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PurposeSmall dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design.MethodsWe identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis.ResultsIn univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117–1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106–1.597, P = 0.002).ConclusionsFindings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

IntroductionTertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed.MethodsThus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining.ResultsWe found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs.DiscussionOur results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.

Abstract Point cloud data is a large collection of high dimensional 3D points with 3D coordinates and attributes, which has been one of the mainstream representations for emerging 3D applications, such as virtual reality, autonomous vehicles, and robotics. Due to the large‐scale unstructured high‐dimensional nature of point clouds, point cloud processing, transmitting and analysing has been challenging issues in multimedia signal processing and communication. Deep learning is a powerful tool to learn statistical knowledge from massive data. Advances in artificial intelligence, especially deep learning models are offering new opportunities for point cloud processing, compression and analysis. This special issue aims at promoting cutting‐edge research on deep learning‐based point cloud processing, including object detection, segmentation, registration, compression, and visual quality assessment.

BackgroundErythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality.MethodsData analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999−2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis.ResultsAmong non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width.ConclusionsThe predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients.

Background: The 4-dose Essen intramuscular (IM) regimen for rabies post-exposure prophylaxis (PEP) has been recommended by Advisory Committee on Immunization Practices (ACIP) and World Health Organization (WHO), but the large-sample clinical evidence is still limited. Method: Rabies virus neutralizing antibodies of 11,752 patients were detected from 409 rabies prevention clinics in 27 provinces in China. Patients with serum collected before or no later than 1 h after injection on the day of the fifth dose (day 28) of 5-dose Essen regimen were included in Group A to observe the immune efficacy of 4-dose Essen IM regimen, and patients with serum collected 14–28 days after injection of the fifth dose were included in Group B to observe the immune efficacy of 5-dose Essen IM regimen. Results: Finally, 2351 cases met the inclusion and exclusion criteria, including 2244 cases in Group A and 107 cases in Group B. The antibody titer of Group A was higher than that of Group B [12.21 (4.15, 32.10) IU/ml vs. 9.41 (3.87, 27.38) IU/ml] (P = 0.002). In Group A, the median antibody titers were 4.01IU/ml, 11.63IU/ml and 29.46IU/ml in patients vaccinated with purified hamster kidney cell vaccine (PHKCV), purified Vero cell vaccine (PVRV), and human diploid cell rabies vaccine (HDCV), respectively, with statistical significance (P

Background: Thirty-three synthetic driver genes of T-cell proliferation have recently been identified through genome-scale screening. However, the tumor microenvironment (TME) cell infiltration, prognosis, and response to immunotherapy mediated by multiple T cell proliferation-related genes (TRGs) in patients with head and neck squamous cell carcinoma (HNSC) remain unclear. Methods: This study examined the genetic and transcriptional changes in 771 patients with HNSC by analyzing the TRGs from two independent datasets. Two different subtypes were analyzed to investigate their relationship with immune infiltrating cells in the TME and patient prognosis. The study also developed and validated a risk score to predict overall survival (OS). Furthermore, to enhance the clinical utility of the risk score, an accurate nomogram was constructed by combining the characteristics of this study. Results: The low-risk score observed in this study was associated with high levels of immune checkpoint expression and TME immune activation, indicating a favorable OS outcome. Additionally, various factors related to risk scores were depicted. Conclusion: Through comprehensive analysis of TRGs in HNSC, our study has revealed the characteristics of the TME and prognosis, providing a basis for further investigation into TRGs and the development of more effective immunotherapy and targeted therapy strategies.

Soil copper (Cu) pollution is a serious environmental risk in the Panax notoginseng planting area. However, the effect of Cu on soil microbial metabolism and nutrient cycling in this area remains unknown. Therefore, Biolog ECO-plate and enzyme stoichiometry methods were utilized in this study to investigate the impact of exogenous Cu (control: 0 mg·kg−1; Cu100: 100 mg·kg−1; Cu400: 400 mg·kg−1; and Cu600: 600 mg·kg−1) on the metabolic function of soil microbial and nutrient limitation in the P. notoginseng soil. The results indicated that Cu100 significantly increased soil organic carbon (SOC), total phosphorus (TP), soil C:N, microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) 9.89%, 15.65%, 17.91%, 61.87%, and 90.56% higher than the control, respectively. Moreover, the carbon source utilization ratio of carbohydrates, amino acids, and amphiphilic compounds of Cu100 also increased by 7.16%, 25.47%, and 84.68%, respectively, compared with the control. The activities of β-1,4-glucosidase, cellobiohyrolase, leucine amino peptidase, β-1,4-N-acetylglucosaminidase, and phosphatase significantly decreased with increasing Cu concentration. Soil enzyme stoichiometry showed that all treatments were limited by nitrogen (vector angle < 45°; 19.045–22.081). Cu600 led to the lowest carbon limitation (1.798) and highest carbon use efficiency (CUE:0.267). The PLS-SEM model also showed that MBC, MBN, MBP, and microbial diversity positively affected carbon and nitrogen limitation (0.654 and 0.424). Soil carbon, nitrogen, phosphorus, stoichiometric ratio, MBC, MBN, and MBP positively affected CUE (0.527 and 0.589). The microbial diversity index significantly negatively affected CUE (−1.490). Multiple linear stepwise regression analyses showed that CUE was mainly influenced by MBC, AP, C:P, and LAP. Thus, P. notoginseng soil can benefit soil microbial carbon and nitrogen limitations at low Cu concentrations. Clarifying the metabolic activity and nutritional status of microorganisms under Cu stress can provide some theoretical basis for realizing China's comprehensive and effective management and control policies for environmental risks from metals by 2035.

BackgroundPatients with chronic obstructive pulmonary disease (COPD) after acute coronary artery syndrome (ACS) are at an increased risk of heart failure and death. However, β-blockers have been underused in this population group due to concerns of adverse reactions.ObjectiveThis study aims to investigate the β-blocker prescription at admission and its impact on the in-hospital outcomes in patients with COPD after ACS in a Chinese national cohort.MethodsAmong 113,650 patients with ACS enrolled in the national registry of the Improving Care for Cardiovascular Disease in China between November 2014 and July 2019, a total of 1,084 ACS patients with COPD were included in this study. The primary endpoint was in-hospital mortality, and the secondary endpoint was the composite of in-hospital all-cause death and heart failure.ResultsEarly oral β-blocker therapy was administered to 49.8% of patients. The Kaplan–Meier analysis showed that the early β-blocker treatment group had lower all-cause mortality (0.9% vs. 2.9%; P

Abstract Constructing heterojunctions with vacancies has garnered substantial attention in the field of piezo‐photocatalysis. However, the presence of interfacial vacancies can serve as charge‐trapping sites, leading to the localization of electrons and hindering interfacial charge transfer. Herein, dual oxygen vacancies in the NiFe‐layered double hydroxide and Bi2MoO6−x induced interfacial bonds have been designed for the piezo‐photocatalytic N2 oxidation to NO3−. Fortunately, it achieves sensational nitric acid production rates (7.23 mg g−1 h−1) in the absence of cocatalysts and sacrificial agents, which is 6.03 times of pure Bi2MoO6 that under ultrasound and light illumination. Theoretical and experimental results indicate that interfacial bonds act as “charge bridge” and “strain center” to break the carrier local effect and negative effects with piezocatalysis and photocatalysis for promoting exciton dissociation and charge transfer. Moreover, the strong electronic interaction of the interfacial bond induces internal reconstruction under ultrasound for promoting the local polarization and adsorption of N2, which accelerates the fracture of the N≡N bonds and reduces the activation energy of the reaction. The research not only establishes a novel approach for optimizing the combined effects of piezo‐catalysis and photocatalysis, but also achieves equilibrium between the synergistic impacts of vacancies and heterojunctions.

Abstract Aqueous zinc‐ion batteries (AZIBs) are highly promising for grid‐scale energy storage due to their high‐safety and low‐cost characteristics. Nevertheless, the progress in AZIBs has been impeded due to challenges encompassing corrosion, hydrogen evolution reaction, and the formation of dendrites on Zn anodes. These issues arise from the decomposition of active water molecules in the Zn2+ solvation structure in the electrolyte. Various strategies have been proposed to regulate the electrode/electrolyte interface to effectively address these problems. In spite of remarkable headway, an inadequacy of comprehensive studies addressing the mechanisms and evolutionary dynamics of the electrode/electrolyte interface is evident within scientific literature. This overview aims to provide a comprehensive overview of the strategies for regulating the electrode/electrolyte interface, focusing on dendrite‐free and side reactions‐suppressed AZIBs. These strategies include the introduction of metal ion additives, inorganic additives, surfactant additives, polymer additives and organic additives. Furthermore, a detailed examination is made on the effects and underlying mechanisms associated with modifying the electrolyte at the interface between the electrode and electrolyte. Moreover, an appraisal is provided on the performance metrics of diverse strategies and prospective research directions are recommended as well.

Summary: Two-dimensional (2D) materials, especially graphene-based materials, have important implications for tissue regeneration and biomedicine due to their large surface area, transport properties, ease of functionalization, biocompatibility, and adsorption capacity. Despite remarkable progress in the field of tissue regeneration and biomedicine, there are still problems such as unclear long-term stability, lack of in vivo experimental data, and detection accuracy. This paper reviews recent applications of graphene-based materials in tissue regeneration and biomedicine and discusses current issues and prospects for the development of graphene-based materials with respect to promoting the regeneration of tendons, neuronal cells, bone, chondrocytes, blood vessels, and skin, as well as applications in sensing, detection, anti-microbial activity, and targeted drug delivery.

BackgroundEvidence from animal experiments and epidemiological studies has reported controversial results about the effects of prenatal bisphenols (BPs) exposure on childhood thyroid function. This study aims to explore the associations of prenatal exposure to BPs with thyroid-related hormones (THs) in newborns and early childhood, with a particular focus on the sex-dependent and exposure level effects.MethodsCorrelated studies were systematically searched from PubMed, Web of Science, Medline, Cochrane, and Embase until February 21, 2024. The exposures assessed include bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), bisphenol AF (BPAF), and tetrachlorobisphenol A (TCBPA). THs measured were thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), free tri-iothyronine (FT3), and free thyroxine (FT4). Effect estimates were quantified using coefficients from multivariable regression models. Statistical analyses were completed using Stata 16.0. The methodological quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS).ResultsEleven cohort studies comprising 5,363 children were included in our meta-analysis. Prenatal bisphenol concentrations were statistically significant related to alterations in thyroid hormones in children, exclusively in female offspring, including reduced TSH (β = -0.020, 95% CI: -0.036, -0.005) and increased TT3 levels (β = 0.011, 95% CI: 0.001, 0.021), and exposure to high concentration of bisphenols (>1.5 ug/g creatinine) significantly reduced FT3 levels in children (β = -0.011, 95% CI: -0.020, -0.003).ConclusionPrenatal bisphenol exposure is linked to alterations in thyroid hormone levels in girls, necessitating enhanced measures to control bisphenol exposure levels during pregnancy for child health protection.Systematic Review Registrationhttps://inplasy.com, identifier INPLASY202450129.

The tumor suppressor p53 is the most common mutated gene in cancer, with the R175H as the most frequent p53 missense mutant. However, there are currently no approved targeted therapies or immunotherapies against mutant p53. Here, we characterized and investigated a monoclonal antibody (mAb) that recognizes the mutant p53-R175H for its affinity, specificity, and activity against tumor cells in vitro. We then delivered DNA plasmids expressing the anti-R175H mAb or a bispecific antibody (BsAb) into mice to evaluate their therapeutic effects. Our results showed that the anti-R175H mAb specifically bound to the p53-R175H antigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells, with no cross-reactivity with wild-type p53. In cultured cells, the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity. We made a recombinant MC38 mouse cell line (MC38-p53-R175H) that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles. In vivo, administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice. The administration of the anti-R175H BsAb plasmid showed no therapeutic effects, yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody. These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

In this study, field tests and numerical simulations are combined to investigate the earth pressure distribution and deformation characteristics of double corrugated steel culvert (DCSC) with different culvert spacings. The results show that with an increase in the horizontal earth pressure caused by the horizontal squeezing of the DCSC, the constraint effect on the culvert enhances. Comparing with the single corrugated steel culvert (SCSC), the bearing capacity of the DCSC is greatly improved. In addition, deformation calculation models of the SCSC and DCSC are established to investigate the deformation characteristics. Based on the Winkler’s foundation model, the relationship between the deformation and passive deformation resistances on the left and right sides of a culvert is established. Introducing critical culvert spacing Lcr, the influence of the culvert spacing on the deformation characteristics of the DCSC is revealed. Further, the relationship between Lcr and culvert radius R is derived. By analysing correlations between culvert deformation and the influencing factors, i.e., height of fill, compressive stiffness of fill and culvert spacing, the deformation calculation models of the SCSC and DCSC proposed in this study are verified.

BackgroundFew studies have explored the associated factors of attitudes of nonpsychiatric nurses towards mental disorders. Therefore, this study is aimed to evaluate the attitudes of nonpsychiatric nurses towards mental disorders and especially explore the association between psychiatric clinical practice and these attitudes.MethodsA total of 1324 nonpsychiatric nurses and students majoring in nursing were recruited through an online questionnaire from December 2021 to March 2022 in Sichuan Province, China. Demographic information, personal care experience, psychiatric nursing education and the Community Attitudes towards the Mentally Ill (CAMI) were collected. A higher score indicates a stigmatizing attitude in the authoritarianism and social restrictiveness (SR) subscales and a positive attitude in the benevolence and community mental health ideology (CMHI) subscales. Multivariate linear regression was employed to analyze associated factors of attitudes towards mental disorders, and hierarchical linear regression was used to analyze the association between psychiatric clinical practice and the attitudes towards mental disorders.ResultsUnder the control of confounders, high education level, long residence in urban and personal care experience were positively correlated with score of authoritarianism and SR (p < 0.05), and negatively correlated with score of benevolence (p < 0.05). Long residence in urban and personal care experience were negatively correlated with score of CMHI (p < 0.05). Hierarchical linear regression analysis showed that after adjusting for demographic information, psychiatric clinical practice was associated with lower score of benevolence (B = -0.09, 95%CI = -0.17 ~ -0.003, p = 0.043) and CMHI (B = -0.09, 95%CI = -0.17 ~ -0.01, p = 0.027), but the initial associations between psychiatric clinical practice and authoritarianism, SR disappeared.ConclusionsHigh education level, long residence in urban, personal care experience and the psychiatric clinical practice were associated with the discrimination of nonpsychiatric nurses towards mental disorders. Further exploring practical strategies to optimize the psychiatric clinical practice experience of nonpsychiatric nurses could help improve their attitudes towards mental disorders.

ObjectiveExecutive dysfunction is a core symptom of vascular cognitive impairment (VCI), which seriously affects patients’ prognosis. This paper aims to investigate the effectiveness of rTMS on executive function in VCI.MethodsThe databases selected for this study included Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Science and Technology Journal Database (VIP), and China Biology Medicine Disc (CBM). The screening times were conducted from the time of library construction until August 23, 2023. The inclusion criteria for this meta-analysis were randomized controlled trials (RCTs) on rTMS for VCI, which include executive function scores. The primary metrics were executive subscale scores of the Cognitive Comprehensive Scale and total scores of the Executive Specificity Scale. The secondary metrics were subscale scores of the Executive Specificity Scale. The quality of each eligible study was assessed using the Cochrane Risk of Bias tool. Meta-analysis and bias analysis were performed using Stata (version 16.0) and RevMan (version 5.3).ResultsA total of 20 high-quality clinical RCTs with 1,049 samples were included in this paper. The findings from the primary outcomes revealed that within the rTMS group, there were significantly higher scores observed for the executive sub-item on the cognitive composite scale (SMD = 0.93, 95% CI = 0.77–1.08, p

Abstract Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated the mechanism of biomaterial‐mediated bone regeneration, a comprehensive single‐cell level transcriptomic map revealing the influence of biomaterials on regulating the temporal and spatial expression patterns of mesenchymal stem cells (MSCs) is still lacking. Herein, the osteoimmune microenvironment is depicted around the classical collagen/nanohydroxyapatite‐based bone repair materials via combining analysis of single‐cell RNA sequencing and spatial transcriptomics. A group of functional MSCs with high expression of matrix Gla protein (Mgp) is identified, which may serve as a pioneer subpopulation involved in bone repair. Remarkably, these Mgp high‐expressing MSCs (MgphiMSCs) exhibit efficient osteogenic differentiation potential and orchestrate the osteoimmune microenvironment around implanted biomaterials, rewiring the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand–receptor pair. The inhibition of Mdk/Lrp1 activates the pro‐inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple immune‐cell subsets also exhibit close crosstalk between MgphiMSCs via the secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles and interactions characterized in this study can broaden the understanding of the functional MSC subpopulations at the early stage of biomaterial‐mediated bone regeneration and provide the basis for materials‐designed strategies that target osteoimmune modulation.

IntroductionAlterations in the gut microbiome and bile acid metabolism are known to play a role in the development and progression of colon cancer. Medicinal plants like Astragalus mongholicus Bunge and Curcuma aromatica Salisb. (AC) have shown preferable therapeutic effect on cancer therapy, especially digestive tract tumors like colon cancer. However, the precise mechanisms of AC inhibiting colon cancer, particularly in relation to the gut microbiome and bile acid dynamics, are not fully understood.MethodsOur research aimed to investigate the anti-tumor properties of AC in mice with CT26 colon cancer and further investigate its underlying mechanism via intestinal microbiota. The size and pathological changes of solid tumors in colon cancer are used to evaluate the inhibitory effect of AC on colon cancer. Metagenomics and 16s rRNA gene sequencing were employed to clarify the dysbiosis in the gut microbiome of colon cancer and its impact on colon cancer. The levels of bile acids (BAs) in the feces of mice from each group were measured using UPLC-Qtrap-MS/MS.ResultsAC effectively suppressed the growth of colon cancer and reduced histological damage. Notably, AC treatment led to changes in the gut microbiome composition, with a decrease in pathogenic species like Citrobacter and Candidatus_Arthromitus, and an increase in beneficial microbial populations including Adlercreutzia, Lachnospiraceae_UCG-001, and Parvibacter. Additionally, AC altered bile acid profiles, resulting in a significant decrease in pro-carcinogenic bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), while increasing the concentration of the cancer-inhibitory bile acid, ursodeoxycholic acid (UDCA). Tracking and analyzing the data, AC may mainly upregulate FabG and baiA genes by increasing the relative abundance of Adlercreutzia and Parvibacter bacteria, which promoting the metabolism of pro-carcinogenic LCA.DiscussionThese findings provide strong evidence supporting the role of AC in regulating gut microbiome-mediated bile acid metabolism, which is crucial in impeding the progression of colon cancer.

ABSTRACT An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces E2 protein stability and here we demonstrate that increased E2 acetylation occurs during mitosis in a TopBP1 interacting-dependent manner, promoting E2 mitotic stabilization. p300 mediates E2 acetylation and acetylation is increased due to E2 switching off SIRT1 function during mitosis in a TopBP1 interacting-dependent manner, confirmed by increased p53 stability and acetylation on lysine 382, a known target for SIRT1 deacetylation. SIRT1 can complex with E2 in growing cells but is unable to do so during mitosis due to the E2-TopBP1 interaction; SIRT1 is also unable to complex with p53 in mitotic E2 wild-type cells but can complex with p53 outside of mitosis. E2 lysines 111 and 112 are highly conserved residues across all E2 proteins and we demonstrate that K111 hyper-acetylation occurs during mitosis, promoting E2 interaction with Topoisomerase 1 (Top1). We demonstrate that K112 ubiquitination promotes E2 proteasomal degradation during mitosis. E2-TopBP1 interaction promotes mitotic acetylation of CHK2, promoting phosphorylation and activation of the DNA damage response (DDR). The results present a new model in which the E2-TopBP1 complex inactivates SIRT1 during mitosis, and activates the DDR. This is a novel mechanism of HPV16 activation of the DDR, a requirement for the viral life cycle.IMPORTANCEHuman papillomaviruses (HPVs) are causative agents in around 5% of all human cancers. While there are prophylactic vaccines that will significantly alleviate HPV disease burden on future generations, there are currently no anti-viral strategies available for the treatment of HPV cancers. To generate such reagents, we must understand more about the HPV life cycle, and in particular about viral-host interactions. Here, we describe a novel mitotic complex generated by the HPV16 E2 protein interacting with the host protein TopBP1 that controls the function of the deacetylase SIRT1. The E2-TopBP1 interaction disrupts SIRT1 function during mitosis in order to enhance acetylation and stability of viral and host proteins. We also demonstrate that the E2-TopBP1 interaction activates the DDR. This novel complex is essential for the HPV16 life cycle and represents a novel anti-viral therapeutic target.

ObjectiveThis systematic review and meta-analysis aims to systematically evaluate the effectiveness and safety of acupuncture in the treatment of aspiration caused by post-stroke dysphagia.MethodsA computer search was conducted in nine databases, including the China National Knowledge Infrastructure (CNKI), China Science and Technology Journal (VIP), Wan-fang Database, China Biomedical Literature Database (CBM), PubMed, Web of Science, Cochrane Library, Embase, and Chinese Clinical Trial Registry (ChiCTR), from their inception until April 2024. Clinical randomized controlled trials comparing acupuncture combined therapy or single therapy with control interventions for the treatment of aspiration caused by post-stroke dysphagia were included. The primary outcome measure was the Penetration Aspiration Scale (PAS), and secondary outcome measures included the overall effective rate, video fluoroscopic swallowing study (VFSS), and hyoid bone displacement. The statistical analysis was performed using RevMan 5.3 and Stata 16.0.ResultsA total of 16 articles involving 1,284 patients were included. The meta-analysis results showed that acupuncture combined therapy or single therapy was more effective in improving PAS scores compared to conventional rehabilitation therapy or balloon dilation of the catheter [WMD = −1.05, 95% CI (−1.30, −0.80), Z = 0.82, p = 0.00

Black ginseng as the functional food, has been used to improve obesity and insulin resistance. However, the underlying mechanism remains unclear. We found that Black ginseng extract (BGS) significantly ameliorated diet-induced obesity and insulin resistance in mice. The components eluted by 70% and 95% ethanol from BGS by using polystyrene resin (BGS/70) had superior anti-obesity effects when compared with other fractions. It significantly decreased the abundance of bile salt hydrolase (BSH)-producing genera and increased serum taurine-bound bile acids in obese mice. BGS/70 administration-related metabolic improvements in obese mice was lost in TGR5 gut-specific knockout mice and antibiotic mixture (ABX)-cleared enterobacteria mice. Fecal microbiota transplantation (FMT) experiments demonstrated that the anti-obesity effects of BGS/70 were mediated by gut flora. Taken together, our results suggest that BGS can treat obesity via gut microbiota and the activation of TGR5. Thus, BGS may be a promising therapy for obesity.

Abstract Background To evaluate the reliability of the Soft Tissue Tension Cloud Chart (STTCC) technology, an original method combining multi-point Cervical Paravertebral Soft Tissue Test (CPSTT) with MATLAB software, we conducted a preliminary analysis on the immediate effects of Orthopaedic Manual Therapy (OMT) on cervical paravertebral soft tissue. Methods 30 patients with Cervical Spondylotic Radiculopathy (CSR) were included in this study. We analyzed the differences in CPSTT before and after treatment with Cervical Rotation-Traction Manipulation (CRTM), a representative OMT technique in Traditional Chinese Medicine, using the STTCC technology. Results The STTCC results demonstrated that post-treatment CPSTT levels in CSR patients were significantly lower than pre-treatment levels after application of CRTM, with a statistically significant difference (P

Abstract Purpose Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism. Methods We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3b Gli1ER ) mice to operated tibia fracture. Fracture callus tissues of Dnmt3b Gli1ER mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay. Results The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3b Gli1ER mice much less than control mice. Dnmt3b Gli1ER mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3b Gli1ER mice as well as the expressions of BCL-2. Conclusions Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.

Abstract As an important forestry pest, Coronaproctus castanopsis (Monophlebidae) has caused serious damage to the globally valuable Gutianshan ecosystem, China. In this study, we assembled the first chromosome-level genome of the female specimen of C. castanopsis by merging BGI reads, HiFi long reads and Hi-C data. The assembled genome size is 700.81 Mb, with a scaffold N50 size of 273.84 Mb and a contig N50 size of 12.37 Mb. Hi-C scaffolding assigned 98.32% (689.03 Mb) of C. Castanopsis genome to three chromosomes. The BUSCO analysis (n = 1,367) showed a completeness of 91.2%, comprising 89.2% of single-copy BUSCOs and 2.0% of multicopy BUSCOs. The mapping ratio of BGI, second-generation RNA, third-generation RNA and HiFi reads are 97.84%, 96.15%, 97.96%, and 99.33%, respectively. We also identified 64.97% (455.3 Mb) repetitive elements, 1,373 non-coding RNAs and 10,542 protein-coding genes. This study assembled a high-quality genome of C. castanopsis, which accumulated valuable molecular data for scale insects.

Abstract Electrospun scaffolds play important roles in the fields of regenerative medicine and vascular tissue engineering. The aim of the research described here was to develop a vascular scaffold that mimics the structural and functional properties of natural vascular scaffolding. The mechanical properties of artificial vascular tissue represent a key issue for successful transplantation in small diameter engineering blood vessels. We blended silk fibroin (SF) and fibrin to fabricate a composite scaffold using electrospinning to overcome the shortcomings of fibrin with respect to its mechanical properties. Subsequently, we then carefully investigated the morphological, mechanical properties, hydrophilicity, hemocompatibility, degradation, cytocompatibility and biocompatibility of the SF/fibrin (0:100), SF/fibrin (15:85), SF/fibrin (25:75), and SF/fibrin (35:65) scaffolds. Based on these in vitro results, we implanted SF/fibrin (25:75) vascular scaffold subcutaneously and analyzed its in vivo degradation and histocompatibility. The fiber structure of the SF/fibrin hybrid scaffold was smooth and uniform, and its fiber diameters were relatively small. Compared with the fibrin scaffold, the SF/fibrin scaffold clearly displayed increased mechanical strength, but the hydrophilicity weakened correspondingly. All of the SF/fibrin scaffolds showed excellent blood compatibility and appropriate biodegradation rates. The SF/fibrin (25:75) scaffold increased the proliferation and adhesion of MSCs. The results of animal experiments confirmed that the degradation of the SF/fibrin (25:75) scaffold was faster than that of the SF scaffold and effectively promoted tissue regeneration and cell infiltration. All in all, the SF/fibrin (25:75) electrospun scaffold displayed balanced and controllable biomechanical properties, degradability, and good cell compatibility. Thus, this scaffold proved to be an ideal candidate material for artificial blood vessels.

Abstract Tennis elbow (lateral epicondylitis) typically responds well to conservative treatment, and few patients require surgical intervention. This study aimed to investigate the influence of lifestyle and clinical factors on the prognosis of tennis elbow. This prospective, multicenter, nested case–control study included patients diagnosed with lateral epicondylitis after excluding other conditions. Patients who required surgery because of inadequate improvement after 6 months of conservative treatment were defined as the case group; the remaining patients constituted the control group. Propensity score matching was performed to eliminate baseline differences. Univariate and multivariate analyses were performed using logistic regression. This study included 265 patients (53 in the case group, 212 in the control group). Multivariate analysis revealed that smoking, alcohol consumption, and frequent physical exercise were independent risk factors for surgical intervention, whereas combined treatment with oral nonsteroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections was a protective factor against surgery. Subgroup analysis showed that heavy drinkers had a 3.74-fold higher risk of requiring surgical treatment within 1 year than occasional drinkers. Smoking and alcohol consumption were associated with non-operative treatment failure in patients with lateral epicondylitis. Combining oral NSAIDs and corticosteroid injections is a favorable conservative treatment option.

Abstract Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.

Abstract Lipid metabolism in cancer cells has garnered increasing attention in recent decades. Cancer cells thrive in hypoxic conditions, nutrient deficiency, and oxidative stress and cannot be separated from alterations in lipid metabolism. Therefore, cancer cells exhibit increased lipid metabolism, lipid uptake, lipogenesis and storage to adapt to a progressively challenging environment, which contribute to their rapid growth. Lipids aid cancer cell activation. Cancer cells absorb lipids with the help of transporter and translocase proteins to obtain energy. Abnormal levels of a series of lipid synthases contribute to the over-accumulation of lipids in the tumor microenvironment (TME). Lipid reprogramming plays an essential role in the TME. Lipids are closely linked to several immune cells and their phenotypic transformation. The reprogramming of tumor lipid metabolism further promotes immunosuppression, which leads to immune escape. This event significantly affects the progression, treatment, recurrence, and metastasis of cancer. Therefore, the present review describes alterations in the lipid metabolism of immune cells in the TME and examines the connection between lipid metabolism and immunotherapy.

In this study, a three dimensional (3D) numerical model of six-degrees-of-freedom (6DOF) is applied to simulate the water entries of twin spheres side-by-side at different lateral distances and time intervals. The turbulence structure is described using the shear-stress transport k-ω (SST k-ω) model, and the volume of fluid (VOF) method is used to track the complex air-liquid interface. The motion of spheres during water entry is simulated using an independent overset grid. The numerical model is verified by comparing the cavity evolution results from simulations and experiments. Numerical results reveal that the time interval between the twin water entries evidently affects cavity expansion and contraction behaviors in the radial direction. However, this influence is significantly weakened by increasing the lateral distance between the two spheres. In synchronous water entries, pressure is reduced on the midline of two cavities during surface closure, which is directly related to the cavity volume. The evolution of vortexes inside the two cavities is analyzed using a velocity vector field, which is affected by the lateral distance and time interval of water entries.

In recent years, the frequent occurrence of lower or higher temperatures in spring is becoming a serious threat to the pear industry in North China. Regulating the flower opening of pear trees is one of the methods to alleviate the threat. Ambient temperature is one of the pathways regulating plant flowering. Melatonin (MT) has been reported to be involved in flower opening of some plants except pear. Therefore, in this study, experiments were designed to explore whether melatonin can mediate temperature-regulating flower opening of pear trees to provide new ideas for reducing losses caused by dramatic temperature changes. The results showed that under higher temperature condition, compared with the control, 20 μM and 200 μM melatonin could delay pear flower opening, while 1,000 μM melatonin could accelerate pear flower opening. While under lower temperature conditions, all melatonin treatments could accelerate pear flower opening. Transcriptome analysis indicated that, compared with C1 group (the control) at a lower temperature, there were 610, 586 and 180 differentially expressed genes (DEGs) in T1, T2 and T3 group, respectively. Compared with the C2 group (the control) at a higher temperature, there were 384, 218, 349 DEGs in T4, T5 and T6 groups, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs showed that at lower temperatures, melatonin regulated the flower opening of pear mainly through the mitogen-activated protein kinase (MAPK) signaling pathway and the plant hormone signaling pathway. While at higher temperatures, melatonin regulated the flower opening of pear dependent on the carotenoid synthesis pathway. Several transcription factor families are involved in the above pathways, such as MYB, WRKY, AP2/EFR and NAC.

In recent years, the use of time series analysis has become widespread, prompting researchers to explore methods to improve classification. Time series self-supervised learning has emerged as a significant area of study, aiming to uncover patterns in unlabeled data for richer information. Contrastive self-supervised learning, particularly, has gained attention for time series classification. However, it introduces inductive bias by generating positive and negative samples. Another approach involves Masked Autoencoders (MAE), which are effective for various data types. However, due to their reliance on the Transformer architecture, they demand significant computational resources during the pre-training phase. Recently, inspired by the remarkable advancements achieved by convolutional networks in the domain of time series forecasting, we aspire to employ convolutional networks utilizing a strategy of mask recovery for pre-training time series models. This study introduces a novel model termed Hierarchical Sparse Convolutional Masked-Autoencoder, “HSC-MAE”, which seamlessly integrates convolutional operations with the MAE architecture to adeptly capture time series features across varying scales. Furthermore, the HSC-MAE model incorporates dedicated decoders that amalgamate global and local information, enhancing its capacity to comprehend intricate temporal patterns. To gauge the effectiveness of the proposed approach, an extensive array of experiments was conducted across nine distinct datasets. The experimental outcomes stand as a testament to the efficacy of HSC-MAE in effectively mitigating the aforementioned challenges.

Background: Considerable morbidity and death are associated with acute kidney damage (AKI) following total aortic arch replacement (TAAR). The relationship between AKI following TAAR and serum magnesium levels remains unknown. The intention of this research was to access the predictive value of serum magnesium levels on admission to the Cardiovascular Surgical Intensive Care Unit (CSICU) for AKI in patients receiving TAAR. Methods: From May 2018 to January 2020, a prospective, observational study was performed in the Guangdong Provincial People's Hospital CSICU. Patients accepting TAAR admitted to the CSICU were studied. The Kidney Disease: Improving Global Outcomes (KDIGO) definition of serum creatinine was used to define AKI, and KDIGO stages two or three were used to characterize severe AKI. Multivariable logistic regression and area under the curve receiver-operator characteristic curve (AUC-ROC) analysis were conducted to assess the predictive capability of the serum magnesium for AKI detection. Finally, the prediction model for AKI was established and internally validated. Results: Of the 396 enrolled patients, AKI occurred in 315 (79.5%) patients, including 154 (38.8%) patients with severe AKI. Serum magnesium levels were independently related to the postoperative AKI and severe AKI (both, P < 0.001), and AUC-ROCs for predicting AKI and severe AKI were 0.707 and 0.695, respectively. Across increasing quartiles of serum magnesium, the multivariable-adjusted odds ratios (95% confidence intervals) of postoperative AKI were 1.00 (reference), 1.04 (0.50-2.82), 1.20 (0.56-2.56), and 6.19 (2.02-23.91) (P for Trend < 0.001). When serum magnesium was included to a baseline model with established risk factors, AUC-ROC (0.833 vs 0.808, P = 0.050), reclassification (P < 0.001), and discrimination (P = 0.002) were further improved. Conclusions: Serum magnesium levels on admission are an independent predictor of AKI. In TAAR patients, elevated serum magnesium levels were linked to an increased risk of AKI. In addition, the established risk factor model for AKI can be considerably improved by the addition of serum magnesium in TAAR patients hospitalized in the CSICU.

The growing abundance of electronic control units and peripheral devices loaded and connected to smart connected cars has resulted in a constant stream of cyber-attacks at various levels and dimensions. The CAN-FD bus plays a crucial role in smart connected cars. Currently, the majority of research efforts remain centered around the traditional CAN bus, with fewer studies addressing intrusion detection for the CAN-FD bus in smart connected vehicles. CAN-FD boasts a notable improvement in transmission speed, capable of reaching up to 8 Mbps compared to the 1 Mbps of the standard CAN bus. Utilizing intrusion detection systems designed for the CAN bus in high-speed CAN-FD applications could potentially hinder normal transmission and detection efficiency. Hence, we focus on the attack and intrusion detection of CAN-FD bus ID nodes to prevent unauthorized access and potential malicious attacks. We propose an ID intrusion detection system based on an improved Generative Adversarial Network (GAN) model, which consists of two parts: a data pre-processing module and a detection module. To apply the GAN model to the vehicle bus, we perform pre-processing of the bus data. We introduce the concept of dual discriminator to improve the detection rate and enable the handling of unknown attacks. With the output of dual discriminator, we can determine whether there are any anomalies in the detection data. First, we use a data pre-processing module to convert the ID segments of the automobile CAN-FD into binary image encoding to form ID images. Subsequently, these ID images are fed into an ID image feature extractor in the detection module to extract various auxiliary features. The discriminator receives these auxiliary features and calculates the probability of whether the received image is a normal ID image or not to determine the authenticity of the ID image. The experimental results show that the proposed intrusion detection system is able to detect a message within 0.15 ms, which fully meets the real-time detection requirements while the vehicle is in motion. The average detection rate of the proposed system for different types of attacks is 99.93%, which is an average of 1.2% improvement of the detection rate over the GIDS algorithm. The proposed system not only ensures the normal communication of CAN-FD bus but also realizes real-time and accurate intrusion detection.

To overcome the challenges posed by the complex structure and large parameter requirements of existing classification models, the authors propose an improved extreme learning machine (ELM) classifier for human locomotion intent recognition in this study, resulting in enhanced classification accuracy. The structure of the ELM algorithm is enhanced using the logistic regression (LR) algorithm, significantly reducing the number of hidden layer nodes. Hence, this algorithm can be adopted for real-time human locomotion intent recognition on portable devices with only 234 parameters to store. Additionally, a hybrid grey wolf optimization and slime mould algorithm (GWO-SMA) is proposed to optimize the hidden layer bias of the improved ELM classifier. Numerical results demonstrate that the proposed model successfully recognizes nine daily motion modes including low-, mid-, and fast-speed level ground walking, ramp ascent/descent, sit/stand, and stair ascent/descent. Specifically, it achieves 96.75% accuracy with 5-fold cross-validation while maintaining a real-time prediction time of only 2 ms. These promising findings highlight the potential of onboard real-time recognition of continuous locomotion modes based on our model for the high-level control of powered knee prostheses.

The joint of multisource remote sensing (RS) data for land cover classification has become a popular research topic. Although studies have shown that the fusion of multisource data can improve the accuracy of classification, the current limitation lies in the inadequate exploitation of information, resulting in spectral confusion categories overlapping, and varying visual differences within the same category. To address these problems, this article proposes a multiscale spectral–spatial attention residual fusion network (MSSARFNet) that aims to enhance the classification performance of multisource RS data through effective spectral–spatial feature extraction and fusion. Specifically, three modules are designed: the multiscale spectral attention residual module (MSpeARM), the multiscale spatial attention residual module (MSpaARM), and multiscale convolution fusion (MCF) module. First, we divide the channels of the features into multiple paths and apply spectral–spatial attention mechanisms on each path. To further enhance connectivity, convolutional operation is utilized to establish connections between different paths, thus forming MSpeARM and MSpaARM. The MSpeARM suppresses redundant features and enhances effective features along the channel dimension to better differentiate spectral-confused categories. The MSpaARM highlights that different visual patterns of objects in the same category can mutually reinforce each other by weighting all positional features, regardless of their spatial differences. Second, to fuse these two sets of features, the MCF module is designed to learn multilevel semantic features and enhance fusion at a granular level. Experimental evaluations on three RS datasets demonstrate that the proposed method achieves excellent classification performance, indicating the effectiveness of MSSARFNet.

Candida albicans is one of the most common opportunistic fungi in cancer patients. This study explored the influence of C. albicans on gut microbiota in oral tumour-bearing mice by means of 16S rRNA sequencing and ITS sequencing. It was found that C. albicans infection induced the decrease of alpha diversity of bacteria and fungi in the gut microbiome. For the bacteria, C. albicans caused the reduction of Ralstonia, Alistipes, Clostridia UCG-014, Ruminococcus, and Lachnospiraceae NK4A136 group. For the fungi, C. albicans inhibited the growth of other fungi including Aspergillus, Cladosporium, and Bipolaris. The neutralisation of γδT cells partly alleviated the out-of-balance of Firmicutes/Bacteroidota (F/B) ratio in the gut caused by C. albicans infection. However, γδT cell neutralisation boosted the overgrowth of C. albicans. Additionally, IL-17A neutralisation aggravated the microbial dysbiosis of bacteria and fungi caused by C. albicans infection. Further analysis indicated that C. albicans overgrowth might influence the correlations between fungal and bacterial kingdoms. In conclusion, C. albicans infection disturbed the gut microbiota of both bacteria and fungi in oral tumour-bearing mice, which may be associated with the intestinal immune components including γδT cells and IL-17A.

A reliable prediction model can greatly contribute to the research of car seating system vibration control. The novelty of this paper lies in the development of a hybrid method of an artificial neural network (ANN) and response surface methodology (RSM) to predict the peak seat-to-head transmissibility ratio of a seating suspension system and to evaluate its ride comfort for different seat design parameters. Additionally, this method can remove the experimental design of the RSM model. In this paper, four seat design parameters are selected as input parameters and arranged using the central composite design method. The peak transmissibility ratio from seat to head at 4 Hz is chosen as the response target output value. To illustrate this hybrid method, the response target output value of the peak transmissibility ratio is calculated from the frequency response of a five-degrees-of-freedom (5-DOF) lumped-parameter biodynamic seating suspension model. The input design parameters and the response target output values are used to train an ANN to establish the relationship between the seat design parameters and the peak transmissibility ratio. At the same time, the input design parameters and the response target output values predicted by the ANN are used to develop the relationship between the seat design parameters and the peak transmissibility ratio using the response surface method and linear regression models. The hybrid of the ANN and response surface methods makes the planning or design of experiments not essential. The hybrid model of the ANN and response surface method is more accurate and convenient than a linear regression model for the study of seating system vibration isolation.

Abstract Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Abstract Background A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC). Methods 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross−validation framework, and patients with CRC were separated into high− and low−CERPI groups. Relationship between immune cell infiltration levels, immune−related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in−vitro verified. Results The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low−CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single−cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration. Conclusion We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.

Current groundwater prediction models often exhibit low accuracy and complex parameter adjustment. To tackle these limitations, a novel prediction model, called improved Aquila optimizer bi-directional long-term and short-term memory (IAO-BiLSTM) network, is proposed. IAO-BiLSTM optimizes the hyperparameters of the BiLSTM network using an IAO algorithm. IAO incorporates three novel enhancements, including population initialization, population updating, and global best individual updating, to overcome the drawbacks of current optimization algorithms. Before making predictions, the challenge posed by the highly nonlinear and non-stationary characteristics of groundwater level signals was addressed through the application of a wavelet multi-scale analysis method. Using a landslide site in Zhejiang Province as an example, a monitoring system is established, and continuous wavelet transform, cross-wavelet transform, and wavelet coherence analysis are employed to perform multi-scale feature analysis on a 2-year dataset of rainfall and groundwater depth. The findings reveal that the groundwater depth of monitoring holes exhibits similar high energy resonating periods and phase relationships, strongly correlating with rainfall. Subsequently, IAO-BiLSTM is employed to predict groundwater depth, and its results are compared with seven popular machine learning regression models. The results demonstrate that IAO-BiLSTM achieves the highest accuracy, as evidenced by its root mean squared error of 0.25. HIGHLIGHTS The wavelet multi-scale analysis method overcomes the limitation of the traditional qualitative analysis method.; The wavelet multi-scale analysis method successfully reveals the multi-scale characteristics and the most significant influencing factors.; An improved Aquila optimizer bi-directional long-term and short-term memory (IAO-BiLSTM) network can predict groundwater level reliably and effectively.; IAO-BiLSTM beats the current seven hot prediction models and showed good performance.;

Sharding technology can address the throughput and scalability limitations that arise when single-chain blockchain are applied in the Internet of Things (IoT). However, existing sharding solutions focus on addressing issues like malicious nodes clustering and cross-shard transactions. Existing sharding solutions cannot adapt to the performance disparities of edge nodes and the characteristic of three-dimensional data queries in building IoT. This leads to problems such as shard overheating and inefficient data query efficiency. This paper proposes a dual-layer architecture called S-DAG, which combines sharded blockchain and DAG blockchain. The sharded blockchain processes transactions within the building IoT, while the DAG blockchain stores block headers from the sharded network. By designing an Adaptive Balancing Load Algorithm (ABLA) for periodic network sharding, nodes are divided based on their load performance values to prevent the aggregation of low-load performance nodes and the resulting issue of shard overheating. By combining the characteristics of the KD tree and Merkle tree, a block structure known as 3D-Merkle tree is designed to support three-dimensional data queries, enhancing the efficiency of three-dimensional data queries in building IoT. By deploying and conducting simulation experiments on various physical devices, we have verified the effectiveness of the solution proposed in this paper. The results indicate that, compared to other solutions, the proposed solution is better suited for building IoT data management. ABLA is effective in preventing shard overheating issue, and the 3D-Merkle tree significantly enhances data query efficiency.

Bone age assessment plays a vital role in monitoring the growth and development of adolescents. However, it is still challenging to obtain precise bone age from hand radiography due to these problems: 1) Hand bone varies greatly and is always masked by the background; 2) the hand bone radiographs with successive ages offer high similarity. To solve such issues, a region fine-grained attention network (RFGA-Net) was proposed for bone age assessment, where the region aware attention (RAA) module was developed to distinguish the skeletal regions from the background by modeling global spatial dependency; then the fine-grained feature attention (FFA) module was devised to identify similar bone radiographs by recognizing critical fine-grained feature regions. The experimental results demonstrate that the proposed RFGA-Net shows the best performance on the Radiological Society of North America (RSNA) pediatric bone dataset, achieving the mean absolute error (MAE) of 3.34 and the root mean square error (RMSE) of 4.02, respectively.

Synthetic aperture radar (SAR) images are often affected by a type of multiplicative noise known as “speckle” due to their active imaging characteristics. This property complicates the processing and interpretation of SAR images. While deep learning techniques have demonstrated success in despeckling, many models are tailored to specific noise levels. This specificity can limit a model's ability to generalize to real SAR images with varying noise levels, potentially leading to oversmoothing or overfocusing on specific details. To address these challenges, we present the Adaptive Noise Estimation and Despeckling Network (ANED-Net). This network consists of a noise-level estimation phase and a noise-level-guided nonblind denoising phase. During the nonblind denoising phase, we develop a noise-feature-guided denoising network. This network integrates a hierarchical encoder–decoder denoising module based on the Transformer block (T-unet) and a denoising enhancement control block. Together, they skillfully capture both local and global dependencies inherent in SAR images, facilitating effective noise removal. Furthermore, we also introduce a deep-attention mechanism to counteract the attentional collapse observed when the Transformer is extended in depth, enhancing the network's feature extraction capability and strengthening the model's denoising performance. Extensive tests on synthetic and real images show that ANED-Net is robust to different noise scenarios. It effectively mitigates speckle noise even at unspecified levels and outperforms many established methods.

Abstract Background China bears a high burden of both hepatitis B virus (HBV) infection and type 2 diabetes mellitus (T2DM). T2DM accelerates the progression of liver disease among individuals infected with HBV. This study aims to assess the excess disease burden caused by comorbid T2DM among HBV-infected individuals in China. Methods We estimated the disease burden of HBV and its complications in China from 2006 to 2030 using individual-based Markov models. The baseline population consisted of 93 million HBV-infected individuals derived from the 2006 National Serological Epidemiological Survey. We developed two models: one incorporated the impact of T2DM on the disease progression of HBV infection, while the other did not consider the impact of T2DM. By comparing the outcomes between these two models, we estimated the excess disease burden attributable to comorbid T2DM among HBV-infected individuals. Results The incidence of severe HBV complications, including cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths, exhibited an increasing trend from 2006 to 2030 among the Chinese HBV-infected population. Comorbid T2DM increased the annual incidence and cumulative cases of severe HBV complications. From 2006 to 2022, comorbid T2DM caused 791,000 (11.41%), 244,000 (9.27%), 377,000 (8.78%), and 796,000 (12.19%) excess cases of compensated cirrhosis, decompensated cirrhosis, HCC, and liver-related deaths, respectively. From 2023 to 2030, comorbid T2DM is projected to result in an 8.69% excess in severe HBV complications and an 8.95% increase in liver-related deaths. Among individuals aged 60 and older at baseline, comorbid T2DM led to a 21.68% excess in severe HBV complications and a 28.70% increase in liver-related deaths from 2006 to 2022, with projections indicating a further 20.76% increase in severe HBV complications and an 18.31% rise in liver-related deaths over the next seven years. Conclusions Comorbid T2DM imposes a substantial disease burden on individuals with HBV infection in China. Healthcare providers and health policymakers should develop and implement tailored strategies for the effective management and control of T2DM in individuals with HBV infection.

Abstract Low back pain (LBP) is a common orthopedic disease over the world. Lumbar intervertebral disc degeneration (IDD) is regarded as an important cause of LBP. Shensuitongzhi formula (SSTZF) is a drug used in clinical treatment for orthopedic diseases. It has been found that SSTZF can have a good treatment for IDD. But the exact mechanism has not been clarified. The results showed that SSTZF protects against LSI-induced degeneration of cartilage endplates and intervertebral discs. Meanwhile, SSTZF treatment dramatically reduces the expression of inflammatory factor as well as the expression of catabolism protein and upregulates the expression of anabolism protein in LSI-induced mice. In addition, SSTZF delayed the progression of LSI-induced IDD via downregulation the level of NF-κB signaling key gene RELA and phosphorylation of key protein P65 in endplate chondrocytes. Our study has illustrated the treatment as well as the latent mechanism of SSTZF in IDD.

Abstract Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Abstract Background Clonidine stimulation test has been widely used in the diagnosis of growth hormone deficiency in children with short stature with a high level of reliability. However, it may cause hypotension, which usually appears as headache, dizziness, bradycardia, and even syncope. It is well known that elevating the beds to make patients’ feet above their cardiac level might relieve this discomfort. However, the real efficiency of this method remains to be proved while the best angle for the elevated bed is still unclear. Methods A total of 1200 children with short stature were enrolled in this retrospective cross-sectional study. Age, gender, weight, and basic systolic and diastolic blood pressure were collected. Blood pressure at 1, 2, 3, and 4 h after stimulation tests were recorded. The participants were divided into 3 groups based on the angles of the elevated foot of their beds named 0°, 20°, and 40° groups. Results At one hour after the commencement of the tests, participants lying on the elevated beds showed a higher mean increase on the change of pulse pressure. The difference in the angles of the elevated beds did not show statistical significance compared with those who did not elevate their beds (0.13 vs. 2.83, P = 0.001; 0.13 vs. 2.18, P = 0.005; 2.83 vs. 2.18, P = 0.369). When it came to 4 h after the tests began, participants whose beds were elevated at an angle around 20° had a significantly higher mean increase in the change of pulse pressure values compared with those whose beds were elevated at an angle around 40° (1.46 vs. -0.05, P = 0.042). Conclusion Elevating the foot of the beds of the patients who are undergoing clonidine stimulation tests at an angle of 20°might be a good choice to alleviate the hypotension caused by the tests.

Aiming at the problems of low processing efficiency and uneven material removal during shear rheological polishing (SRP) of polycrystalline tungsten, this paper introduces the Fenton-like reaction between H2O2 and Cu2+ to enhance the chemical effect on material removal. Passivation behavior and removal mechanisms were investigated using electrochemical tests, scanning electron microscopy, atomic force microscopy, and other characterization methods. Results show that the Fenton-like reaction exhibits excellent activity under the combined action of H2O2 and Cu(NO3)2, obtaining a satisfactory material removal rate of 702.22 Å⋅min−1 and a surface roughness Rq of 7.05 nm. The efficacy of the H2O2+Cu(NO3)2 slurry lies in its superior removal and passivation performance, attributed to the generation of hydroxyl radicals through the Fenton-like reaction. These radicals facilitate the formation of a WO3 passivation layer with good corrosion resistance on the surface, while enabling easy removal through mechanical wear. In addition, the plastic deformation mechanism of passivation layer was also studied by nanoscratch tests and transmission electron microscopy. It is found that a pure plastic flow groove can be obtained in the load range of 3–100 mN, accompanied by the formation of asymmetric deformation and pile-ups in the subsurface of the main plastic zone.