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Abstract Background Robot-assisted surgery (RAS) is being performed with increasing frequency in pediatric oncology. We report our experience with RAS for renal tumors in children and compare the outcomes between RAS and laparoscopic surgery (LAS). Methods A total of 23 patients with renal tumor who underwent minimally invasive surgery (MIS) between January 2020 and December 2023 were included in the study. The inclusion criteria enrolled in this study was unilateral tumors with maximum tumor diameter less than 10 cm. Patients who had enlarged lymph node, venous thrombosis, preoperative tumor rupture, bilateral renal tumor, or extrarenal extension on imaging were deemed contraindications and excluded. Patient demographics, operative details, postoperative outcomes and follow-up were recorded. Results Among these patients, 17 underwent RAS and 6 underwent LAS. In the RAS group, the median age was 64 months (range, 9–156) with a median weight of 19.48 kg (range, 8.4–46.5); the maximum tumor diameter at operation was 55.65 mm (range, 22–88); the operation time was 188.8 min (range, 120–210), the intraoperative blood loss was 20 ml (range, 5–50), and the length of postoperative hospital stay was 4 days (range 1–9). There was no significant difference in patients’ age, weight, location, tumor size, histological pattern and operation time between the two groups (P > 0.05). The RAS group had a significantly less intraoperative blood loss (P = 0.026) and less length of postoperative stay (P = 0.01) than the LAS group. Conclusion Our initial experience suggested that RAS in pediatric renal tumor was feasible and safe, and it reduced surgical trauma and accelerate postoperative recovery for the patients. Due to the limitations of sample size and study quality, the clinical importance of these findings still needs to be further verified.

Abstract Background BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505.

Abstract The Ideal Plant Architecture 1 (IPA1) transcription factor promotes rice yield and immunity through phosphorylation at its amino acid residue Ser163 as a switch. Although phosphorylated IPA1 mimic, IPA1(S163D), directly targets the promoter of immune response gene WRKY45, it cannot activate its expression. Here, we identified a co-activator of IPA1(S163D), a RING-finger E3 ligase IPA1 interactor 7 (IPI7), which fine-tunes the transcriptional activity of IPA1 to timely promote plant immunity and simultaneously maintain growth for yield. IPI7 interacts with IPA1 and promotes K29-polyubiquitination of IPA1 in vitro and in vivo. However, the stability of IPA1 protein is not affected by IPI7-mediated ubiquitination. The IPI7-promoted K29-polyubiquitination of IPA1 is induced by Magnaporthe oryzae infection and required for phosphorylated IPA1 to transactivate WRKY45 expression for immune response but not for plain IPA1 to transactivate DENSE AND ERECT PANICLES 1 (DEP1) expression for panicle development. IPI7 knockout impairs IPA1-mediated immunity but not yield. Our study reveals that plants utilize non-proteolytic K29-ubiquitination as a response to pathogen infection to fine-tune IPA1 transactivation activity for promoting immunity.

Objective To investigate the prevalence of human parvovirus B19 (B19V) infection among college students, so as to provide reference for the development of blood donor screening strategies and blood supply policies. Methods From March 2023 to February 2024, blood donor samples from college students in Changchun were retrospectively analyzed using the principle of random numbers, with samples taken 1 to 3 days per month. B19V IgG/IgM were detected by ELISA, and B19V DNA and viral load were measured by real-time quantitative PCR. Results Among 1 456 blood donor samples from college students, the positive rates for B19V IgG, IgM and DNA were 11.54%, 0.34% and 2.68%, respectively. The viral load in 39 B19V DNA-positive samples ranged from 5.60×102 IU/mL to 9.10×106 IU/mL, with 28 samples (1.92%) having a viral load above 104 IU/mL. There were 11 samples (0.76%) that were positive for B19V DNA but negative for IgG/IgM. Conclusion The college students have a low prevalence of past B19V infection, but a higher risk of infections and a higer proportion of acute infections with high viral loads in individuals who are]B19V IgG negative, presenting a risk of transmission through blood transfusion. Targeted blood safety monitoring is necessary for college students to track the prevalence of B19V DNA.

Steel containment vessels for nuclear power plants can experience gas leakage due to minute defects such as cracks, corrosion, and aging, leading to gas leakage. A gas leakage model for microchannels is established to elucidate the mechanism underlying gas leakage within microchannels caused by these defects, specifically addressing the issue of unidirectional gas flow. Computational Fluid Dynamics (CFD) and the UK R6 method are employed to calculate the gas leakage rate within microchannels. Furthermore, the characteristics of gas flow within microchannels are explored, including the factors affecting the gas leakage rate. Validation of the calculation results is verified experimentally. The results indicate that the gas mass flow rate exhibits a linear decrease with decreasing internal pressure and a non-linear decline as temperature increases. Additionally, the gas mass flow rate demonstrates a negative correlation with the microchannel length but a positive association to its hydraulic diameter. The primary influencing factors on gas leakage rates are hierarchically ranked as follows: pressure difference, microchannel cross-sectional area, temperature, microchannel length, and microchannel hydraulic diameter.

Abstract The analysis of the differences in metabolic profiles between naturally Ophiocordyceps sinensis (NO) and cultivated Ophiocordyceps sinensis (CO) is an essential process for the medicinal value mining of Ophiocordyceps sinensis. Non-targeted metabolomics was used to compare the differences in metabolite composition and abundance between NO and CO. Total metabolite composition found that NO is rich in organic acids and derivatives, and CO is rich in lipids and lipid-like molecules. HCA found that organooxygen compounds, cinchona alkaloid, and fatty acyls had different abundances in NO and CO. The variable importance in projection value and quantitative analysis of metabolites found that NO was rich in l-iditol, malate, linoleic acid, and oleic acid; CO is rich in sucrose, perseitol, hydroquinidine, nonanoic acid, 1-hydroxy-2-naphthoic acid, hymol-β-d-glucoside, and gly-his-lys. these compounds have the potential to be biomarkers of NO and CO. KEGG enrichment analysis showed that ascorbate and aldarate metabolism, carbon metabolism, pyrimidine metabolism, and fatty acid biosynthesis were the most different metabolic pathways between NO and CO. Therefore, the analysis of the characteristics of NO and CO metabolites has reference value for finding their different medicinal functions.

Abstract Background This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene. Methods A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis. Results The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon–intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19. Conclusion This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

Background and aim: The most effective among the acupoints remains to be determined for treating diabetic gastroparesis (DGP). This study aimed to compare single and combination acupoints for their effectiveness in DGP. Experimental procedure: A prospective, patient-assessor-blinded randomised controlled trial was designed to compare the efficacy of 8-week acupuncture at a single acupoint (Zhongwan, CV-12), combination acupoints (Zhongwan, CV-12 and Zusanli, ST-36), and a sham-acupoint, in 99 adults with DGP. The primary clinical outcome was measured using the Gastroparesis Cardinal Symptom Index (GCSI), while barium meal examination, fasting plasma glucose, the 2-h plasma glucose, short-form health survey (SF-36), and GCSI subscales were performed for evaluating secondary clinical outcomes. These results were analysed by two factorial analysis of variance (ANOVA) test, Chi-Square, Fisher Exact, Kruskal–Wallis tests and Tukey's Honest Significant Difference (HSD) test. Results: After randomization, 97 patients completed the study. GCSI scores of all groups decreased during both post-treatment and the follow-up period, they were statistically significant compared to the baseline period (p 0.05) during the post-treatment period. GCSI scores improved more in the combination acupoints group than in the single acupoint group which was better than the sham group after treatment. During the follow-up period, the same trend was observed. Conclusions: Among patients with DGP, the combination acupoints were more beneficial compared with single and sham acupoints. Trial registration number: NCT02452489.

This paper introduces a base isolation system-tuned mass damper inerter (BIS-TMDI) hybrid system to the AP1000 nuclear power plant (NPP), which reduces seismic damage potential of the NPP structure. The effects of fluid-structure interaction (FSI) caused by the passive containment cooling system water storage tank (PCCWST) on NPP's seismic performance are investigated. The FSI of water tank theoretical model is considered based on the Housner's model, and a series of time history analyses are performed to prove the rationality of the proposed model. Three single-objective optimization strategies are employed to minimize the relative displacement variance and absolute acceleration variance of the upper structure, as well as the filtered energy index (FEI). Furthermore, a multi-objective optimization strategy considering all these three indexes is proposed to obtain optimal parameters of vibration control. The influence of vibration control strategies on the relative deformation and acceleration of the upper structure is explored with various water level ratios. The analytical results indicate that the proposed BIS-TMDI strategy has significantly reduced the NPP structure's seismic response. The effectiveness of the vibration control strategy is influenced by the water level ratio, emphasizing the significance of designing an appropriate water level ratio to reduce NPP structure's seismic response.

Abstract Background Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals. Understanding the mechanism underlying HSPC development is a holy grail of hematopoietic biology, which is helpful for HSPC clinical application. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision; however, its dynamic and role in HSPC development is poorly investigated. Methods We performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish for the first time, including Hi-C, RNA-seq, ATAC-seq, H3K4me3 and H3K27ac ChIP-seq. Results The chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure. We revealed the multi-scale reorganization of chromatin structure and its influence on transcriptional regulation and transition of cell fate during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression of HSPC. Conclusions Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factors involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.

At present, suture bridge is a feasible choice in the treatment of massive rotator cuff tears (MRCTs). However, high tension on the repair site and medial tension during suture tightening and after medial knotting are unavoidable problems in MRCT repair with a suture bridge. Arthroscopic V-shaped double-pulley suture-bridge repair is a pragmatic surgical technique for the repair of MRCTs. The unique parallel design of medial- and lateral-row anchors can minimize tendon tension on the apex portion; 6 sets of double-pulley suture bridges can not only provide sufficient tendon-bone contact area but also reduce the tendon retear rate. Moreover, medial knotless techniques can reduce tendon tension.

ObjectiveObesity has emerged as a worldwide problem. In recent years, it has been verified that there is an association between sleep duration and obesity indicators. This provides a new approach to control obesity. In this study, the relationship between duration of sleep and body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) among Americans ≥45 years old was investigated.MethodsData was collected from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2014. The link between sleep duration and obesity indicators was analysed using multiple regression models and weighted smoothed curve fitting. Subgroup analysis was conducted to assess the consistency of the connection between sleep duration and obesity indicators across various groups.ResultsThis study involved 7,118 males and 7,265 females, with an average age of 62.09. After total adjustment, sleep duration was negatively correlated with BMI (β = −0.19, 95%CI: −0.26, −0.12), WC (β = −0.36, 95%CI: −0.53, −0.19) and WHtR (β = −0.27, 95%CI: −0.38, −0.17). Subgroup analyses revealed more significant negative associations between sleep duration and BMI, WC, and WHtR among non-Hispanic White participants, and those without diabetes and hypertension.ConclusionSleep duration was significantly negatively associated with BMI, WC, and WHtR, suggesting that longer sleep duration may contribute to lower obesity indicators in middle-aged and elderly Americans. Subgroup analysis showed that their negative correlation differed between races, diabetes, or hypertension status. However, additional prospective studies are required to validate these findings and investigate potential causal relationships.

Introduction Stimulating acupoints is beneficial for improving heart health but the clinical efficacy of transcutaneous electrical acupoint stimulation (TEAS) as a complementary therapy for chronic coronary syndromes (CCSs) remains unclear. This study aims to evaluate whether TEAS can alleviate angina severity in patients with CCS and to explore the potential mechanisms underlying TEAS.Methods and analysis This study, conducted across two clinical centres, involved 90 participants distributed equally into three groups via simple randomisation (1:1:1 ratio). The research cycle was 28 weeks including a 4-week baseline, 12-week treatment and 12-week follow-up period. All groups will receive basic treatment with the TEAS group additionally receiving 36 sessions of TEAS stimulation over the 12 weeks. The two control groups will either undergo sham TEAS or no additional intervention alongside their basic treatment. The primary outcome is the 6-minute walk test; eight other indicators will serve as secondary outcomes.Ethics and dissemination Approval for this study was granted by the Medical Research Ethics Committee of the Third Clinical Affiliated Hospital of Changchun University of Chinese Medicine in May 2023. Findings will be disseminated through peer-reviewed publications.Trial registration number ChiCTR2400079383.

Abstract Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP‐associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP‐enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP‐depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up‐regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi‐omics analysis in the Rax‐CreERT2::BrafV600E/+::PtenFlox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co‐variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up‐regulated purine metabolism as signatures of CP‐associated hypothalamic‐comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP‐associated hypothalamic‐comorbidities.

Transtendon repair is increasingly applied in the treatment of PASTA (partial articular supraspinatus tendon avulsion) lesions, but a “tendon hole” from anchor insertion, which will break the intact bursal layer and potentially result in tear completion, is an unavoidable problem. The “mini-incision” transtendon double-pulley suture bridge presented in the study is a pragmatic technique in treatment of PASTA lesion. The 4 suture strands on the medial-row anchor provide enough biomechanical strength on the reattached articular layer, the “mini-incision” minimizes iatrogenic trauma on the bursal layer, and double-pulley suture-bridge smoothly covers the “mini-incision” so as to achieve anatomical reduction of articular and bursa side of supraspinatus tendon. The surgical technique is described, as well as pearls, pitfalls, advantages, and disadvantages.

ObjectivesMany studies have confirmed that antibacterial agents can disrupt the human gut microbiota. In China, Tanreqing injection (TRQ) is a drug with antibacterial activity that is widely used in the treatment of respiratory infections. However, its specific influence on gut microbiota remains unclear. This study aimed to investigate the effect of TRQ on the gut microbiota of healthy volunteers.MethodsTwelve healthy adults received 20 ml of TRQ intravenously daily for 7 consecutive days. At six timepoints (Pre, on D1, D3, D5, D7 and follow-up visit) fecal samples were collected and analyzed using 16S rRNA gene sequencing.ResultsEleven people were included in the analysis finally. TRQ did not significantly alter gut microbiota diversity or richness (Shannon and Simpson and Chao1 index) in healthy people during the intervention. Gut microbial structure was stable (weighted and unweighted Unifrac). Using a machine learning method based on PLS-DA analysis, the separation trend on D7 at the genus level was found, returning to baseline two days after discontinuation. The abundance of major genus fluctuated on D7 compared with that prior to treatment, including an increase of unclassified_f_Enterobacteriaceae (13.0611%), a decrease of Bifidobacterium and Escherichia-Shigella (6.887%, 10.487%). Functional prediction analysis did not reveal any significant difference.ConclusionsOur study showed short-term use of TRQ at conventional doses may not cause perturbations to the gut microbiota in healthy adults. This finding provides some useful information for the safe use of TRQ in the treatment of respiratory infections.Clinical trial registrationhttps://www.medicalresearch.org.cn/, identifier MR-31-24-014367.

BackgroundEmerging evidence indicates a significant link between various immune cell types and the development of heart valve disorders. Mitral valve prolapse (MVP) is a common condition that can lead to heart failure, arrhythmias, and even sudden death. Currently, the role of immune cells in MVP is not well understood. Thus, this study aimed to explore the causal relationship between immunophenotypes and the risk of MVP.MethodsThis study conducted a two-sample Mendelian randomization (MR) analysis to examine the link between 731 immunophenotypes and MVP. Publicly available data from genome-wide association studies were used for both the exposures and outcomes. The primary method for assessing the causal relationship between mitral valve prolapse and the 731 immunophenotypes was the inverse variance weighted method. Additionally, to ensure the MR results were reliable and valid, sensitivity analyses, including leave-one-out analysis, the Cochran Q-test, and the Egger intercept test, were conducted.ResultsThe findings indicated that multiple immune cell phenotypes potentially cause changes in the risk of developing MVP. After adjusting for the false discovery rate, nine immune phenotypes were found to increase the risk of MVP, while nine others appeared to decrease it. In addition, reverse MR analysis found no causal relationship between MVP and these eighteen immunophenotypes.ConclusionThrough genetic analyses, this research demonstrated a significant causal relationship between certain immune cells and MVP, providing new insights for future basic and clinical research.

BackgroundThe global prevalence of stroke has been increasing. Motor dysfunction is observed in approximately 55 to 75% of stroke patients, with upper limb impairment affecting around 85% of them. Following upper limb dysfunction, the body’s recovery time is not only slower compared to the lower limbs, but the restoration of its fine motor skills is significantly more challenging, greatly impacting the daily lives of patients. Consequently, there is an increasing urgency for study on the upper limb function in stroke.MethodsA search was conducted in the Web of Science Core Collection: Science Citation Index Expanded (SCI-Expanded) database for material published from January 1, 2004 to December 31, 2023. We included all relevant literature reports and conducted an analysis of annual publications, countries/regions, institutions, journals, co-cited references, and keywords using the software packages CiteSpace, VOSviewer, and Bibliometrix R. Next, we succinctly outlined the research trends and hotspots in post-stroke upper limb dysfunction.ResultsThis analysis comprised 1,938 articles from 1,897 institutions, 354 journals, and 53 countries or regions. A yearly rise in the production of publications was noted. The United States is the foremost nation on the issue. Northwestern University has the most amounts of papers compared to all other institutions. The journal Neurorehabilitation and Neural Repair is a highly significant publication in this field, with Catherine E. Lang serving as the principal author. The majority of the most-cited references focus on subjects such as the reliability and validity of assessment instruments, RCT of therapies, systematic reviews, and meta-analyses. The intervention measures primarily comprise three types of high-frequency phrases that are related, as determined by keyword analysis: intelligent rehabilitation, physical factor therapy, and occupational therapy. Current areas of focus in research include randomized clinical trials, neurorehabilitation, and robot-assisted therapy.ConclusionCurrent research has shown a growing interest in studying upper limb function assessment, occupational therapy, physical therapy, robot-assisted therapy, virtual reality, brain-computer interface, telerehabilitation, cortical reorganisation, and neural plasticity. These topics have become popular and are expected to be the focus of future research.

Summary: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. The availability of appropriate and well-characterized preclinical models for RMS is limited, posing a challenge for investigating the molecular mechanisms and evaluating new targeted compounds in preclinical settings. Here, we collected 51 RMS specimens (referred to as ZJUCH-RMS cohort) and established 9 patient-derived cells (PDCs) and validated the identity of these cells by the expression of RMS-specific markers. Whole-transcriptome analysis identified high-confidence mutations in ZJUCH-RMS cohort including RAS, TP53, ARID1A, MYOD1, and MYCN. Further studies showed that RMS PDCs retained the genetic alterations and the expression of RMS hallmark and dependency genes in matched primary tumors and acted as valuable tools to assess drug responses and pharmacogenomic interactions. Our study provides unique PDCs that are available for preclinical studies of RMS and further advances the feasibility of RMS PDCs as valuable tools for developing personalized treatments for patients.

ObjectiveType 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD).MethodsThe study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis.ResultsT2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P=0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance.ConclusionsT2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD.

Background Coagulopathy is associated with poor prognosis of traumatic brain injury (TBI) patients. This study is performed to explore the association between serum magnesium level and the risk of coagulopathy in TBI. Methods TBI patients from the Medical Information Mart for Intensive Care-III database were included for this study. Logistic regression analysis was performed to explore risk factors and develop a predictive model for coagulopathy in TBI. The restricted cubic spline (RCS) was utilized to analyze the association between serum magnesium level and the development of coagulopathy. Receiver operating characteristic curve was drawn to evaluate the performance of the predictive model for coagulopathy. Results The incidence of coagulopathy in TBI was 32.6%. The RCS indicated the association between magnesium and coagulopathy was U-shaped. Multivariate logistic regression confirmed age, coronary heart disease, cerebral vascular disease, chronic liver disease, GCS, ISS, epidural hematoma, hemoglobin, shock index and magnesium level were independently associated with the coagulopathy in TBI. Compared with patients of magnesium level between 1.7 and 2.3 mg/dL, those with magnesium level below 1.7 mg/dL or above 2.2 mg/dL had a higher risk of coagulopathy. Conclusion Both hypermagnesemia and hypomagnesemia are associated with higher risk of coagulopathy in TBI patients. Physicians should pay more attention on preventing coagulopathy in TBI patients with hypomagnesemia or hypermagnesemia.

Abstract Successful dental pulp regeneration is closely associated with rapid revascularization and angiogenesis, processes driven by the Jagged1(JAG1)/Notch signaling pathway. However, soluble Notch ligands have proven ineffective in activating this pathway. To overcome this limitation, a Notch signaling hydrogel is developed by indirectly immobilizing JAG1, aimed at precisely directing the regeneration of vascularized pulp tissue. This hydrogel displays favorable mechanical properties and biocompatibility. Cultivating dental pulp stem cells (DPSCs) and endothelial cells (ECs) on this hydrogel significantly upregulate Notch target genes and key proangiogenic markers expression. Three‐dimensional (3D) culture assays demonstrate Notch signaling hydrogels improve effectiveness by facilitating encapsulated cell differentiation, enhancing their paracrine functions, and promoting capillary lumen formation. Furthermore, it effectively communicates with the Wnt signaling pathway, creating an odontoinductive microenvironment for pulp‐dentin complex formation. In vivo studies show that short‐term transplantation of the Notch signaling hydrogel accelerates angiogenesis, stabilizes capillary‐like structures, and improves cell survival. Long‐term transplantation further confirms its capability to promote the formation of pulp‐like tissues rich in blood vessels and peripheral nerve‐like structures. In conclusion, this study introduces a feasible and effective hydrogel tailored to specifically regulate the JAG1/Notch signaling pathway, showing potential in advancing regenerative strategies for dental pulp tissue.

Purpose: To investigate the inhibitory effect of antimicrobial peptide merecidin on triple-negative breast cancer (TNBC) and the mechanism of inhibiting epithelial-mesenchymal transformation (EMT) by regulating miR-30d-5p/vimentin. Methods: TNBC cell lines (MDA-MB-231, MDA-MB-468) were treated with merecidin to assess proliferation, migration, invasion ability, and EMT. Confocal laser localization was used to examine the role of merecidin and TNBC cells. The relationship between merecidin and miR-30d-5p was determined through RT-qPCR and dual-luciferase reporter gene, and the relationship between merecidin and vimentin was verified through pulling down the experiment. The effects of miR-30d-5p on the migration and invasion ability of TNBC cells were confirmed through scratch and transwell experiments. Vimentin levels, tumor volume, shape, size, and weight were observed in the MDA-MB-231 subcutaneous tumor model in nude mice. Results: merecidin inhibited the proliferation, migration, invasion, and EMT of TNBC cells. merecidin was primarily located in the cytoplasm of TNBC cells, and the expression of miR-30d-5p was low in TNBC cells. merecidin significantly up-regulated the expression of miR-30d-5p. miR-30d-5p negatively regulated vimentin. merecidin could bind to vimentin in vitro. miR-30d-5p inhibited the migration and invasion ability of TNBC cells, while vimentin promoted their migration and invasion ability. Down-regulation of miR-30d-5p or overexpression of vimentin partially counteracted the inhibitory effects of merecidin on TNBC cell migration, invasion ability, and EMT. In nude mouse tumor models, merecidin significantly suppressed tumor growth. Conclusion: Merecidin effectively blocks the EMT process and inhibits the migration and invasion of TNBC cells by regulating miR-30d-5p/vimentin.

IntroductionThis study explores the dynamics of Linguistic Landscapes (LL) in the commercial tourist district near Labrang Monastery by analyzing the use of Tibetan, Mandarin, and English on café menus. Traditionally, LL research has focused on language visibility as an indicator of vitality, overlooking contextual complexities. We challenge this approach by considering geocultural contexts, instigators’ language proficiency, and intended audience.MethodThis study employed a triangulation approach, combining multiple methods of data collection and analysis. First, we conducted a preliminary observation of shop names in the region. Second, with the consent of shop owners, we comprehensively documented visual and textual artifacts both inside and outside the cafés, including signboards, menus, wall billboards, and displayed books. Third, we conducted extensive semi-structured interviews with shop owners and customers. These interviews, transcribed for analysis, provided insights into language usage preferences and decision-making processes.ResultsBy advocating for a holistic LL research approach, integrating qualitative insights with quantitative data, this study contributes to a deeper understanding of LL dynamics. Our findings show that geocultural contexts, instigators’ language proficiency, and intended audience all play a role in shaping language representation and vitality.DiscussionThe absence of a language on signage does not necessarily signify diminished vitality but can reflect strategic decisions influenced by religious, individual and commercial factors. Beyond mere visibility, languages on café menus serve as symbolic markers of ethnic identity and reflect the functions they assume within the speech community, offering insights into language vitality across different usage contexts. This research enriches scholarly discourse on LL, particularly within the Chinese context, by emphasizing the multifaceted nature of language presence and its vitality.

Functional dyspepsia (FD) is a brain–gut interaction disorder located in the stomach and duodenum, which has complex pathophysiological mechanisms, and there is no effective treatment for FD. Acupuncture and moxibustion have been proven to have definite and significant efficacy on FD. Focusing on the affected area and combined with the potential pathophysiology of FD, here we discuss the possible mechanisms of acupuncture and moxibustion in treating FD to guide future clinical and experimental research. We argue that the pathological causes of FD can be roughly divided into gastrointestinal dysfunction, duodenal low-grade inflammation, visceral hypersensitivity, and duodenal intestinal barrier and microbial imbalance. Correspondingly, the possible mechanisms of acupuncture and moxibustion in treating FD are elucidated from the perspective of how they improve gastric accommodation, regulate gastrointestinal motility, reduce gastric visceral sensitivity, regulate eosinophil–mast cell axis, inhibit low-grade inflammatory responses, and possibly regulate intestinal microbial homeostasis and duodenal barrier function through the microbiota–gut–brain axis. Although some evidence is still lacking, acupuncture remains a promising treatment for FD. In the future, it is necessary to conduct additional clinical and experimental research on acupuncture and moxibustion in treating FD to further explore their effects and mechanisms.

Abstract Background The Endothelial Activation and Stress Index (EASIX) is a novel marker of endothelial injury and correlates with survival of various patients. The endothelial dysfunction plays an important role on the pathophysiological process of traumatic brain injury (TBI). This study was designed to explore the prognostic value of EASIX on TBI patients. Methods 358 TBI patients hospitalized in the West China hospital between October 2018 and October 2022 were enrolled for this study. The EASIX was calculated based on the formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L). The univariate and multivariate logistic regression with forward method was performed to explore the association between EASIX and mortality. A prognostic model was developed combining significant risk factors in the multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to compare the predictive accuracy of the EASIX and the developed model. Results The 30-day mortality of enrolled 358 TBI patients was 51.1%. Non-survivors had higher EASIX than survivors (p

Abstract Backgrounds Long nonconding RNAs (lncRNAs) have been found to be a vital regulatory factor in the development process of human cancer, and could regarded as diagnostic or prognostic biomarkers for human cancers. Here, we aim to confirm the expression and molecular mechanism of RP11-171K16.5 (lnc171) in hepatocellular carcinoma (HCC). Methods Screening of differentially expressed lncRNAs by RNA sequencing. Expression level of gene was studied by quantitative real-time PCR (qRT-PCR). The effects of lnc171, mir-873-5p, and ethanol on migration and invasion activity of cells were studied used transwell assay, and luciferase reporter assay was used to confirm the binding site. Results RNA sequencing showed that lnc171 was markedly up-regulated in HCC. siRNA-mediated knockdown of lnc171 repressed the migration and invasion ability of HCC cells. Bioinformatic analysis, dual luciferase reporter assay, and qRT-PCR indicated that lnc171 interacted with mir-873-5p in HCC cells, and Zin-finger E-box binding homeobox (ZEB1) was a downstream target gene of mir-873-5p. In addition, lnc171 could enhance migration and invasion ability of HCC cells by up-regulating ZEB1 via sponging mir-873-5p. More interestingly, ethanol stimulation could up-regulate the increase of lnc171, thereby regulating the expression of competing endogenous RNA (ceRNA) network factors which lnc171 participated in HCC cells. Conclusions Our date demonstrates that lnc171 was a responsive factor of ethanol, and plays a vital role in development of HCC via binding of mir-873-5p.

Automatic modal identification via automatically interpreting the stabilization diagram provides key technique in bridge structural health monitoring. This paper reviews the progress in the area of automatic modal identification based on interpreting the stabilization diagram. The whole identification process is divided into four steps from establishing the stabilization diagram to removing the outliers in the identification results. The criteria and algorithms used in each step in the existing studies are carefully summarized and classified. Comparisons between typical methods in cleaning and interpreting the stabilization diagram are also conducted. Real structure benchmarks used in the existing studies to validate the proposed automatic modal identification methods are also summarized. Based on the review and comparison, the specific ratio method for cleaning the stabilization diagram, the hierarchical clustering method for interpreting the stabilization diagram and the adjusted boxplot for removing the outliers in the identification results are the most suitable methods for each step. The key point of automatic modal identification based on interpreting the stabilization diagram has also discussed, and it is recommended to pay more attention to cleaning the stabilization diagram. Future study about automatic modal identification under situation with very few sensors deployed should be more concerned. This review aims to help researchers and practitioners in implementing existing automatic modal identification algorithms effectively and developing more suitable and practical methods for civil engineering structures in the future.

Abstract Heavy metal contamination is an urgent ecological governance problem in mining areas. In order to seek for a green and environmentally friendly reagent with better plant restoration effect to solve the problem of low efficiency in plant restoration in heavy metal pollution soil. In this study, we evaluated the effects of three biodegradable chelating agents, namely citric acid (CA), fulvic acid (FA) and polyaspartic acid (PASP), on the physicochemical properties of copper tailings, growth of ryegrass (Lolium perenne L.) and heavy metal accumulation therein. The results showed that the chelating agent application improved the physicochemical properties of copper tailings, increased the biomass of ryegrass and enriched more Cu and Cd in copper tailings. In the control group, the main existing forms of Cu and Cd were oxidizable state, followed by residual, weak acid soluble and reducible states. After the CA, FA or PASP application, Cu and Cd were converted from the residual and oxidizable states to the reducible and weak acid soluble states, whose bioavailability in copper tailings were thus enhanced. Besides, the chelating agent incorporation improved the Cu and Cd extraction efficiencies of ryegrass from copper tailings, as manifested by increased root and stem contents of Cu and Cd by 30.29–103.42%, 11.43–74.29%, 2.98–110.98% and 11.11–111.11%, respectively, in comparison with the control group. In the presence of multiple heavy metals, CA, FA or PASP showed selectivity regarding the ryegrass extraction of heavy metals from copper tailings. PCA analysis revealed that the CA-4 and PASP-7 treatment had great remediation potentials against Cu and Cd in copper tailings, respectively, as manifested by increases in Cu and Cd contents in ryegrass by 90.98% and 74.29% compared to the CK group.

Introduction: Ovarian cancer is the most malignant gynecological tumor. Previous studies have demonstrated that chimeric antigen receptor (CAR)-engineered NK-92 cells targeting folate receptor α (αFR) (NK-92-αFR-CAR) can specifically kill αFR-positive ovarian cancer cells. However, the migration barrier restricts antitumor effects of CAR-engineered cells. Objectives: To elucidate the mechanism by which NK-92-αFR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92-αFR-CAR-CXCR3A can target αFR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer. Methods: Study the mechanism of CXCL10 expression strongly induced by TNF-α and IFN-γ combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92-αFR-CAR-CXCR3A cells, which were co-expressed CXCR3A and αFR-CAR. Evaluate the killing and migration effects of NK-92-αFR-CAR-CXCR3A in vitro and in vivo. Results: RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92-αFR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN-γ and TNF-α secreted by NK-92-αFR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN-γ and TNF-α enhanced the activation level of the IFN-γ-IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92-αFR-CAR-CXCR3A cells could not only efficiently kill αFR-positive ovarian cancer cells in vitro but also secrete IFN-γ and TNF-α. Higher migration than that of NK-92-αFR-CAR was detected in NK-92-αFR-CAR-CXCR3A using transwell assay. NK-92-αFR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and increased infiltration into tumor tissue. Conclusion: This study confirmed that IFN-γ and TNF-α secreted by αFR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving αFR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.

Objective To develop a novel scoring system based on magnetic resonance imaging (MRI) for predicting the difficulty of ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation for uterine fibroids.Materials and methods A total of 637 patients with uterine fibroids were enrolled. Sonication time, non-perfused volume ratio (NPVR), and ultrasound energy delivered for ablating 1 mm3 of fibroid tissue volume (E/V) were each classified as three levels and assigned scores from 0 to 2, respectively. Treatment difficulty level was then assessed by adding up the scores of sonication time, NPVR and E/V for each patient. The patients with score lower than 3 were categorized into low difficulty group, with score equal to or greater than 3 were categorized into high difficulty group. The potential predictors for treatment difficulty were compared between the two groups. Multifactorial logistic regression analysis model was created by analyzing the variables. The difficulty score system was developed using the beta coefficients of the logistic model.Results Signal intensity on T2WI, fibroid location index, largest diameter of fibroids, abdominal wall thickness, homogeneity of the signal of fibroids, and uterine position were independent influencing factors for the difficulty of USgHIFU for uterine fibroids. A prediction equation was obtained: difficulty score = 17 × uterine position (anteverted =0, retroverted =1)+71 × signal intensity (hypointense = 0, isointense/hyperintense = 1) +8 × enhancement (homogenous = 0, heterogeneous = 1)+25×(largest diameter of fibroids-20) +35 × (fibroid location index −0.2) +1×(abdominal wall thickness −5).Conclusions This scoring system established based on MRI findings can be used to reliably predict the difficulty level of USgHIFU treatment of uterine fibroids.

Objective To develop a diagnostic model for predicting occult uterine sarcoma in patients with presumed uterine fibroids.Materials and methods We retrospectively reviewed 41631 patients with presumed uterine fibroids who presented for HIFU treatment in 13 hospitals between November 2008 and October 2023. Of these patients, 27 with occult uterine sarcoma and 54 with uterine fibroids were enrolled. Univariate analysis and multivariate logistics regression analysis were used to determine the independent risk factors for the diagnosis of occult uterine sarcoma. A prediction model was constructed based on the coefficients of the risk factors.Results The multivariate analysis revealed abnormal vaginal bleeding, ill-defined boundary of tumor, hyperintensity on T2WI, and central unenhanced areas as independent risk factors. A scoring system was created to assess for occult uterine sarcoma risk. The score for abnormal vaginal bleeding was 56. The score for ill-defined lesion boundary was 90. The scores for lesions with hypointensity, isointensity signal/heterogeneous signal intensity, and hyperintensity on T2WI were 0, 42, and 93, respectively. The scores for lesions without enhancement on the mass margin, uniform enhancement of tumor, and no enhancement in the center of tumor were 0, 20, and 100, respectively. Patients with a higher total score implied a higher likelihood of a diagnosis of occult uterine sarcoma than that of patients with a lower score. The established model showed good predictive efficacy.Conclusions Our results demonstrated that the diagnostic prediction model can be used to evaluate the risk of uterine sarcoma in patients with presumed uterine fibroids.

ABSTRACTPaxilline (PAX) is a tremorgenic mycotoxin that is thought to be associated with various syndromes in animals. To facilitate the determination of this toxin, a hapten was chemically synthesized and then respectively conjugated to Bovine Thyroglobulin (BTG) and Bovine serum albumin (BSA) for antibody production. Monoclonal antibody (mAb) 4F8 was finally obtained and used to establish an accurate and sensitive indirect competitive ELISA (icELISA). Various parameters that could impact the performance of icELISA were optimized, including the ion concentration, pH value and organic solvent. Under optimal condition, this assay exhibits an IC50 value as low as 0.84 µg L−1. The limit of detection (LOD) of the established icELISA method for PAX was 0.03–0.3 µg L−1. In conclusion, this study provided a rapid, sensitive, and high-throughput immunoassay for the detection of PAX in grains.

AbstractObjectives To quantify the reintervention rate and analyze the risk factors for reintervention after high-intensity focused ultrasound (HIFU) ablation of uterine fibroids.Methods Eighteen studies were selected from the seven databases. A meta-analysis was applied to synthesize the reintervention rates for fibroids across various follow-up durations. Subgroup-analysis was conducted based on the year of surgery, sample size, guide methods, and non-perfusion volume ratio (NPVR). Signal intensity of T2-weighted imaging (T2WI) was independently evaluated for reintervention risk.Results The study enrolled 5216 patients with fibroids treated with HIFU. There were 3247, 1239, 1762, and 2535 women reaching reintervention rates of 1% (95% confidence interval (CI): 1-1), 7% (95% CI: 4-11), 19% (95% CI: 11-27), and 29% (95% CI: 14-44) at 12, 24, 36, and 60-month after HIFU. The reintervention rates of patients treated with US-guided HIFU (USgHIFU) were significantly lower than those of patients treated with MR-guided focused ultrasound surgery (MRgFUS). When the NPVR of fibroids was over 50%, the reintervention rates at 12, 36 and 60-month after HIFU were 1% (95% CI: 0.3–2), 5% (95% CI: 3–8), and 15% (95% CI: 9–20). The reintervention risk for hyper-intensity fibroids on T2WI was 3.45 times higher (95% CI: 2.7–4.39) for hypo-/iso-intensity fibroids.Conclusion This meta-analysis showed that the overall reintervention rates after HIFU were acceptable and provided consultative suggestions regarding treatment alternatives for patients with fibroids. Subgroup-analysis revealed that USgHIFU, NPVR ≥ 50%, and hypo-/iso-intensity of fibroids on T2WI were significant factors in reducing reintervention.Systematic Review Registration PROSPERO, CRD42023456094

Noroviruses are a group of non-enveloped single-stranded positive-sense RNA virus belonging to Caliciviridae family. They can be transmitted by the fecal-oral route from contaminated food and water and cause mainly acute gastroenteritis. Outbreaks of norovirus infections could be difficult to detect and investigate. In this study, we developed a simple threshold detection approach based on variations of the P2 domain of the capsid protein. We obtained sequences from the norovirus hypervariable P2 region using Sanger sequencing, including 582 pairs of epidemiologically-related strains from 35 norovirus outbreaks and 6402 pairs of epidemiologically-unrelated strains during the four epidemic seasons. Genetic distances were calculated and a threshold was performed by adopting ROC (Receiver Operating Characteristic) curve which identified transmission clusters in all tested outbreaks with 80 % sensitivity. In average, nucleotide diversity between outbreaks was 67.5 times greater than the diversity within outbreaks. Simple and accurate thresholds for detecting norovirus transmissions of three genotypes obtained here streamlines molecular investigation of norovirus outbreaks, thus enabling rapid and efficient responses for the control of norovirus.

Background Gross motor coordination (GMC) plays a crucial factor in children’s motor development and daily activities. It encompasses various sub-capacities, such as spatial orientation, rhythm, and motor reaction, collectively referred to as basic coordination capacities (BCC). However, children who are overweight and obese (OW/OB) often display poorer GMC. This study aims to examine the impact of gender and weight status (BMI categories) on children’s GMC and BCC. It also seeks to investigate the impact of BCC and BMI on GMC. Method The study involved 266 participants, 135 in the NW group (boys: n = 75; girls: n = 60) and 131 in the OW/OB group (boys: n = 68; girls: n = 63). An NW status is defined by a BMI z-score between ≥−2SD to ≤1SD, while an OW/OB status corresponds to a BMI z-score > 1SD. Physical activity was assessed using the Physical Activity Questionnaire for Children, developed by the University of Saskatchewan, Canada. We used six field tests to evaluate BCC, including single leg standing test (static balance), YBT (dynamic balance), rhythmic sprint test (rhythm), reaction time test (motor reaction), target standing broad test (kinesthetic differentiation), and numbered medicine ball running test (spatial orientation). GMC was evaluated with Kiphard-Schilling’s Body Coordination Test (KTK). Result The motor quotient (MQ) was primarily affected by weight status (F = 516.599, p < 0.001; gender: F = 6.694, p = 0.01), with no significant interaction effect (F = 0.062, p = 0.803). In BCC, gender had a significant main effect on rhythm capacity (F = 29.611, p < 0.001) and static balance (F = 11.257, p = 0.001) but did not significant influence other sub-capacities (p > 0.05). Weight status impacted dynamic balance (F = 11.164, p = 0.001). The interaction of gender and weight status significantly impacted motor reaction (F = 1.471, p = 0.024) and kinesthetic differentiation (F = 5.454, p = 0.02), but did not affect other sub-capacities (p > 0.05). The physical activity was not significant affected by gender (F = 0.099, p = 0.753), weight status (F = 0.171, p = 0.679) and the interactions of two variables (F = 0.06, p = 0.806). In the regression analysis, except motor reaction (p > 0.05), other BCC sub-capacities influenced GMC to varying extents (β = −0.103–0.189, p < 0.05). Nonetheless, only two types of balance significantly mediated the relationship between BMI and GMC (BMI→MQ: β = −0.543, p < 0.001; BMI→YBT: β = −0.315, p < 0.001; BMI→SLS: β = −0.282, p < 0.001; SLS→MQ: β = 0.189, p < 0.001; YBT→MQ: β = 0.182, p < 0.001). Conclusion Compared to gender, the main effect of weight status on most GMC and BCC’s sub-capacities was more pronounced. OW/OB children exhibited poorer GMC, which is related to their reduced static and dynamic balance due to excess weight. Kinesthetic differentiation, spatial orientation, and rhythm capacity are not significantly associated with BMI, but these sub-capacities positively influence gross motor coordination (GMC), except for hand-eye motor reaction.

Summary: Background: Toripalimab, a novel PD-1 antibody, is approved for treatment of multiple solid tumors; however, its neoadjuvant use with chemotherapy for triple-negative breast cancer (TNBC) remains unevaluated. Additionally, induction chemotherapy followed by de-escalation of neoadjuvant immunotherapy remains underexplored. Therefore, we conducted a phase II trial investigating a novel neoadjuvant chemoimmunotherapy regimen including de-escalation of immunotherapy for early-stage TNBC. Methods: Chemotherapy and anti-PD-1 therapy were sequentially administered in a neoadjuvant setting to female patients with histologically confirmed stage II–III TNBC between June 9, 2020, and March 24, 2022. Patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks, followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0). Key secondary endpoints included breast pCR (bpCR; ypT0/is), event-free survival and biomarker analysis. Safety was also assessed. This study was registered with ClinicalTrials.gov (NCT04418154). Findings: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 completed treatment without progression and subsequently underwent surgery. The percentages of patients with a tpCR and bpCR were 39 of 70 (55.7%, 95% confidence interval [CI]: 43.3–67.6) and 41 of 70 (58.6%, 95% CI 46.2–70.2), respectively. Sixteen (22.9%) patients experienced grade ≥3 adverse events (AEs), frequently neutropenia (12, 17.1%) and leukopenia (11, 15.7%). The most common immune-related AE was hypothyroidism (5, 7.1%, all grade 1–2). Interpretation: Including 12 weeks of toripalimab in neoadjuvant chemotherapy conferred encouraging activity and manageable toxicity in patients with early TNBC, and this regimen warrants further investigation. Funding: National Natural Science Foundation of China, Junshi Biosciences, and Jiangsu Hengrui Pharmaceuticals.

Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as ''aberrant cell cycle re-entry,'' which plays a critical role in the progression of these diseases. Addressing the dysregulation in cell cycles offers a promising therapeutic approach for cancers and CNS disorders. MicroRNAs (miRNAs) play a crucial role as regulators of gene expression in cell cycle transitions, presenting a promising therapeutic avenue for treating these disorders and their comorbidities. This review consolidates the progress made in the last three years regarding miRNA-based treatments for diseases associated with aberrant cell cycle re-entry. It encompasses exploring fundamental mechanisms and signaling pathways influenced by miRNAs in cancers and CNS disorders, particularly focusing on the therapeutic effects of exosome-derived miRNAs. The review also identifies specific miRNAs implicated in comorbidity of cancers and CNS disorders, discusses the future potential of miRNA reagents in managing cell cycle-related diseases.

BackgroundTraumatic brain injury (TBI) is a global health concern that often leads to poor prognosis. We designed this study to explore whether thiamine use is associated with a better prognosis of TBI.MethodsTBI patients selected from the Medical Information Mart for Intensive Care-III database were included in the study. Univariate and multivariate Cox regression analyses were performed to examine the relationship between thiamine use and mortality in TBI patients. Propensity score matching (PSM) was utilized to generate balanced cohorts of the non-thiamine use group and the thiamine use group. Subgroup analysis was performed in the cohort after PSM to verify the association between thiamine use and mortality in TBI patients across different stratifications.ResultsThe incidence of thiamine use in TBI was 18.3%. The thiamine use group had a lower 30-day mortality rate (p < 0.001), a longer length of ICU stay (p < 0.001), and a longer length of hospital stay (p < 0.001) than the non-thiamine use group, both in the primary cohort before PSM and the cohort after PSM. A multivariate Cox regression analysis confirmed that thiamine use was independently associated with mortality (OR = 0.454, p < 0.001) after adjusting for confounding effects. In the cohort after PSM, the subgroup analysis showed that thiamine use is associated with lower mortality in TBI patients with a Glasgow Coma Scale (GCS) score of < 13, but it is not associated with mortality in TBI patients whose GCS score is ≥13.ConclusionThiamine supplementation is effective in improving the outcome of TBI, except in cases of mild TBI. The optimal thiamine supplementation strategy for TBI is worthwhile to be explored in future studies.

Background: The prognosis of hepatocellular carcinoma (HCC) is universally poor. Early diagnosis plays a pivotal role in determining the outcome of HCC. Methods: We employed a comparative proteomics approach to identify potential biomarkers and validated the application of retinol-binding protein 4 (RBP4) as a biomarker for HCC. RBP4 protein expression was examined in liver tissues from 80 HCC patients through immunohistochemical analysis. Serum RBP4 concentrations were measured by ELISA in a cohort comprising 290 HCC patients, matched 202 chronic hepatitis B patients and 269 healthy controls. Survival data were collected from HCC patients. The diagnostic and prognostic values of RBP4 were evaluated using receiver operating curve (ROC) analysis. Results: The validation results demonstrated a significant reduction in RBP4 levels in both liver tissues and serum samples from HCC patients. ROC analysis of the diagnostic value of RBP4 revealed an AUC of 0.879 (95 % CI: 0.854∼0.903) for HCC. When combined with AFP, the AUC increased to 0.919, with a sensitivity of 87.9 % and specificity of 80 %. Survival analysis revealed significantly reduced overall survival time in individuals with low-expression of RBP4 compared to those with high-expression. The joint prognostic model exhibited an AUC of 0.926 (95 % CI: 0.888∼0.964), which was significantly higher than that of AFP alone (AUC=0.809; P

As a complementary and alternative therapy, acupuncture is widely used in the prevention and treatment of various diseases. However, the understanding of the mechanism of acupuncture effects is still limited due to the lack of systematic biological validation. Notably, proteomics technologies in the field of acupuncture are rapidly evolving, and these advances are greatly contributing to the research of acupuncture. In this study, we review the progress of proteomics research in analyzing the molecular mechanisms of acupuncture for neurological disorders, pain, circulatory disorders, digestive disorders, and other diseases, with an in-depth discussion around acupoint prescription and acupuncture manipulation modalities. The study found that proteomics has great potential in understanding the mechanisms of acupuncture. This study will help explore the mechanisms of acupuncture from a proteomic perspective and provide information to support future clinical decisions.

BackgroundAneurysmal subarachnoid hemorrhage (aSAH) patients typically have poor prognoses. The anion gap (AG) has been proven to correlate with mortality in various critically ill patients. However, hypoalbuminemia can lead to underestimations of the true anion gap levels. This study was conducted to verify the prognostic value of single AG and albumin-corrected anion gap (ACAG) among aSAH patients.MethodsSignificant factors in the univariate logistic regression analysis were included in the multivariate logistic regression analysis to explore the risk factors for mortality in aSAH patients and to confirm the independent relationship between ACAG and mortality. The restricted cubic spline (RCS) was used to visually show the relationship between ACAG level and mortality risk of aSAH patients. The predictive model for mortality was developed by incorporating significant factors into the multivariate logistic regression analysis. The prognostic value of ACAG and the developed model was evaluated by calculating the area under the receiver operating characteristics curve (AUC).ResultsAmong 710 aSAH patients, a 30-day mortality was observed in 20.3% of the cases. A positive relationship was demonstrated between the ACAG level and mortality in aSAH patients using the RCS curve. The multivariate logistic regression analysis helped discover that only six factors were finally and independently related to mortality of aSAH patients after adjusting for confounding effects, including the Hunt–Hess scale score (p = 0.006), surgical options (p < 0.001), white blood cell count (p < 0.001), serum chloride levels (p = 0.023), ACAG (p = 0.039), and delayed cerebral ischemia (p < 0.001). The AUC values for the AG, albumin, and ACAG in predicting mortality among aSAH patients were 0.606, 0.536, and 0.617, respectively. A logistic regression model, which includes the Hunt–Hess scale score, surgical options, white blood cell count, serum chloride levels, ACAG, and delayed cerebral ischemia, achieved an AUC of 0.911 for predicting mortality.ConclusionThe ACAG is an effective prognostic marker for aSAH patients. A prognostic model incorporating ACAG could help clinicians evaluate the risk of poor outcomes among aSAH patients, thereby facilitating the development of personalized therapeutic strategies.

Abstract The capability to gather heterogeneous data, alongside the increasing power of artificial intelligence to examine it, leading a revolution in harnessing multimodal data in the life sciences. However, most approaches are limited to unimodal data, leaving integrated approaches across modalities relatively underdeveloped in computational pathology. Pathogenomics, as an invasive method to integrate advanced molecular diagnostics from genomic data, morphological information from histopathological imaging, and codified clinical data enable the discovery of new multimodal cancer biomarkers to propel the field of precision oncology in the coming decade. In this perspective, we offer our opinions on synthesizing complementary modalities of data with emerging multimodal artificial intelligence methods in pathogenomics. It includes correlation between the pathological and genomic profile of cancer, fusion of histology, and genomics profile of cancer. We also present challenges, opportunities, and avenues for future work.

Abstract Due to self-incompatibility (SI) prevents self-fertilization, natural or artificial cross-pollination has been conducted in many orchards to stabilize fruit yield. However, it is still puzzled which routes of self S-RNase arresting pollen tube growth. Herein, 17 COBRA genes were isolated from pear genome. Of these genes, the pollen-specifically expressed PbCOB.A.1 and PbCOB.A.2 positively mediates pollen tube growth. The promoters of PbCOB.A.1 and/or PbCOB.A.2 were bound and activated by PbABF.E.2 (an ABRE-binding factor) and PbC2H2.K16.2 (a C2H2-type zinc finger protein). Notably, the expressions of PbCOB.A.1, PbCOB.A.2, and PbC2H2.K16.2 were repressed by self S-RNase, suggesting that self S-RNase reduces the expression of PbCOB.A.1 and PbCOB.A.2 by decreasing the expression of their upstream factors, such as PbC2H2.K16.2, to arrest pollen tube growth. PbCOB.A.1 or PbCOB.A.2 accelerates the growth of pollen tubes treated by self S-RNase, but can hardly affect level of reactive oxygen species and deploymerization of actin cytoskeleton in pollen tubes and cannot physically interact with any reported proteins involved in SI. These results indicate that PbCOB.A.1 and PbCOB.A.2 may not relieve S-RNase toxicity in incompatible pollen tube. The information provides a new route to elucidate the arresting pollen tube growth during SI reaction. Graphical Abstract

Abstract Fungal pathogens typically use secreted effector proteins to suppress host immune activators to facilitate invasion. However, there is rarely evidence supporting the idea that fungal secretory proteins contribute to pathogenesis by transactivating host genes that suppress defense. We previously found that pathogen Magnaporthe oryzae induces rice Bsr-d1 to facilitate infection and hypothesized that a fungal effector mediates this induction. Here, we report that MoSPAB1 secreted by M. oryzae directly binds to the Bsr-d1 promoter to induce its expression, facilitating pathogenesis. Amino acids 103-123 of MoSPAB1 are required for its binding to the Bsr-d1 promoter. Both MoSPAB1 and rice MYBS1 compete for binding to the Bsr-d1 promoter to regulate Bsr-d1 expression. Furthermore, MoSPAB1 homologues are highly conserved among fungi. In particular, Colletotrichum fructicola CfSPAB1 and Colletotrichum sublineola CsSPAB1 activate kiwifruit AcBsr-d1 and sorghum SbBsr-d1 respectively, to facilitate pathogenesis. Taken together, our findings reveal a conserved module that may be widely utilized by fungi to enhance pathogenesis.

In recent years, a new technique called computed tomography-derived fractional flow reserve (CT-FFR) has been developed. CT-FFR overcomes many limitations in the current gold-standard fractional flow reserve (FFR) techniques while maintaining a better concordance with FFR. This technique integrates static coronary CT angiography data with hydrodynamic models, employing algorithms rather than guidewire interventions to compute the FFR. In addition to diagnosing coronary heart disease, CT-FFR has been applied in the preoperative risk assessment of major adverse cardiovascular events (MACEs) in organ transplantation and transcatheter aortic valve replacement (TAVR). Continuous advancements in CT-FFR techniques and algorithms are expanding their applicability to other methodologies. Subsequently, with robust clinical trial validation, CT-FFR can potentially supersede FFR as the primary “gatekeeper” for interventions.

The motion control system of a lower-limb exoskeleton rehabilitation robot (LLERR) is designed to assist patients in lower-limb rehabilitation exercises. This research designed a motion controller for an LLERR-based on the Twin Delayed Deep Deterministic policy gradient (TD3) algorithm to control the lower-limb exoskeleton for gait training in a staircase environment. Commencing with the establishment of a mathematical model of the LLERR, the dynamics during its movement are systematically described. The TD3 algorithm is employed to plan the motion trajectory of the LLERR’s right-foot sole, and the target motion curve of the hip (knee) joint is deduced inversely to ensure adherence to human physiological principles during motion execution. The control strategy of the TD3 algorithm ensures that the movement of each joint of the LLERR is consistent with the target motion trajectory. The experimental results indicate that the trajectory tracking errors of the hip (knee) joints are all within 5°, confirming that the LLERR successfully assists patient in completing lower-limb rehabilitation training in a staircase environment. The primary contribution of this study is to propose a non-linear control strategy tailored for the staircase environment, enabling the planning and control of the lower-limb joint motions facilitated by the LLERR.

Many compartments are prone to pose safety hazards such as loose fasteners or object intrusion due to their confined space, making manual inspection challenging. To address the challenges of complex inspection environments, diverse target categories, and variable scales in confined compartments, this paper proposes a novel GMS-YOLO network, based on the improved YOLOv8 framework. In addition to the lightweight design, this network accurately detects targets by leveraging more precise high-level and low-level feature representations obtained from GhostHGNetv2, which enhances feature-extraction capabilities. To handle the issue of complex environments, the backbone employs GhostHGNetv2 to capture more accurate high-level and low-level feature representations, facilitating better distinction between background and targets. In addition, this network significantly reduces both network parameter size and computational complexity. To address the issue of varying target scales, the first layer of the feature fusion module introduces Multi-Scale Convolutional Attention (MSCA) to capture multi-scale contextual information and guide the feature fusion process. A new lightweight detection head, Shared Convolutional Detection Head (SCDH), is designed to enable the model to achieve higher accuracy while being lighter. To evaluate the performance of this algorithm, a dataset for object detection in this scenario was constructed. The experiment results indicate that compared to the original model, the parameter number of the improved model decreased by 37.8%, the GFLOPs decreased by 27.7%, and the average accuracy increased from 82.7% to 85.0%. This validates the accuracy and applicability of the proposed GMS-YOLO network.