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Abstract Comprehensive and non-invasive preoperative molecular diagnosis is important for prognostic and therapy decision-making in adult-type diffuse gliomas. We employed a deep learning method for automatic segmentation of brain gliomas directly from conventional magnetic resonance imaging (MRI) scans of the tumor core and peritumoral edema regions based on available glioma MRI data provided in the BraTS2021. Three-dimensional volumes of interest were segmented from 424 cases of glioma imaging data retrospectively obtained from two medical centers using the segmentation method and radiomic features were extracted. We developed a subtype prediction model based on extracted radiomic features and analyzed significance and correlations between glioma morphological characteristics and pathological features using data from patients with adult-type diffuse glioma. The automated segmentation achieved mean Dice scores of 0.884 and 0.889 for the tumor core and whole tumor, respectively. The area under the receiver operating characteristic curve for the prediction of adult-type diffuse gliomas subtypes was 0.945. “Glioblastoma, IDH-wildtype”, “Astrocytoma, IDH-mutant”, and “Oligodendroglioma, IDH-mutant, 1p/19q-coded” showed AUCs of 0.96, 0.914, and 0.961, respectively, for subtype prediction. Glioma morphological characteristics, molecular and pathological levels, and clinical data showed significant differences and correlations. An automatic segmentation model for gliomas based on 3D U-Nets was developed, and the prediction model for gliomas built using the parameters obtained from the automatic segmentation model showed high overall performance.

Objective To investigate the effect and potential molecular mechanism of PTGS2 on the prognosis of colon cancer patients. Methods The transcriptomic and proteomic data of pan-cancer were collected from TCGA, HPA, UALCAN and other databases, and the expression pattern and prognostic value of PTGS2 were analyzed by combining the clinical data such as staging, histology, survival time and so on. Based on GSEA, the biological functions which were significantly activated in patients with high expression of PTGS2 were identified and the colon cancer cell line SW480 was used as an example for in vitro validation. PTGS2 over-expressing cell strains were constructed, and the effect on cell proliferation was determined by CCK8 method. Different concen- trations of H2O2 were used to form gradient oxidative stress, and the changes in cell antioxidant capacity were detected. The regulatory mechanism was preliminarily verified by Western blot. Results The transcription and expression of PTGS2 were found to be significantly up-regulated in colon cancer patients (P＜0.05), and the increased expression of PTGS2 was associated with an increased mortality risk (P＜0.05). Data analysis and in vitro experiments showed that over-expression of PTGS2 may promote the proliferation of colon cancer cells by activating the mTOR pathway. The antioxidant effect of cells was regulated by up-regulating oxidative stress regulatory proteins SOD2 and NRF2. Conclusions PTGS2 is a potential risk factor for colon cancer and its over-expression promotes cell proliferation, enhances cell antioxidant effect and is associated with poor prognosis of colon cancer patients.

Abstract To explore a method to identify the sensory and motor fascicles of the peripheral nerve to achieve accurate peripheral nerve functional fascicle suture. The peripheral nerve Sunderland V injury model, muscle branch of the femoral nerve and saphenous nerve were established in the bilateral femoral nerves of Sprague-Dawley (SD) rats. The specific samples were grouped as follows: the main trunk of the femoral nerve was exposed bilaterally and cut with microscopic scissors in the main trunk of the femoral nerve to prepare a model of Sunderland V injury in the mixed fascicle of peripheral nerves; the muscle branch of the femoral nerve was exposed bilaterally and cut in the middle section of the muscle branch of the femoral nerve to prepare a model of Sunderland V injury in the motor fascicle of peripheral nerves; the saphenous nerve was exposed bilaterally and cut at 1 cm below the patella to prepare a model of Sunderland V injury to the sensory fascicle of the peripheral nerves. A carbon quantum dot (CD)-annexin V antibody complex was prepared and applied to the distal and proximal nerve stumps of the peripheral nerve Sunderland V injury model groups of SD rats. Under the excitation light source of a 380 nm uv lamp, fluorescence color development was observed under a fluorescence microscope after 5, 10, 15, and 20 min. At 5 min, sections of the bilateral femoral nerve trunk, muscular branches of the femoral nerve, and Sunderland V lesion of the saphenous nerve in SD rats were only dark in color under the microscope, and there was no difference in fluorescence. The intensity of the staining increased significantly for 10–20 min. The sensory fascicles and saphenous nerves of the femoral nerve trunk showed blue fluorescence under the CD-Annexin V antibody complex staining, while the motor fascicles and muscle branches of the femoral nerve trunk showed no fluorescence. Fluorescence intensity gradually decreased after 20 min of staining. There was no significant difference in the staining intensity at 5, 10, 15, and 20 min in each group. Our results suggest that the CD-Annexin antibody complex can be used to identify functional fascicles of peripheral nerves in SD rats.

Abstract Spinal cord stimulation (SCS) has shown effectiveness in relieving zoster-associated pain (ZAP), but some patients still experience moderate or severe pain after SCS treatment. This study aims to evaluate the impact of SCS combined with dorsal root ganglion (DRG) pulsed radiofrequency (PRF) as a dual neuromodulation strategy on the prognosis of ZAP. The clinical records of patients diagnosed with ZAP who underwent SCS (SCS group) or SCS combined with PRF (SCS + PRF group) at The Third Xiangya Hospital, Central South University, were retrospectively analyzed to compare the effectiveness of the two treatment approaches for ZAP. Outcome measures included changes in Visual Analog Scale (VAS) scores before and after neuromodulation treatment, response rates, and incidence of progression to postherpetic neuralgia (PHN).13 SCS patients and 15 SCS + PRF patients were analyzed. Admission VAS scores were similar (P = 0.934). Upon discharge, no significant differences in VAS or response rates were observed (P > 0.05). However, at 6-month follow-up, the SCS + PRF group had lower VAS scores (1.53 ± 1.06 vs. 3.23 ± 1.50, P

Abstract The potential benefit of neoadjuvant toripalimab plus axitinib in cases with clear cell renal cell carcinoma (ccRCC) and inferior vena cava tumor thrombus (IVC-TT) remains unclear. NEOTAX was a phase 2 study to investigate the efficacy and safety of neoadjuvant toripalimab plus axitinib in patients with ccRCC and IVC-TT (ChiCTR2000030405). The primary endpoint was the down-staging rate of IVC-TT level. Secondary endpoints included change in TT length, response rate, percentage change in surgical approach, surgical morbidity, progression-free survival (PFS), safety, and biomarker analyses. In all, 25 patients received study treatment, 44.0% (11/25) patients had a reduction in thrombus level, and none experienced an increase in Mayo level. The median change in tumor thrombus length was −2.3 cm (range: −7.1 to 1.1 cm). Overall, 61.9% (13/21) patients experienced changes in surgical strategy compared with planned surgery, three patients experienced major complications. The median PFS was 25.3 months (95% CI: 17.0-NE). The 1-year PFS was 89.1% (95% CI: 62.7–97.2). No any of grade 4 or 5 treatment-related adverse event was identified. Biopsy samples of non-responders exhibited increased T cytotoxic cell infiltration, but these cells were predominantly PD-1 positive. Biopsy samples of responders exhibited lower T helper cells, however, their subtype, regulatory T cells remained unchanged. In surgical samples of the TT, non-responders exhibited increased CD8T_01_GZMK_CXCR4 subset T cells. NEOTAX met preset endpoints proving that toripalimab in combination with axitinib downstages IVC-TT in a significant proportion of patients leading to simplification in the procedure of surgery.

Abstract With the 5G and the popularity of high-definition and ultrahigh-definition equipment, people have increasingly higher requirements for the resolution of images or videos. However, the transmission pressure on servers is also gradually increasing. Therefore, superresolution technology has attracted much attention in recent years. Simultaneously, with the further development of deep learning techniques, superresolution research is shifting from the calculation of traditional algorithms to the deep learning method, which exhibits a greatly superior final display. First, the traditional block-matching-3D (BM3D) algorithm is formed as the postprocessing module, which can avoid the uneven edge of GAN network recovery, make the picture appear more authentic, and improve the viewer’s subjective feelings. Next, the adaptive-downsampling model (ADM) is utilized to train models for specific camera styles. The high-resolution (HR) data sequence is subsequently downsampled to a low-resolution (LR) data sequence, enabling the superresolution algorithm to utilize this training set. This method can obtain better results and improve overall performance by 0.1~0.3 dB.

Background The effective evaluation of scientific and technological achievements in traditional Chinese medicine (TCM) is of great significance in promoting the innovative development of TCM. Previous evaluations of scientific and technological achievements in TCM often used a generalized evaluation method, leading to problems such as inappropriate indicators and limited dimensions, which is not conducive to reflecting the multiple values of achievements in a scientific and comprehensive way. Consequently, there is an urgent need to establish categorized and multi-dimensional evaluation index system for the evaluation of scientific and technological achievements in TCM in the new period. Objective To establish a scientific, categorized, reliable and comprehensive evaluation index system that reflects the principles of TCM and highlights its unique advantages aiming at the scientific and technological achievements in TCM, in accordance with the contemporary requirements for scientific and technological evaluation in China. Methods This study began in November 2022 and was completed in May 2023. A preliminary index framework was developed through literature review and focus group discussions. Delphi expert consultation was then conducted over two rounds to determine the evaluation indexes and points. The hierarchical analysis method was used to calculate the weight of each index. Results The final evaluation index system of scientific and technological achievements in TCM clinical research comprised 10 threshold indicators, 4 primary indicators, 17 secondary indicators, and 17 evaluation points. After testing, the positive coefficient of experts in both rounds of Delphi method implementation was 100%, the authority coefficient was 0.94 and 0.93, respectively. The Kendall's W consistency test for each level of indicators yielded two-tailed significance (P

Abstract The ecological benefits and concerns surrounding fossil fuels had led to increased interest in bio-based rigid polyurethane foam (RPUF). Nonetheless, due to its flammability, it had limited application in various fields. To solve this problem, a green bio-flame retardant, cobalt hydroxystannate (CoSn(OH)6), was prepared and compounded with montmorillonite (MMT) and chick feather protein (CF), and applied to RPUF, which not only realized the regeneration of resources, but also provided RPUF with better thermal stability, flame retardancy and smoke suppression properties. The experimental results showed that when 3 wt% CoSn(OH)6 was added, the RPUF (CF1/MMT3/Co3) had the greatest activation energy. In addition, the peak heat release rate (PHRR) and total heat release (THR) of CF1/MMT3/Co3 decreased by 12.73%, and 11.16% respectively, compared with no CoSn(OH)6. In addition, its Ds decreased by 28.9% and the light transmittance increased by 17.6% compared with the RPUF without CoSn(OH)6. At the same time, its peak smoke production rate (PSPR) and the total smoke release (TSR) decreased by 25% and 18%. And CF1/MMT3/Co3 also had the lowest fire risk evaluation index. This study presented possibilities for practical utilization of the RPUF substances founded on bio-based flame inhibitors.

Abstract Analysis of protein modifications is critical for quality control of therapeutic biologics. However, the identification and quantification of naturally occurring glycation of membrane proteins by mass spectrometry remain technically challenging. We used highly sensitive LC MS/MS analyses combined with multiple enzyme digestions to determine low abundance early-stage lysine glycation products of influenza vaccines derived from embryonated chicken eggs and cultured cells. Straightforward sequencing was enhanced by MS/MS fragmentation of small peptides. As a result, we determined a widespread distribution of lysine modifications attributed by the region-selectivity and site-specificity of glycation toward influenza matrix 1, hemagglutinin and neuraminidase. Topological analysis provides insights into the site-specific lysine glycation, localizing in the distinct structural regions of proteins surrounding the viral envelope membrane. Our finding highlights the proteome-wide discovery of lysine glycation of influenza membrane proteins and potential effects on the structural assembly, stability, receptor binding and enzyme activity, demonstrating that the impacts of accumulated glycation on the quality of products can be directly monitored by mass spectrometry-based structural proteomics analyses.

Abstract The concept of sustainable development has led to a growing research interest in bio-based flame-retardant polyurethane foams. These foams offer environmentally friendly, sustainable, and flame-retardant raw materials for the construction, automotive, and furniture industries. The 15 wt% soybean oil-based polyol rigid polyurethane foams (RPUF-S3A20B system) were modified with 20 wt% ammonium polyphosphate (APP) and homemade magnesium borate hydroxide (MgBO2(OH)). Thermogravimetric analysis, pyrolysis kinetic analysis, limiting oxygen index (LOI) test, cone calorimetry (CONE), morphological analysis, and smoke density (Ds) were employed to investigate the impact of MgBO2(OH) on the thermal stability and flame-retardant properties of the RPUF-S3A20B system. The results indicated that RPUF-S3A20B12.5 with 12.5 wt% MgBO2(OH) had better thermal stability and higher activation energy. In addition, its LOI was increased by 3.1% compared to RPUF-S3A20 without MgBO2(OH). The peak heat release rate (PHRR) and total heat release rate (THR) of RPUF-S3A20B12.5 at a radiant flux of 25 kW/m2 were reduced by 45.8% and 35.0% compared with RPUF-S3A20. RPUF-S3A20B12.5 demonstrated the lowest smoke density (17.4 and 17.5) and highest light transmission (73.9% and 73.7%) in both flameless and flame conditions, indicating superior flame-retardant and smoke-suppression properties. These findings offered valuable insights for further research on synergistic flame-retardant systems in bio-based polyurethane foams.

Abstract Lane line images have the essential attribute of large-scale variation and complex scene information, and the similarity between adjacent lane lines is high, which can easily cause classification errors. And remote lane lines are difficult to recognize due to visual angle changes in width. To address this issue, this paper proposes an effective lane detection framework, which is a hybrid feature fusion network that enhances multiple spatial features and distinguishes key features throughout the entire lane line segment. It enhances and fuses lane line features at multiscale to enhance the feature representation of lane line images, especially at the far end. Firstly, in order to enhance the correlation of multiscale lane features, a multi-head self attention is used to construct a multi-space attention enhancement module for feature enhancement in multispace. Secondly, a spatial separable convolutional branch is designed for the jumping layer structure connecting multiscale lane line features. While retaining feature information of different scales, important lane areas in multiscale feature information are emphasized through the allocation of spatial attention weights. Finally, considering that lane lines are elongated areas in the image, and the background information in the image is much more abundant than lane line information, the flexibility of traditional pooling operations in capturing widely existing anisotropic contexts in actual environments is limited. Therefore, before embedding feature output branches, strip pooling is introduced to refine the representation of lane line information and optimize model performance. The experimental results show that the accuracy on the TuSimple dataset reaches 96.84%, and the F1 score on the CULane dataset reaches 75.9%.

Abstract A bio-based flame retardant nickel phytate (PA-Ni) was synthesized and combined with soybean oil-based polyol (SO) to create a green rigid polyurethane foam (RPUF) with enhanced compressive strength, good thermal stability and flame retardant. The results showed that the RPUF-SO2/Ni3 with 3 wt% PA-Ni had the highest initial and termination temperature, maximum thermal decomposition rate temperature and carbon residue, and better thermal stability. Its limiting oxygen index was increased by 2.6% compared with RPUF-SO2 without PA-Ni added, and the peak heat release rate (PHRR) and total heat release rate (THR) were reduced by 14.92% and 19.92%, respectively. In addition, RPUF-SO2/Ni3 had the lowest Ds under the conditions of flame (18.90) and flameless (22.41), and had the best smoke suppression effect. And the compressive strength of RPUF-SO/Ni3 was significantly enhanced by the addition of PA-Ni. The results show that the improvement of flame retardancy of RPUF is mainly the result of the combined effect of gas-phase and condensed-phase flame retardancy, among which the flame retardancy of RPUF-SO/Ni3 was the best. The current findings offer a practical way to produce green and low-carbon RPUF as well as promising prospects for the material's safe application.

Abstract Our objective was to examine the impact of elective neck dissection (END) on the prognosis of patients with cT2N0 maxillary sinus squamous cell carcinoma (MS-SCC) and to determine factors that predict the occurrence of occult metastasis in this patient population. A retrospective analysis was conducted using data from the SEER database. Patients with cT2N0 MS-SCC were included in the study and divided into two groups: those who received END and those who did not. The impact of END on disease-specific survival (DSS) and overall survival (OS) was assessed using propensity score matching. Multivariate logistic regression analysis was performed to determine predictors for occult metastasis. A total of 180 patients were included in the study, with 40 cases receiving END. Following propensity score matching, patients treated with END and those without showed similar DSS and OS rates. Occult metastasis was observed in 9 patients, corresponding to a rate of 22.5%. High-grade tumors were independently associated with a higher risk of occult metastasis compared to low-grade tumors (hazard ratio 1.52, 95% confidence interval 1.17–2.00). cT2 MS-SCC carries an occult metastasis rate of 22.5%, with histologic grade being the primary determinant of occult metastasis. END does not confer a significant survival benefit in this patient population.

Objectives We aimed to explore the lived experiences and needs of women after a recent stillbirth event.Design Qualitative phenomenological study.Setting The current study was conducted in a tertiary obstetric hospital in East China between 25 January 2024 and 29 March 2024.Participants 14 women having experienced a stillbirth within the last 6 months.Results Researchers agreed on four key themes including individual variations in emotional reaction and recovery, physical recovery and concerns about future pregnancies, the critical role of social support systems and variations in perceptions of stillbirth as the death of a fetus versus a human being, along with related mourning rituals. These themes collectively highlight the multifaceted nature of the stillbirth experience, underscoring the complex interplay between personal, cultural and medical factors that shape women’s emotional and physical responses.Conclusions Post-stillbirth experiences among Chinese women are deeply individualised and influenced by a complex interplay of personal emotions, cultural contexts and medical interactions. It is imperative for healthcare systems to implement tailored care strategies beyond standard protocols to proactively address their varied emotional landscapes and physical concerns with an enhanced awareness of cultural sensitivities. Specialised training for healthcare providers should be devised to recognise and respond to the unique grief processes. Comprehensive support systems should be established to significantly enhance the recovery journey by providing essential resources and community connections.

Abstract Prostate cancer lineage plasticity is a key driver in the transition to neuroendocrine prostate cancer (NEPC), and the RTK/RAS signaling pathway is a well-established cancer pathway. Nevertheless, the comprehensive link between the RTK/RAS signaling pathway and lineage plasticity has received limited investigation. In particular, the intricate regulatory network governing the interplay between RTK/RAS and lineage plasticity remains largely unexplored. The multi-omics data were clustered with the coefficient of argument and neighbor joining algorithm. Subsequently, the clustered results were analyzed utilizing the GSEA, gene sets related to stemness, multi-lineage state datasets, and canonical cancer pathway gene sets. Finally, a comprehensive exploration of the data based on the ssGSEA, WGCNA, GSEA, VIPER, prostate cancer scRNA-seq data, and the GPSAdb database was conducted. Among the six modules in the clustering results, there are 300 overlapping genes, including 3 previously unreported prostate cancer genes that were validated to be upregulated in prostate cancer through RT-qPCR. Function Module 6 shows a positive correlation with prostate cancer cell stemness, multi-lineage states, and the RTK/RAS signaling pathway. Additionally, the 19 leading-edge genes of the RTK/RAS signaling pathway promote prostate cancer lineage plasticity through a complex network of transcriptional regulation and copy number variations. In the transcriptional regulation network, TP63 and FOXO1 act as suppressors of prostate cancer lineage plasticity, whereas RORC exerts a promoting effect. This study provides a comprehensive perspective on the role of the RTK/RAS pathway in prostate cancer lineage plasticity and offers new clues for the treatment of NEPC.

Abstract Herpesviruses are large double-stranded DNA viruses that cause infections in animals and humans with a characteristic of latent infectious within specific tissues. Bats are natural hosts of variety human-infecting viruses and recently have been described as hosts for herpesviruses in several countries around the world. In this study we collected 140 insectivorous bats in the neighboring urban areas of Wuhan City, Hubei Province in the central China between 2020 and 2021. Nested PCR targeting the dpol gene sequence indicated that a total of 22 individuals (15.7% of the sample) tested positive for herpesvirus with 4 strains belonging to the genus Betaherpesvirus and the remaining 18 strains classified as Gammahersvirus. Furthermore, the herpesvirus prevalence in Rhinolophus pusillus was higher at 26.3%, compared to 8.4% in Myotis davidii. The RP701 strain from R. pusillus was the predominant gammaherpesvirus strain detected in bats, accounting for 94.4% (17/18) of all strains. The variations in γ-herpesviruses genomic sequences was evident in phylogenetic tree, where RP701 strain was clustered together with ruminant γ-herpesviruses, while MD704 strain formed a distinct clade with a hedgehog γ-herpesvirus. Four betaherpesviruses exclusively identified from M. davidii, with nucleotide identities ranging from 79.7 to 82.6% compared to known betaherpesviruses. Our study provided evidence that M. davidii can sever as natural host for β-herpesviruses, which extended the host species range. In conclusion, we found that bats from central China harbored novel β-herpesviruses and γ-herpesviruses which were phylogenetically related to ruminant γ-herpesvirus and hedgehog γ-herpesvirus. Our study indicates that bats are natural hosts of β- and γ-herpesviruses and further studies are needed to determine whether there is cross-species transmission of herpesviruses between bats and other animals, or humans.

Background: Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others. Aims: To investigate the role of TSLP in the pathogenesis of psoriasis. Study Design: In vitro and in vivo study. Methods: To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells. Conclusion: These findings indicated that TSLP exerted its immune-modulating effect in psoriasis through the JAK/SYK pathway.

Abstract Depression, a pervasive global mental disorder, profoundly impacts daily lives. Despite numerous deep learning studies focused on depression detection through speech analysis, the shortage of annotated bulk samples hampers the development of effective models. In response to this challenge, our research introduces a transfer learning approach for detecting depression in speech, aiming to overcome constraints imposed by limited resources. In the context of feature representation, we obtain depression-related features by fine-tuning wav2vec 2.0. By integrating 1D-CNN and attention pooling structures, we generate advanced features at the segment level, thereby enhancing the model's capability to capture temporal relationships within audio frames. In the realm of prediction results, we integrate LSTM and self-attention mechanisms. This incorporation assigns greater weights to segments associated with depression, thereby augmenting the model's discernment of depression-related information. The experimental results indicate that our model has achieved impressive F1 scores, reaching 79% on the DAIC-WOZ dataset and 90.53% on the CMDC dataset. It outperforms recent baseline models in the field of speech-based depression detection. This provides a promising solution for effective depression detection in low-resource environments.

Abstract It is important to investigate the responses of greenhouse gases to climate change (temperature, precipitation) and anthropogenic factors in plateau wetland. Based on the DNDC model, we used meteorological, soil, and land cover data to simulate the soil CO2 emission pattern and its responses to climate change and anthropogenic factors in Guizhou, China. The results showed that the mean soil CO2 emission flux in the Caohai Karst Plateau Wetland was 5.89 ± 0.17 t·C·ha−1·yr−1 from 2000 to 2019, and the annual variation showed an increasing trend with the rate of 23.02 kg·C·ha−1·yr−1. The soil total annual mean CO2 emissions were 70.62 ± 2.04 Gg·C·yr−1 (annual growth rate was 0.28 Gg·C·yr−1). Caohai wetland has great spatial heterogeneity. The emissions around Caohai Lake were high (the areas with high, middle, and low values accounted for 3.07%, 70.96%, and 25.97%, respectively), and the emission pattern was characterized by a decrease in radiation from Caohai Lake to the periphery. In addition, the cropland and forest areas exhibited high intensities (7.21 ± 0.15 t·C·ha−1·yr−1 and 6.73 ± 0.58 t·C·ha−1·yr−1, respectively) and high total emissions (54.97 ± 1.16 Gg·C·yr−1 and 10.24 ± 0.88 Gg·C·yr−1, respectively). Croplands and forests were the major land cover types controlling soil CO2 emissions in the Caohai wetland, while anthropogenic factors (cultivation) significantly increased soil CO2 emissions. Results showed that the soil CO2 emissions were positively correlated with temperature and precipitation; and the temperature change had a greater impact on soil respiration than the change in precipitation. Our results indicated that future climate change (increased temperature and precipitation) may promote an increase in soil CO2 emissions in karst plateau wetlands, and reasonable control measures (e.g. returning cropland to lakes and reducing anthropogenic factors) are the keys to controlling CO2 emissions.

Abstract Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20–1.45, p = 1.66E−08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.

Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients’ cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. Methods In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. Results Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. Conclusions In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.

Abstract Background Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood–brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. Methods To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53−/−). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). Results FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3–4 weeks post-RT. Conclusion Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

Purposes To probe the expression, clinical significance, roles, and molecular mechanisms of circRNA_000166 in breast cancer (BC).Methods Clinical tissue samples were gathered from 84 BC patients who underwent surgery at the Affiliated Hospital of Chengde Medical College. Clinical data were obtained from medical records and postoperative follow-up. Expression levels of circRNA_000166, miR-326, miR-330-5p, and ELK1 mRNA in BC tissues and cells were measured by qRT-PCR, and ELK1 protein levels were assessed by WB. Pearson’s correlation analysis evaluated the interrelationships between these RNAs in clinical samples. Luciferase reporter assays verified the interactions between miR-326/miR-330-5p and circRNA_000166, as well as between miR-326/miR-330-5p and ELK1. Cell proliferation, migration, and apoptosis were examined using CCK-8, colony formation, transwell, and flow cytometry assays, respectively.Results CircRNA_000166 was highly expressed in BC tissues and inversely correlated with miR-326/miR-330-5p levels but positively with ELK1 mRNA levels. ELK1 mRNA also inversely associated with miR-326/miR-330-5p levels in BC tissues. Importantly, our findings demonstrated that circRNA_000166 targets miR-326 and miR-330-5p, while ELK1 is the target of miR-326 and miR-330-5p in BC cells. CircRNA_000166 levels positively correlated with tumour size, TNM stage, histological grade, and lymph node metastasis, and negatively associated with postoperative progression-free survival (PFS) and overall survival (OS) in BC patients. CircRNA_000166 was also highly expressed in BC cells, and knockdown of circRNA_000166 reduced proliferation and migration, and increased apoptosis via miR-326/ELK1 and miR-330-5p/ELK1 pathways in vitro.Conclusion CircRNA_000166 enhances BC progression through miR-326/ELK1 and miR-330-5p/ELK1 pathways and shows potential as a biomarker for BC diagnosis and treatment.

Abstract Maturation of the secondary antibody repertoire requires class‐switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high‐affinity antibodies. Following immune response or infection within the body, activation of T cell‐dependent and T cell‐independent antigens triggers the activation of activation‐induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper‐IgM syndrome, Waldenström macroglobulinemia, hyper‐IgD syndrome, selective IgA deficiency, hyper‐IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Abstract Microplastics are exotic pollutants and are increasingly detected in soil, but it remains poorly understood how microplastics impact soil and plant systematically. The present study was conducted to evaluate the effects of polyvinyl chloride microplastics (PVC-MPs) on wheat seedlings performance and soil properties. Under the stress of PVC-MPs, no new substance and functional groups were generated in soil by X-ray diffraction and the fourier transform infrared spectroscopy analyses, whereas the diffraction and characteristic peaks and of soil was affected by PVC-MPs. Wheat seedlings shoot biomass and soil nitrate nitrogen were significantly inhibited by PVC-MPs. Chlorophylls were not significant affected by PVC-MPs. Superoxide dismutase, catalase, and peroxidase activities in wheat seedlings increased, while malondialdehyde and proline contents decreased significantly. Redundancy analysis displayed that wheat seedlings traits can be largely explained by soil nitrate nitrogen. Our results indicate that PVC-MPs have more significant influence on soil structure than on soil substance composition. Moreover, even though antioxidant enzyme activities were improved to respond the stress of PVC-MPs, wheat seedlings are not severely impacted by PVC-MPs. Besides, soil nitrate nitrogen is the main factor on wheat seedlings performance and wheat seedlings are prone to ensure the root growth under the stress of PVC-MPs.

Abstract Several studies have reported the effects of DJ-1 gene and miR-199a/b-3p on HCC development. However, whether miR-199a/b-3p regulates HCC progression through a novel compensatory signaling pathway involving DJ-1, Ras, and PI3K/AKT remains unknown. We used (TCGA, HPA, miRWalk and Target scan) databases, cancer and para-tissue HCC patients, dual-luciferase reporter gene analysis, proteomic imprinting, qPCR, cell proliferation, scratch, transport, and flow cytometry to detect the molecular mechanism of DJ-1 and miR-199a/b-3p co-expression in HCC cell lines. Bioinformatics analysis showed that DJ-1 was highly expressed in HCC ((P

Abstract In recent years, deep neural networks have evolved rapidly in engineering technology, with models becoming larger and deeper. However, for most companies, developing large models is extremely costly and highly risky. Researchers usually focus on the performance of the model, neglecting its cost and accessibility. In fact, most regular business scenarios do not require high-level AI. A simple and inexpensive modeling method for fulfilling certain demands for practical applications of AI is needed. In this paper, a Fragmented neural network method is proposed. Inspired by the random forest algorithm, both the samples and features are randomly sampled on image data. Images are randomly split into smaller pieces. Weak neural networks are trained using these fragmented images, and many weak neural networks are then ensembled to build a strong neural network by voting. In this way, sufficient accuracy is achieved while reducing the complexity and data volume of each base learner, enabling mass production through parallel and distributed computing. By conducting experiments on the MNIST and CIFAR10 datasets, we build a model pool using FNN, CNN, DenseNet, and ResNet as the basic network structure. We find that the accuracy of the ensemble weak network is significantly higher than that of each base learner. Meanwhile, the accuracy of the ensemble network is highly dependent on the performance of each base learner. The accuracy of the ensemble network is comparable to or even exceeds that of the full model and has better robustness. Unlike other similar studies, we do not pursue SOTA models. Instead, we achieved results close to the full model with a smaller number of parameters and amount of data.

Abstract It is difficult to predict the surgical effect and outcome of severe traumatic brain injury (TBI) before surgery. This study aims to approve an evaluation method of computed tomography angiography (CTA) to predict the effect of surgery and outcome in severe TBI. Between January 2010 and January 2020, we retrospectively reviewed 358 severe TBI patients who underwent CTA at admission and reexamination. CTA data were evaluated for the presence of cerebrovascular changes, including cerebrovascular shift (CS), cerebral vasospasm (CVS), large artery occlusion (LAO), and deep venous system occlusion (DVSO). Medical records were reviewed for baseline clinical characteristics and the relationship between CTA changes and outcomes. Cerebrovascular changes were identified in 247 (69.0%) of 358 severe TBI patients; only 25 (10.12%) of them had poor outcomes, and 162 (65.6%) patients had a good recovery. Eighty-three (23.18%) patients were diagnosed with CVS, 10 (12.05%) had a good outcome, 57 (68.67%) had severe disability and 16 (19.28%) had a poor outcome. There were twenty-six (7.3%) patients who had LAO and thirty-one (8.7%) patients who had DVSO; no patients had good recovery regardless of whether they had the operation or not. Cerebrovascular injuries and changes are frequent after severe TBI and correlate closely with prognosis. CTA is an important tool in evaluating the severity, predicting the operation effect and prognosis, and guiding therapy for severe TBI. Well-designed, multicenter, randomized controlled trials are needed to evaluate the value of CTA for severe TBI in the future.

Abstract Background Glioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM. Methods The synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. Results Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity. Conclusion Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials. Video Abstract

Abstract Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.

Abstract The shear mechanical properties of F-type socket joints in rectangular pipe jacking tunnels are currently unknown. To investigate the shear mechanical response and deformation failure of the F-type socket joint in rectangular pipe jacking tunnels under different foundation coefficients, a laboratory joint test and numerical simulation method were used, considering the structural features of the joint. The results showed that the deformation process of a joint subjected to shear consists of four stages: gap closure, elastic growth, shear strengthening, and yield failure. The ultimate shear capacity of the joint increases by 25% to 34% for every 3 mm increase in the steel ring thickness. The chamfer yield damage area comprises approximately 15% of the steel ring. The joint concrete crack first appears at the top of the socket joint, and the concrete damage area accounts for about 40% of the whole pipe section. The failure characteristics of the joint are primarily manifested as drum and warp of the steel ring or cracking of the weld, and the concrete at the joint is crushed. In practical engineering, the weld should not be located at the chamfer. The steel ring at the chamfer needs to be locally strengthened, and the chamfer and the reinforcement at the top and bottom need to be increased to improve the bearing capacity of the concrete.

Objectives: To address the poor efficacy and percutaneous penetration of grape seed oil, ionic liquids and nanotechnology were combined to prepare a grape seed oil emulsion. Methods: A novel Menthol-CoQ10 ionic liquid and ionic liquid based grapeseed oil emulsion were prepared and confirmed. Results: The average size of the grapeseed oil emulsion was 218 nm, and its zeta potential was −33.5 mV. The ionic liquid-based grape seed oil emulsion exhibited a transdermal penetration effect 4.63-fold higher than that of ordinary grape seed oil emulsion. Ionic liquid also displayed enhanced efficiency both in vitro and in vivo. It significantly inhibited the production of DPPH free radicals and tyrosinase, inhibited melanin and matrix metalloproteinase-1 (MMP-1) produced by cells, and promoted type I collagen expression in fibroblasts. After 28 days of continuous use, the grapeseed oil emulsion improved the water content of the stratum corneum and the rate of transepidermal water loss, enhanced the firmness and elasticity of the skin, and significantly improved the total number and length of under-eye lines, tail lines, nasolabial folds, and marionette lines on the face. Conclusions: Menthol-CoQ10 ionic liquid is a promising functional excipient for both transdermal delivery increase and efficient enhancement. Ionic liquid and nanotechnology for grape seed oil facial mask displayed significantly enhanced efficacy and permeability.

Objective To systematically assess the diagnostic accuracy of CXCL13 testing of cerebrospinal fluid (CSF) for neurosyphilis diagnosing.Design Systematic review and meta-analysis.Data sources PubMed, Embase, Cochrane Library and Web of Science databases from their inception until 1 May 2023.Eligibility criteria Both cross-sectional and case–control diagnostic test studies evaluating the diagnostic value of CSF CXCL13 in diagnosing neurosyphilis were included, with no language restrictions.Data extraction and synthesis Two researchers extracted data independently from all finally included articles. The updated Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. Quantitative synthesis was done using a bivariate random-effects model.Results This meta-analysis included seven eligible studies involving a total of 1152 patients with syphilis and 430 patients with neurosyphilis. The pooled sensitivity, specificity and summary area under the curve (AUC) of CSF CXCL13 testing for the diagnosis of neurosyphilis were 0.76 (95% CI 0.64 to 0.85; I2=82%), 0.83 (95% CI 0.80 to 0.85; I2=32.29%) and 0.84 (95% CI 0.81 to 0.87), respectively. Sensitivity analysis confirmed the stability of the combined results. Meta-regression analysis revealed that the heterogeneity of pooled sensitivity was related to different study regions; subgroup analysis indicated that the diagnostic value of CSF CXCL13 testing reported in studies from China was superior to that reported in non-Chinese studies (pooled sensitivity, specificity and summary AUC values were 0.84 (I2=0) vs 0.64 (I2=79.53%), 0.83 (I2=42.03%) vs 0.83 (I2=32.87%) and 0.87 vs 0.83, respectively). The diagnostic value reported in studies with a sample size ≥200, unclassified neurosyphilis and HIV-negative subgroups was superior to the total combined value.Conclusions This meta-analysis has demonstrated a reasonable level of accuracy for diagnosis of neurosyphilis with CSF CXCL13 testing. Further multicentre, prospective diagnostic studies, especially in asymptomatic neurosyphilis and HIV-infected patients, are needed to provide more evidence for evaluation before clinical application.PROSPERO registration number CRD42023414212.

Abstract Colorectal cancer (CRC) is a common and deadly cancer worldwide with a high lethality rate. Disulfidptosis has been found to be an emerging mode of death in cancer, and the purpose of this study was to explore the relationship between disulfidptosis-related lncRNAs (DRLs) and CRC and to develop a prognostic model for CRC and DRLs. The gene expression data and clinicopathologic information of colorectal cancer patients were obtained from The Cancer Genome Atlas (TCGA) and screened for DRLs based on correlation analysis. The least absolute shrinkage and selection operator (LASSO) and Cox regression were used to construct the prognostic model, and its validation was carried out by PCA and receiver operating characteristic (ROC) curves. We constructed nomograms combined with the model. Finally, the possible mechanisms by which lncRNAs affect CRC were explored by functional enrichment analysis, immune infiltration and immune escape analysis. In summary, we developed a prognostic marker consisting of lncRNAs associated with disulfidptosis to help clinicians predict the survival of different CRC patients and use different targeted therapies and immunotherapies depending on the condition.

Abstract The transit signal priority leads to the delay of private vehicles in the priority and non-priority phases. To address this problem, a bi-level programming model is proposed based on the dynamic cycle and arrival rate of private vehicles under connected environment. The upper model is built by a delay triangle, with the maximum delay reduction of private vehicles between the decreased delay and increased delay in the experimental period. The lower model is constructed based on the Stackelberg model of game theory, and the objective is to obtain the dynamic cycle. A genetic algorithm (GA) is implemented to solve the proposed model. Based on SUMO, a case study of a self-driving bus in the city of Zhengzhou is conducted to demonstrate the effectiveness of the proposed model. The results from GA and SUMO are consistent, which verifies the effectiveness of the proposed model. The delay of the private vehicles with dynamic signal priority declines by 21.32% on average compared to that without priority. Compared with active signal priority, it declines by 22.63% on average. The proposed method is compared with the method proposed by other papers, and the delay per private vehicle is small. The effectiveness of the proposed method is further illustrated. The proposed methodology is helpful for improving the operation efficiency of intersections with minimum delay.

Abstract Background Infection rate of varicella zoster virus (VZV) is 95% in humans, and VZV infection is strongly associated with ischemic stroke (IS). However, the underlying molecular mechanisms of VZV-induced IS are still unclear, and there are no effective agents to treat and prevent VZV-induced IS. Objective By integrating bioinformatics, this study explored the interactions between VZV and IS and potential medication to treat and prevent VZV-induced IS. Methods In this study, the VZV and IS datasets from the GEO database were used to specify the common genes. Then, bioinformatics analysis including Gene Ontology, Kyoto Encyclopedia Genes Genomes and Protein–Protein Interaction network analysis was performed. Further, the hub genes, transcription factor (TF) gene interactions, TF-miRNA co-regulatory network and potential drug were obtained. Finally, validation was performed using molecular docking and molecular dynamics simulations. Results The potential molecular mechanisms of VZV-induced IS were studied using multiple bioinformatics tools. Ten hub genes were COL1A2, DCN, PDGFRB, ACTA2, etc. TF genes and miRNAs included JUN, FOS, CREB, BRCA1, PPARG, STAT3, miR-29, etc. A series of mechanism may be involved, such as inflammation, oxidative stress, blood–brain barrier disruption, foam cell generation and among others. Finally, we proposed resveratrol as a potential therapeutic medicine for the prevention and treatment of VZV-induced IS. Molecular docking and molecular dynamics results showed that resveratrol and hub genes exhibited strong binding score. Conclusions Resveratrol could be an alternative for the prevention and treatment of VZV-IS. More in vivo and in vitro studies are needed in the future to fully explore the molecular mechanisms between VZV and IS and for medication development.

Abstract Abnormal expression of the potassium channel tetramerization domain containing 12 (KCTD12) is closely related to the occurrence and development of various tumors, but a pan-cancer analysis of KCTD12 has not yet been conducted. We explored the association between KCTD12 and more than 30 human malignancies using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, the mRNA and protein levels of KCTD12 were examined and their correlations with tumor stage and survival were explored. Second, we analyzed the infiltration of CD8+ and CD4+ T cells and cancer-associated fibroblasts in tumors and explored the correlation between KCTD12 expression and tumor cell stemness, genomic heterogeneity, and diagnostic specificity. Finally, we explored the molecular mechanisms associated with KCTD12 using KEGG/GO analysis. The results showed that KCTD12 mRNA and protein expression levels decreased in most tumors was significantly associated with the prognosis of tumor patients, and the phosphorylation level of KCTD12 decreased in several tumors, such as S200 and T196, pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), and breast invasive cancer (BRCA). The expression of KCTD12 was positively correlated with the degree of cancer-associated fibroblasts infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), PAAD, and stomach adenocarcinoma (STAD). The relationship between KCTD12 expression and CD8+ and CD4+ T cell infiltration was also clarified. KCTD12 showed high diagnostic sensitivity for various types of tumors and may be involved in tumor cell biology by affecting tumor cell stemness, tumor burden, and other characteristics. Finally, we analyzed the molecular functions of KCTD12 and possible KEGG/GO signaling pathways. In this study, we developed a biological marker for diagnosis, prognosis, and immune infiltration of the pan-cancers.

Abstract Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword “ubiquitin-dependent protein catabolic process”, “protein ubiquitination”, and “protein polyubiquitination” (OR = 4.2, P = 7.5 × 10–5). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 × 10–5). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.

Abstract Background Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. Methods The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. Results The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. Conclusion Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.

Abstract Background Two cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes. Methods Locally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy. Results Forty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles (P = 0.03). The most common treatment-related adverse events were grades 1–2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year disease-free survival and overall survival rates were both 97.6%, and the 2-year disease-free survival and overall survival rates were 92.3% and 97.6%, respectively. Three patients experienced disease recurrence or metastasis ranging from 12.5 to 25.8 months after surgery, and one patient died 6 months after surgery due to cardiovascular disease. Neither programmed death-ligand 1 expression nor tumor mutational burden was associated with pathological response. An increased infiltration of CD56 dim natural killer cells in the pretreatment tumor was correlated with better pathological response in the primary tumor. Conclusions It seems probable that intensive cycles of neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine increased tumor regression and improved survival outcomes. Randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings. Trial registration Chinese Clinical Trial Registry, ChiCTR2000029807, Registered February 14, 2020, https://www.chictr.org.cn/showproj.aspx?proj=49459 .

Abstract Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.

BackgroundPrevious studies have found that psychological interventions have a positive effect on improving physical and psychological problems in colorectal cancer survivors. However, there is still a lack of high-quality evidence reviews that summarize and compare the impact of different psychological interventions. The aim of this study was to synthesize existing psychological interventions and use network meta-analysis to explore whether psychological interventions improve anxiety, depression, fatigue and quality of life in colorectal cancer (CRC) survivors.MethodsWe will extract relevant randomized controlled trials of psychological interventions for CRC survivors from eight electronic databases, including PubMed, Embase, The Cochrane Library, Web of Science, CINAHL, PsycInFO, CNKI, and Wanfang database. Two reviewers will independently screen the literature and extract data. The risk of bias of the included studies will be assessed using the RoB2: Revised Cochrane Risk of Bias Tool. We will then conduct paired meta-analyses and network meta-analyses of the extracted data, using a frequency-based framework and random effects models.DiscussionTo the best of our knowledge, this study is the first proposed qualitative and quantitative integration of existing evidence using systematic evaluation and network meta-analysis. This study will inform health policy makers, healthcare providers' clinical intervention choices and guideline revisions, and will help to reduce depression and anxiety in CRC survivors, reduce fatigue, improve quality of life.

Glaucoma infection is rapidly spreading globally and the number of glaucoma patients is expected to exceed 110 million by 2040. Early identification and detection of glaucoma is particularly important as it can easily lead to irreversible vision damage or even blindness if not treated with intervention in the early stages. Deep learning has attracted much attention in the field of computer vision and has been widely studied especially in the recognition and diagnosis of ophthalmic diseases. It is challenging to efficiently extract effective features for accurate grading of glaucoma in a limited dataset. Currently, in glaucoma recognition algorithms, 2D fundus images are mainly used to automatically identify the disease or not, but do not distinguish between early or late stages; however, in clinical practice, the treatment of early and late glaucoma is not the same, so it is more important to proceed to achieve accurate grading of glaucoma. This study uses a private dataset containing modal data, 2D fundus images, and 3D-OCT scanner images, to extract the effective features therein to achieve an accurate triple classification (normal, early, and moderately advanced) for optimal performance on various measures. In view of this, this paper proposes an automatic glaucoma classification method based on the attention mechanism and EfficientNetB3 network. The EfficientNetB3 network and ResNet34 network are built to extract and fuse 2D fundus images and 3D-OCT scanner images, respectively, to achieve accurate classification. The proposed auto-classification method minimizes feature redundancy while improving classification accuracy, and incorporates an attention mechanism in the two-branch model, which enables the convolutional neural network to focus its attention on the main features of the eye and discard the meaningless black background region in the image to improve the performance of the model. The auto-classification method combined with the cross-entropy function achieves the highest accuracy up to 97.83%. Since the proposed automatic grading method is effective and ensures reliable decision-making for glaucoma screening, it can be used as a second opinion tool by doctors, which can greatly reduce missed diagnosis and misdiagnosis by doctors, and buy more time for patient's treatment.

This paper presents new evidence on knowledge flows in the Beijing-Tianjin-Hebei region of China, involving 43 cities (districts) in the Beijing-Tianjin-Hebei region, based on the invention patent transfer data from the State Intellectual Property Office of China. First, the characteristics of technology flows in the Beijing-Tianjin-Hebei region are analyzed in terms of changes in the number of flows, types of flowing subjects and spatial distribution characteristics. Then, a multi-level patent technology flow network in the Beijing-Tianjin-Hebei region was constructed, and the structural characteristics and node characteristics of each level network were explored separately. The key findings of the study are as follows. (1) The number of patented technology flows has been growing over time, showing obvious phase characteristics during the study period. As a whole, the intra-city (district) technology flow in the Beijing-Tianjin-Hebei region is higher than the inter-city (district). (2) The multi-level patent technology flow network in the Beijing-Tianjin-Hebei region shows dynamic characteristics, with more and more mobile subjects participating in the patent technology flow network, some network nodes becoming closer to each other, and the trend of small group technology flow increasing significantly. (3) Enterprises are the core hub of the patent technology flow network in Beijing-Tianjin-Hebei region. Individual invention patent technology transfer also occupies a high proportion and the participation of universities and colleges in the patent technology flow network in the Beijing-Tianjin-Hebei region is gradually increasing. (4) Over time, the flow of patent technology in the 43 cities (districts) in the Beijing-Tianjin-Hebei region has gradually become active and no longer relies excessively on a particular city (district) for patent technology transfer.

The expeditious advancement and elevation of the manufacturing industry's transformation and upgrading represent pivotal strides for China in its ascent toward the upper echelons of the global manufacturing value chain. Currently, China's manufacturing-industry transformation faces the dual-lag quandary of digitalization and servitization. The notion of digital servitization elucidates the interdependent relationship between digitalization and servitization, unveiling the mechanisms underlying the formation of digital servitization. This holds significant implications for advancing the comprehension of digitalization and servitization and, crucially, facilitates the acceleration of China's manufacturing sector transitioning from production-centric to service-centric paradigms. Harnessing the technology-organization-environment (TOE) theoretical framework, we constructed a model elucidating the driving factors underpinning manufacturing digital servitization. By employing the fuzzy-set qualitative comparative analysis (fsQCA), we explored strategic decisions and path dependencies in the transformation of manufacturing digital servitization, offering valuable insights to foster China's manufacturing sector in its digital-servitization journey. The following findings were obtained. (1) A singular condition was insufficient as a prerequisite for manufacturing digital servitization and necessitated the coordinated alignment of multiple variables. (2) Three pathways existed for achieving manufacturing digital servitization: TOE, organization-environment collaborative-oriented, and technology-organization collaborative-oriented. (3) The progression of manufacturing digital servitization resulted from the collective impact of numerous factors, exhibiting a characteristic of different paths leading to the same destination. Various manufacturing enterprises pursued distinct trajectories to achieve digital servitization, contingent upon their unique circumstances. These findings have the potential to provide valuable insights for effectively fostering manufacturing digital servitization.

Sepsis-Associated Liver Injury (SALI) is an independent risk factor for death from sepsis. The aim of this study was to develop an interpretable machine learning model for early prediction of 28-day mortality in patients with SALI. Data from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2, MIMIC-III, v1.4) were used in this study. The study cohort from MIMIC-IV was randomized to the training set (0.7) and the internal validation set (0.3), with MIMIC-III (2001 to 2008) as external validation. The features with more than 20% missing values were deleted and the remaining features were multiple interpolated. Lasso-CV that lasso linear model with iterative fitting along a regularization path in which the best model is selected by cross-validation was used to select important features for model development. Eight machine learning models including Random Forest (RF), Logistic Regression, Decision Tree, Extreme Gradient Boost (XGBoost), K Nearest Neighbor, Support Vector Machine, Generalized Linear Models in which the best model is selected by cross-validation (CV_glmnet), and Linear Discriminant Analysis (LDA) were developed. Shapley additive interpretation (SHAP) was used to improve the interpretability of the optimal model. At last, a total of 1043 patients were included, of whom 710 were from MIMIC-IV and 333 from MIMIC-III. Twenty-four clinically relevant parameters were selected for model construction. For the prediction of 28-day mortality of SALI in the internal validation set, the area under the curve (AUC (95% CI)) of RF was 0.79 (95% CI: 0.73-0.86), and which performed the best. Compared with the traditional disease severity scores including Oxford Acute Severity of Illness Score (OASIS), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Systemic Inflammatory Response Syndrome (SIRS), and Acute Physiology Score III (APS III), RF also had the best performance. SHAP analysis found that Urine output, Charlson Comorbidity Index (CCI), minimal Glasgow Coma Scale (GCS_min), blood urea nitrogen (BUN) and admission_age were the five most important features affecting RF model. Therefore, RF has good predictive ability for 28-day mortality prediction in SALI. Urine output, CCI, GCS_min, BUN and age at admission(admission_age) within 24 h after intensive care unit(ICU) admission contribute significantly to model prediction.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3–5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3–4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

Objectives Carcinosarcoma (CS) is a rare and biphasic malignancy characterised by a highly invasive biological nature and poor prognosis. This study explored the epidemiology, site-specific characteristics and survival outcome of CS.Design We conducted a retrospective study in the Surveillance, Epidemiology and End Results (SEER) database (1975–2018) for primary CS.Setting and participants SEER database includes publicly available information from regional and state cancer registries in the US centres. A total of 5042 CS patients were identified. We selected the top five anatomic CS (uterus, double adnexa, lung, bladder and breast) patients for further analysis.Primary outcome measures Incidence was estimated by geographical region, age, sex, race, stage and primary site. Trends were calculated using joinpoint regression. The cancer-specific survival (CSS) rate and initial treatment were summarised.Results Nearly 80% of CS occurred in the uterus and double adnexa, followed by lung, bladder and breast. The elderly and black population presented the highest age-adjusted rate of CS. The rates of distant metastasis in CS progressively increased from 1989 to 2018. Atlanta was the area with the highest incidence at 0.7 per 100 000. Pulmonary and bladder CS more frequently occurred in men and were diagnosed with regional stage. Distant metastasis was mostly found in ovary/fallopian tube CS. Radiotherapy was more commonly applied in uterine CS, while adnexa CS cases were more likely to receive chemotherapy. Multiple treatments were more used in breast CS. Pulmonary CS seemed to suffer worse CSS (median: 9.92 months), for which radiotherapy might not provide survival benefits (HR 0.60, 95% CI 0.42 to 0.86). Compared with the common histological types in each site, CS had the shortest survival.Conclusions CS has unique clinical features in each primary site. Substantial prognosis variances exist based on tumour locations. The aggressive course is the common feature in CS at all sites.

AbstractBackground The aim of this current study was to identify the prevalence and risk factors of H. pylori infection in the low-risk area of gastric cancer in China, and evaluate the value of different gastric cancer screening methods.Methods An epidemiological study was conducted in Yudu County, Jiangxi, China, and participants were followed up for 6 years. All participants completed a questionnaire, laboratory tests and endoscopy. Patients were divided into H. pylori positive and negative groups, and risk factors for H. pylori infection were identified using multivariate logistic regression analysis.Results A total of 1962 residents were included, the prevalence of H. pylori infection was 33.8%. Multivariate analysis showed that annual income ≤20,000 yuan (OR: 1.44, 95% CI: 1.18–1.77, p 37.23 ng/mL (OR: 2.11, 95% CI: 1.50–2.97, p 1.5 and ≤5.7 pmol/L (OR: 2.52, 95% CI: 1.93–3.30, p 5.7 pmol/L (OR: 1.96, 95% CI: 1.48–2.60, p

Objective To explore the clinical significance of serum C-type lectin domain 1（CTLD1） for prognosis of patients with idiopathic membranous nephropathy（IMN）. Methods A total of 116 patients with IMN diagnosed in Shengjing Hospital from September 2016 to December 2019 were selected as the case group, and healthy volunteers with age and gender matching in the physical examination center during the same period were selected as the health control group. Clinical data of patients in case group were collected and followed up for ≥ 2 years to record treatment and outcome. The expression level of PLAZR antigen and CTLD1 antigen epitope were detected by ELISA. The differences of clinical indexes between CTLD1 positive group and negative group were compared, and the prognostic influencing factors of IMN patients were analyzed. b>Results There was a statistical difference in CTLD1 expression level between health control group and case group（P