacy indicators to assist surgeons in making surgical decisions on the axilla.

As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to −178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.

Aircraft information service systems, such as airborne information systems, airborne integrated maintenance management systems, and cabin management systems, have greatly improved the ease of use and maintenance of civil aircraft. The current computing platforms used for accommodating these systems are unable to satisfy the multifaceted requirements of future information-based aircraft, such as energy conservation, emission reduction, high-performance computing, and information security protection, due to their high computing capacity, weight, and power consumption. Based on multi-core multi-threaded processors, a security hardware unit with microkernel virtualization technology and a virtualization airborne trusted general computing service architecture is proposed, and key technologies, including a high-performance processing and high-security hardware unit, virtualization management software unit, and virtualization security protection architecture were designed. By building a verification environment, the proposed platform was verified in terms of its application accommodation function, platform performance, and network security protection, for comparison with the existing platforms. The results showed that our method can fulfill the requirements of these technical indicators and is applicable, not only to new-generation civil aircraft, but also to unmanned aerial vehicles (UAVs) and emergency rescue aircraft with high-performance safety-critical computing needs.

Abstract Background Osteoclasts are key determinant cellular components implicated in the development and progression of disorders driven by bone damage. Herein, we studied the upshot of T007, an antagonist of peroxisome proliferator-activated receptor-gamma (PPARγ), on osteoclastogenesis using cell and animal models. Results The in vitro assays revealed that T007 hindered the osteoclastogenesis caused by the treatment with the receptor activator of nuclear factor-κB ligand (RANKL) through inhibiting the levels of PPARγ in cells. The PPARγ siRNA partially reproduced the inhibitory action of T007. The opposite findings were produced after PPARγ overexpression. Furthermore, T007 prevented from bone loss in a mouse model of osteoporosis induced by ovariectomy (OVX). These findings implied that T007 is a potential efficient drug for the prophylaxis and cure of osteoclast-related disorders. Conclusions Taken together, our findings demonstrated that T007 impedes osteoclastogenesis and will be useful for the therapy of bone related diseases, essentially osteoporosis.

In the immunocompromised setting, recipients of solid-organ or hematopoietic stem-cell transplants carry an increased risk of post-transplant lymphoproliferative disorder (PTLD). Burkitt lymphoma (BL) PTLD is a rare form of monomorphic B-cell PTLD, which lacks a standard best treatment. Here, we report the successful treatment of refractory BL-PTLD with autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. A male patient was diagnosed with BL-PTLD, with an increasing Epstein-Barr virus (EBV) viral load, at 21 months after undergoing living liver transplantation from his mother due to neonatal biliary atresia. After 10 cycles rituximab +/− intensive chemotherapy and surgical tumor resection, the tumors significantly advanced. Next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded tumor tissue, revealing one mutation in exon 5, TP53: p.A159 V, which may be associated with chemo-resistance. Thus, treatment was started with autologous anti-CD19 CAR T-cell therapy. We administered 9.0 × 10 6 /kg autologous anti-CD19 CAR T-cells, after conditioning with cyclophosphamide and fludarabine. Unexpectedly, the patient experienced only mild (Grade II) cytokine release syndrome (CRS) without neurotoxicity. Finally, he went into complete remission (CR), and has achieved 16-month event-free survival to date. In addition, liver function has remained stably within the normal range without any immunosuppressive therapy. The literature includes only five previously reported BL cases treated with CAR T-cell therapy. In conclusion, the present case suggests that autologous anti-CD19 CAR T-cell therapy may represent a new therapeutic option for some cases of refractory BL-PTLD. Clinical trial number: ChiCTR2000032211.

Lipid metabolism is involved in the regulation of numerous cellular processes, such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement, membrane homeostasis, chemotherapy response, and drug resistance. Reprogramming of lipid metabolism is a typical feature of malignant tumors. In a variety of cancers, fat uptake, storage and fat production are up-regulated, which in turn promotes the rapid growth, invasion, and migration of tumors. This paper systematically summarizes the key signal transduction pathways and molecules of lipid metabolism regulating tumors, and the role of lipid metabolism in programmed cell death. In conclusion, understanding the potential molecular mechanism of lipid metabolism and the functions of different lipid molecules may facilitate elucidating the mechanisms underlying the occurrence of cancer in order to discover new potential targets for the development of effective antitumor drugs.

Many studies have sought to construct a substitute to partially replace irreparably damaged meniscus. Only the meniscus allograft has been used in clinical practice as a useful substitute, and there are concerns about its longevity and inherent limitations, including availability of donor tissue and possibility of disease transmission. To overcome these limitations, we developed an acellular xenograft from whole porcine meniscus. Samples were treated with 2% Triton X-100 for 10 days and 2% sodium dodecyl sulfate for 6 days. The DNA content of extracellular matrix (ECM) scaffolds was significantly decreased compared with that of normal porcine menisci (p < 0.001). Histological analysis confirmed the maintenance of ECM integrity and anisotropic architecture in the absence of nuclei. Biochemical and biomechanical assays of the scaffolds indicated the preservation of collagen (p = 0.806), glycosaminoglycan (p = 0.188), and biomechanical properties (elastic modulus and transition stress). The scaffolds possessed good biocompatibility and supported bone marrow mesenchymal stem cells (BMSCs) proliferation for 2 weeks in vitro, with excellent region-specific recellularization in vivo. The novel scaffold has potential value for application in recellularization and transplantation strategies.

Summary: B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma. : BCL6 overexpression contributes to the pathobiology of diffuse large B cell lymphoma (DLBCL). Sun et al. find that the co-chaperone aryl hydrocarbon receptor interacting protein (AIP), whose high expression is associated with reduced survival of DLBCL patients, helps maintain BCL6 expression by facilitating the removal of ubiquitin from BCL6. Keywords: AIP, BCL6, FBXO11, UCHL1, ubiquitination, lymphoma

Seeking the optimal strategy of a multi-reservoir system is an important approach to develop hydropower energy, in which the Genetic Algorithm (GA) is commonly used as an effective tool. However, when the traditional GA is applied in solving the problem, the constraints of water balance equation, hydraulic continuity relationship and power system load demand might be violated by the crossover and mutation operator, which decreases the efficiency of the algorithm in searching for a feasible region or even leads to a convergence on an infeasible chromosome within the expected generations. A modified GA taking stochastic operators within the feasible region of variables is proposed. When determining the feasible region of constraints, the progressive optimal approach is applied to transform constraints imposed on reservoirs into a singular-reservoir constraint, and a joint solution with consideration of adjacent periods at crossover or mutation points is used to turn the singular-reservoir constraints into singular variable constraints. Some statistic indexes are suggested to evaluate the performances of the algorithms. The experimental results show that compared to GA adopting a penalty function or pair-wise comparison in constraint handling, the proposed modified GA improves the refinement of the quality of a solution in a more efficient and robust way.

A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their therapeutic outcomes, especially through development of their micro- and nano-particles. This review article describes current perspectives on the fabrication, characterization, and application of LMWHs-loaded micro- and nano-particles to achieve ameliorated bioavailability. The valuable applications of LMWH will continue to encourage researchers to identify efficient delivery systems that have specific release characteristics and ameliorated bioavailability, overcoming the challenges presented by biological obstructions and the physicochemical properties of LMWHs.

Abstract A fungal effector that is toxic to plant cells was identified in Verticillium dahliae. The effector contains a non-canonical Common in several Fungal Extracellular Membrane proteins (CFEM) domain, a tandem repeat region consisting of four 14-amino acid repeats rich in proline, and a C-terminal region, thus is designated V. dahliae tetrapeptide repeat protein (VdTRP). The membrane targeting of VdTRP is vital for its cell toxicity. CFEM mediates the membrane targeting and the tandem repeat region exerts the toxic function upon cell membrane. The chitinase-like 1 (CTL1), an essential apoplastic protein of cotton, can redirect VdTRP from cell membrane to apoplast. Transgenic cotton overexpressing CTL1 greatly enhances cotton resistance to V. dahliae without affecting cotton growth and development, implicating its potential application in breeding cotton with high wilt resistance. Our data demonstrates that genetic manipulation of effector target constitutes potential strategy for improving crop resistance to fungal pathogens.

Abstract Background Efferocytosis (ER) refers to the process of phagocytic clearance of programmed dead cells, and studies have shown that it is closely related to tumor immune escape. Methods This study was based on a comprehensive analysis of TCGA, GEO and CTRP databases. ER-related genes were collected from previous literature, univariate Cox regression was performed and consistent clustering was performed to categorize lung adenocarcinoma (LUAD) patients into two subgroups. Lasso regression and multivariate Cox regression analyses were used to construct ER-related prognostic features, and multiple immune infiltration algorithms were used to assess the correlation between the extracellular burial-related risk score (ERGRS) and tumor microenvironment (TME). And the key gene HAVCR1 was identified by deep learning, etc. Finally, pan-cancer analysis of the key genes was performed and in vitro experiments were conducted to verify the promotional effect of HAVCR1 on LUAD progression. Results A total of 33 ER-related genes associated with the prognosis of LUAD were identified, and the prognostic signature of ERGRS was successfully constructed to predict the overall survival (OS) and treatment response of LUAD patients. The high-risk group was highly enriched in some oncogenic pathways, while the low-ERGRS group was highly enriched in some immune-related pathways. In addition, the high ERGRS group had higher TMB, TNB and TIDE scores and lower immune scores. The low-risk group had better immunotherapeutic response and less likelihood of immune escape. Drug sensitivity analysis revealed that BRD-K92856060, monensin and hexaminolevulinate may be potential therapeutic agents for the high-risk group. And ERGRS was validated in several cohorts. In addition, HAVCR1 is one of the key genes, and knockdown of HAVCR1 in vitro significantly reduced the proliferation, migration and invasion ability of lung adenocarcinoma cells. Conclusion Our study developed a novel prognostic signature of efferocytosis-related genes. This prognostic signature accurately predicted survival prognosis as well as treatment outcome in LUAD patients and explored the role of HAVCR1 in lung adenocarcinoma progression.

Abstract In complicated urban environments, Global Navigation Satellite System (GNSS) signals are frequently affected by building reflection or refraction, resulting in Non-Line-of-Sight (NLOS) errors. In severe cases, NLOS errors can cause a ranging error of hundreds of meters, which has a substantial impact on the precision and dependability of GNSS positioning. To address this problem, we propose a reliable NLOS error identification method based on the Light Gradient Boosting Machine (LightGBM), which is driven by multiple features of GNSS signals. The sample data are first labeled using a fisheye camera to classify the signals from visible satellites as Line-of-Sight (LOS) or NLOS signals. We then analyzed the sample data to determine the correlation among multiple features, such as the signal-to-noise ratio, elevation angle, pseudorange consistency, phase consistency, Code Minus Carrier, and Multi-Path combined observations. Finally, we introduce the LightGBM model to establish an effective correlation between signal features and satellite visibility and adopt a multifeature-driven scheme to achieve reliable identification of NLOSs. The test results show that the proposed method is superior to other methods such as Extreme Gradient Boosting (XGBoost), in terms of accuracy and usability. The model demonstrates a potential classification accuracy of approximately 90% with minimal time consumption. Furthermore, the Standard Point Positioning results after excluding NLOSs show the Root Mean Squares are improved by 47.82%, 56.68%, and 36.68% in the east, north, and up directions, respectively, and the overall positioning performance is significantly improved.

Abstract To analyze the causes, locations, associated injuries, and relevant factors of lower limb and pelvic fractures in hospitalized children in China to provide a theoretical basis for reducing the incidence of such fractures. A retrospective analysis of children with lower limb and pelvic fractures admitted to 27 tertiary children’s hospitals affiliated with China’s Futang Research Center of Pediatric Development between December 1, 2015, and December 31, 2019, was conducted. Inpatient cases were analyzed in the following age groups: Infants (

Developing an oral in situ-forming hydrogel that targets the inflamed intestine to suppress bleeding ulcers and alleviate intestinal inflammation is crucial for effectively treating ulcerative colitis (UC). Here, inspired by sandcastle worm adhesives, we proposed a water-immiscible coacervate (EMNs-gel) with a programmed coacervate-to-hydrogel transition at inflammatory sites composed of dopa-rich silk fibroin matrix containing embedded inflammation-responsive core-shell nanoparticles. Driven by intestinal peristalsis, the EMNs-gel can be actuated forward and immediately transform into a hydrogel once contacting with the inflamed intestine to yield strong tissue adhesion, resulting from matrix metalloproteinases (MMPs)-triggered release of Fe3+ from embedded nanoparticles and rearrangement of polymer network of EMNs-gel on inflamed intestine surfaces. Extensive in vitro experiments and in vivo UC models confirmed the preferential hydrogelation behavior of EMNs-gel to inflamed intestine surfaces, achieving highly effective hemostasis, and displaying an extended residence time (> 48 h). This innovative EMNs-gel provides a non-invasive solution that accurately suppresses severe bleeding and improves intestinal homeostasis in UC, showcasing great potential for clinical applications.

Abstract Due to the strong coupling effect between the internal magnetic field and the structural field of the transformer, the magnetic‐structural coupling should be considered in axial vibration process of the winding short‐circuit impact. A 110 kV transformer is taken as the research object. Firstly, the vibration modal characteristics of the transformer are calculated using the classical axial vibration model, and the spatial distribution of the leakage magnetic flux density of the iron core window is obtained based on the image method, which is used as the basis for calculating the excitation electromagnetic force. With the consideration of the non‐linear mechanical characteristic of the pad, the dynamic stiffness equation is analysed and established and the magnetic‐structural coupling correction model is constructed. Finally, the winding vibration amplitudes obtained respectively by the classical model, the magnetic‐structural coupling model, and the magnetic‐structural coupling correction model considering the dynamic stiffness are compared. The results show that, compared with the classical model, the vibration amplitude increment with the magnetic‐structural coupling correction model is less. The dynamic stiffness will hinder the vibration intensification. The magnetic‐structural coupling correction model can provide a more accurate calculation scheme for the winding vibration characteristic analysis.

This study introduces a pioneering design concept termed the “dual-feedback healing mechanism”, which investigates the relationship between oxidation products and protective coatings. Specifically, it focuses on channeling oxidation products generated at exposed cracks in the substrate to interact with the antioxidant coatings, enabling a self-repair mechanism for cracks. BNf/SiBN was chosen as the ceramic matrix, while the Si‒O‒Al system served as the antioxidant coating. The dynamic process of obtaining Si–O–Al (SOAC) coating involving the pyrolysis of organic precursors and the dual-feedback healing mechanism were systematically investigated. These findings indicate that when the temperature surpasses 1150 °C, the exposed BN fibers at the cracks are oxidized, transforming into B2O3(g). Subsequently, B2O3(g) reacts with SiO2, forming a SiBO mixture. The mixture effectively diminishes the viscosity of the coating, enabling it to flow and form a fresh protective layer that effectively blocks O2 infiltration. Consequently, after oxidation at 1500 °C, the coated samples experience a mere 3% weight loss. This technology emphasizes the interconnectivity during material transformation, utilizing matrix oxidation products as a driving force for self-healing of the coating. This approach achieves intelligent-like, targeted closure of oxygen pathways, thereby pioneering a novel concept and direction for the advancement of antioxidant coatings. Consequently, this approach not only enhances our understanding of the fundamental nature of “self-healing” but also holds significant potential in the development of reparable antioxidant coatings.

In view of the problem that the traditional ventilation total amount control management mode of the fully mechanized heading face cannot carry out wind flow control according to the actual demand, which causes gas and dust accumulation and pollution hidden danger, the multi-source data fusion neural network prediction model of wind speed, gas and dust concentration under wind flow control is studied. The gas-solid coupling model of gas and dust under wind flow control is established by using the Euler-Lagrange method and tested and verified. The distribution of gas and dust particles in the integrated excavation roadway is simulated and analyzed, and numerous sample data of gas and dust concentration in wind speed under different wind flow control schemes are obtained. Multilayer perceptron neural network technology is used to establish the prediction model structure, and parameters such as wind flow regulation, which have a great impact on gas and dust concentration, are selected as the input layer, and the output layer is determined according to the hidden danger location of gas and dust in wind speed. The sample data is preprocessed, and the differential evolution algorithm is introduced to search the node number and learning rate of the best hidden layer. TensorFlow framework is used to build a multi-source data fusion neural network prediction model. Taking the fully mechanized heading face of a mine in northern Shaanxi as the research object, different wind flow control schemes are predicted and verified by underground measurement. The results show that the maximum relative error of the model is 9.7%, which has high accuracy. The optimal control scheme is selected under the conditions of the shortest distance of 5 m from the outlet and the farthest distance of 10 m from the working face. Compared with before the control, the wind speed meets the standard requirements, the gas concentration in the dead corner of the working face is reduced by 34% and 35%, the average dust concentration at the pedestrian side of the return air side is reduced by 40% and 41%, and the dust concentration at the driver’s side is reduced by 38% and 36%, respectively. The study can provide reference for wind flow control.

Abstract Web command injection attacks pose significant security threats to web applications, leading to potential server information leakage or severe server disruption. Traditional detection methods struggle with the increasing complexity and obfuscation of these attacks, resulting in poor identification of malicious code, complicated feature extraction processes, and low detection efficiency. To address these challenges, a novel detection model, the Convolutional Channel-BiLSTM Attention (CCBA) model, is proposed, leveraging deep learning techniques to enhance the identification of web command injection attacks. The model utilizes dual CNN convolutional channels for comprehensive feature extraction and employs a BiLSTM network for bidirectional recognition of temporal features. An attention mechanism is also incorporated to assign weights to critical features, improving the model’s detection performance. Experimental results demonstrate that the CCBA model achieves 99.3% accuracy and 98.2% recall on a real-world dataset. To validate the robustness and generalization of the model, tests were conducted on two widely recognized public cybersecurity datasets, consistently achieving over 98% accuracy. Compared to existing methods, the proposed model offers a more effective solution for identifying web command injection attacks.

Abstract Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.

Abstract This post hoc analysis explored the age-specific risk of cervical precancer in women infected with human papillomavirus (HPV), using data from a cohort of 7263 participants aged 21-71years undergoing cervical screening. We found a slightly varied prevalence of high-risk HPV (hrHPV) in different age, with highest in women under 30 years old (9.28% for 13 hrHPVs tested by HC2-HPV, 10.82% for 14 hrHPVs tested by DH3-HPV). However, the prevalence of cytology abnormalities peaked in age 30–39 years (~ 3.6%). A total of 5840 women completed 3-year follow-up. Among them, 558 were positive for HC2 assay and 583 were positive for DH3-HPV at baseline. Of note, the 3-year cumulative risks for cervical intraepithelial neoplasia grade 2+ (CIN2+) or grade 3+ (CIN3+) in women infected with high-risk HPV did not increase with age but declined (e.g., 41.67%, 27.78%, 26.42%, 15.98%, and 18% for CIN2 + risk in HC2-positive women at year 25–29, year 30–39, year 40–49, year 50–59, and year 60–71, respectively). If stratified by the median age, younger women (25–48 years) positive with HC2-HPV at baseline had a higher 3-year CIN2+/CIN3 + risk than older women (49–71 years) [26.55% (95%CI = 21.8-31.92%) vs. 18.28% (95%CI = 14.11-23.34%), P = 0.019; 15.52% (95%CI = 11.81-20.14%) vs. 9.7% (95%CI = 6.71-13.83%), P = 0.039]. Similarly, for women positive with DH3-HPV at baseline, younger group had a higher 3-year CIN2+/CIN3 + risk than older group [26.44% (95%CI = 21.73-31.75%) vs. 17.01% (95%CI = 13.11-21.78%), P = 0.006; 15.25% (95%CI = 11.6-19.8%) vs. 9.03% (95%CI = 6.24-12.9%), P = 0.021]. These findings indicate the potential value of age-specific risk assessment in cervical cancer screening.

Abstract Osteopetrosis is an inherited metabolic disease, characterized by increased bone density and narrow marrow cavity. Patients with severe osteopetrosis exhibit abnormal bone brittleness, anemia, and infection complications, which commonly cause death within the first decade of life. Pathologically, osteopetrosis impairs not only the skeletal system, but also the hemopoietic and immune systems during development, while the underlying osteoimmunological mechanisms remain unclear. Osteoclastic mutations are regarded as the major causes of osteopetrosis, while osteoclast non-autonomous theories have been proposed in recent years with unclear underlying mechanisms. Retinoic acid (RA), the metabolite of Vitamin A, is an essential requirement for skeletal and hematopoietic development, through the activation of retinoic acid signaling. RA can relieve osteopetrosis symptoms in some animal models, while its effect on bone health is still controversial and the underlying mechanisms remain unclear. In this study, we constructed an osteoblast-specific inhibitory retinoic acid signaling mouse model and surprisingly found it mimicked the symptoms of osteopetrosis found in clinical cases: dwarfism, increased imperfectly-formed trabecular bone deposition with a reduced marrow cavity, thin cortical bone with a brittle skeleton, and hematopoietic and immune dysfunction. Micro-CT, the three-point bending test, and histological analysis drew a landscape of poor bone quality. Single-cell RNA sequencing (scRNA-seq) of the femur and RNA-seq of osteoblasts uncovered an atlas of pathological skeletal metabolism dysfunction in the mutant mice showing that osteogenesis was impaired in a cell-autonomous manner and osteoclastogenesis was impaired via osteoblast-osteoclast crosstalk. Moreover, scRNA-seq of bone marrow and flow cytometry of peripheral blood, spleen, and bone marrow uncovered pathology in the hematopoietic and immune systems in the mutant mice, mimicking human osteopetrosis. Results showed that hematopoietic progenitors and B lymphocyte differentiation were affected and the osteoblast-dominated cell crosstalk was impaired, which may result from transcriptional impairment of the ligands Pdgfd and Sema4d. In summary, we uncovered previously unreported pathogenesis of osteopetrosis-like disorder in mice with skeletal, hematopoietic, and immune system dysfunction, which was induced by the inhibition of retinoic acid signaling in osteoblasts, and sheds new insights into a potential treatment for osteopetrosis.

Abstract Background This study aimed to investigate the effect of laser peripheral iridotomy (LPI) on intraocular lens (IOL) power in patients with primary angle closure disease (PACD), and to construct mathematical models to assess changes in IOL power. Methods This study included 58 eyes of PACD patients. IOL Master700 was used to analyze and compare the changes of IOL power and ocular related parameters in each formula before and after LPI. The number of cases with IOL power changes greater than 0.5 diopters (D) in each group were counted and significant differences were analyzed using Fisher’s exact test. Pearson’s linear correlation analysis was used to ascertain the relationship between IOL power changes and ocular parameter changes to establish mathematical models. Results No significant difference was found in calculated IOL power changes before and after LPI in each group. There was significant difference in the number of cases with IOL change values greater than 0.5D between the primary angle closure glaucoma (PACG) and the other two groups for each formula. IOL power changes were mainly associated with △K and △AL. Mathematical models of IOL power changes after LPI were constructed based on linear regression analysis.(PAC group: △IOLHaigis=0.026–2.950×△AL-1.414×△K, △IOLHoffer Q=-3.578×△AL-1.412×△K, △IOLSRK/T=-3.152×△AL-1.114×△K, △IOLHolladay 1=-3.405×△AL-1.291×△K, △IOLHolladay 2=-3.467×△AL-1.483×△K, △IOLBUII=-3.185×△AL-1.301×△K; PACG group:△IOLHaigis=-1.632×△K, △IOLHoffer Q=-3.770×△AL-1.434×△K, △IOLSRK/T=-3.427×△AL-1.102×△K, △IOLHolladay 1=-3.625×△AL-1.278×△K, △IOLHolladay 2=-4.764×△AL-1.272×△K, △IOLBUII=-4.935×△AL-1.304×△K). Conclusions LPI will cause changes in some ocular parameters in patients with PACD, with great effects on IOL power calculations was observed in patients with PACG. Mathematical models based on multivariate analysis hold promise for predicting IOL power changes subsequent to LPI.

Abstract Porcine circoviruses, particularly porcine circovirus type 2 (PCV2) and porcine circovirus type 3 (PCV3), significantly impact the global pig industry due to their high prevalence and pathogenicity. Conversely, porcine circovirus type 1 (PCV1) and porcine circovirus type 4 (PCV4) currently have low positivity rates. This study aimed to characterize the distribution and epidemiology of porcine circoviruses in Xinjiang, while also analyzing the genetic diversity and evolution of PCV2 and PCV3, which pose the greatest threats to the industry. In this study, we collected blood and tissue samples from 453 deceased pigs across eight regions in Xinjiang Province from 2022 to 2024. We utilized real-time PCR to detect the presence of PCV1, PCV2, PCV3, and PCV4. The positive rates were 15%, 71%, 25%, and 17%, respectively. Genetic analysis showed 9 PCV2 sequences and 12 PCV3 sequences. The capsid protein of PCV2 showed significant variability. In contrast, the amino acid sequences of capsid in PCV3 were relatively stable. Moreover, we predicted antigenic epitopes for PCV3 capsid using IEDB and ElliPro. The findings from this study provide valuable epidemiological data on PCV coinfection in the Xinjiang region and enhance the understanding of virus diversity nationwide. This research may serve as an important reference for the development of strategies to prevent and control porcine circovirus infections.