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Abstract Background Colorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis. Methods We conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects. Results SLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1’s transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers. Conclusions Our findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.

Abstract Background Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer. Methods A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis. Results In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival. Conclusions Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis.

Abstract Objective The study aimed to investigate the predictive value of dynamic contrast-enhanced ultrasound (DCE-US) in differentiating small-duct (SD) and large-duct (LD) types of intrahepatic cholangiocarcinoma (ICC). Methods This study retrospectively enrolled 110 patients with pathologically confirmed ICC lesions who were subject to preoperative contrast-enhanced ultrasound (CEUS) examinations between January 2022 and February 2023. Patients were further classified according to the subtype: SD-type and LD-type, and an optimal predictive model was established and validated using the above pilot cohort. The test cohort, consisting of 48 patients prospectively enrolled from March 2023 to September 2023, was evaluated. Results In the pilot cohort, compared with SD-type ICCs, more LD-type ICCs showed elevated carcinoembryonic antigen (p

High-speed railway tunnels in various countries have continuously reported accidents of vault falling concrete blocks. Once the concrete block falling occurs, serious consequences follow, and traffic safety may be endangered. The aerodynamic shockwave evolves from the initial compression wave may be an important inducement causing the tunnel lining cracks to grow and form falling concrete blocks. A joint calculation framework is established based on ANSYS Fluent, ABAQUS, and FRANC3D for calculating the crack tip field under the aerodynamic shockwave. The intensification effect of aerodynamic shockwaves in the crack is revealed, and the evolution characteristics of the crack tip field and the influence factors of stress intensity factor (SIF) are analyzed. Results show that (1) the aerodynamic shockwave intensifies after entering the crack, resulting in more significant pressure in the crack than the input pressure. The maximum pressure of the inclined and longitudinal cracks is higher than the corresponding values of the circumferential crack, respectively. (2) The maximum SIF of the circumferential, inclined, and longitudinal crack appears at 0.5, 0.68, and 0.78 times the crack front length. The maximum SIF of the circumferential crack is higher than that of the inclined and longitudinal crack. The possibility of crack growth of the circumferential crack is the highest under aerodynamic shockwaves. (3) The influence of train speed on the SIF of the circumferential crack is more than 40%. When the train speed, crack depth, and crack length change, the change of pressure in the crack is the direct cause of the change of SIF.

Abstract Background In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models. Results Measurements of the ambient dose rate equivalent Ḣ * (10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99mTc-HDP/MDP, 18FDG and Na131I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate Ė of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of Ḣ * (10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration. Conclusions The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions.

Abstract Background The family Rhabdiasidae (Nematoda: Rhabditida) is a globally distributed group of nematode parasites, with over 110 species parasitic mainly in amphibians and reptiles. However, the systematic position of the family Rhabdiasidae in the order Rhabditida remains unsolved, and the evolutionary relationships among its genera are still unclear. Moreover, the present knowledge of the mitochondrial genomes of rhabdiasids remains limited. Methods Two rhabdiasid species: Rhabdias kafunata Sata, Takeuchi & Nakano, 2020 and R. bufonis (Schrank, 1788) collected from the Asiatic toad Bufo gargarizans Cantor (Amphibia: Anura) in China, were identified based on morphology (light and scanning electron microscopy) and molecular characterization (sequencing of the nuclear 28S and ITS regions and mitochondrial cox1 and 12S genes). The complete mitochondrial genomes of R. kafunata and R. bufonis were also sequenced and annotated for the first time. Moreover, phylogenetic analyses based on the amino acid sequences of 12 protein-coding genes (PCGs) of the mitochondrial genomes were performed to clarify the systematic position of the family Rhabdiasidae in the order Rhabditida using maximum likelihood (ML) and Bayesian inference (BI). The phylogenetic analyses based on the 28S + ITS sequences, were also inferred to assess the evolutionary relationships among the genera within Rhabdiasidae. Results The detailed morphology of the cephalic structures, vulva and eggs in R. kafunata and R. bufonis was revealed using scanning electron microscopy (SEM) for the first time. The characterization of 28S and ITS regions of R. kafunata was reported for the first time. The mitogenomes of R. kafunata and R. bufonis are 15,437 bp and 15,128 bp long, respectively, and both contain 36 genes, including 12 PCGs (missing atp8). Comparative mitogenomics revealed that the gene arrangement of R. kafunata and R. bufonis is different from all of the currently available mitogenomes of nematodes. Phylogenetic analyses based on the ITS + 28S data showed Neoentomelas and Kurilonema as sister lineages, and supported the monophyly of Entomelas, Pneumonema, Serpentirhabdias and Rhabdias. Mitochondrial phylogenomic results supported Rhabdiasidae as a member of the superfamily Rhabditoidea in the suborder Rhabditina, and its occurrance as sister to the family Rhabditidae. Conclusions The complete mitochondrial genome of R. kafunata and R. bufonis were reported for the first time, and two new gene arrangements of mitogenomes in Nematoda were revealed. Mitogenomic phylogenetic results indicated that the family Rhabdiasidae is a member of Rhabditoidea in Rhabditina, and is closely related to Rhabditidae. Molecular phylogenies based on the ITS + 28S sequence data supported the validity of Kurilonema, and showed that Kurilonema is sister to Neoentomelas. The present phylogenetic results also indicated that the ancestors of rhabdiasids seem to have initially infected reptiles, then spreading to amphibians. Graphical Abstract

While the topic of attracting and maintaining inbound international students has received much scholarly attention in higher education, attracting female international students has rarely been discussed. This study addresses the issue of attracting degree-seeking female international students. Based on the notion of situational factors and total quality management (TQM), we assumed both institutional design and students’ satisfaction are core concepts for attracting and retaining female international students that will make a difference in higher education. A total of 215 survey responses were analyzed, and a covariance-based structural equation modeling (CB-SEM) approach was developed. The results confirm female international students’ perception of 14 observed variables in the three first-order components and suggest that they can create a second-order construct of push factors, institutional situations, and satisfaction (latent variables). This study demonstrates that higher-order modeling leads to theoretical parsimony and reduces model complexity in the proposed CB-SEM. The findings suggest that the casual relationship works well and both institutional leadership and international strategy can play crucial roles in the process of transforming female international students’ learning satisfaction.

Introduction Spinal cord injury (SCI) is a catastrophic event with devastating physical, social and occupational consequences for patients and their families. The number of patients with acute SCI in China continues to grow rapidly, but there have been no large prospective cohort studies of patients with acute SCI. This proposed study aims to establish a multicentre, extensive sample cohort of clinical data and biological samples of patients in China, which would aid the systematisation and standardisation of clinical research and treatment of acute SCI, thus reducing the heavy burden of acute SCI on patients and society.Methods and analysis The Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study is an observational, multicentre cohort study of patients with acute SCI admitted to the Qilu Hospital of Shandong University and other participating centres with prospective collection of their clinical data and biological samples. We aim to recruit 2097 patients in this study. Demographics, disease history, emergency intervention information, motor and sensory examinations, surgical information, medication information and rehabilitation evaluation will be recorded. This will facilitate the development of a prediction model for complications and prognosis of patients with acute SCI and an evaluation of the current management of acute SCI. Among these variables, detailed information on surgical treatment will also be used to assess procedures for acute SCI treatment. Outcome measurements, including the International Standard for Neurological Classification of Spinal Cord Injury examinations, the occurrence of complications and death, will be performed repeatedly during follow-up. We will analyse imaging data and blood samples to develop SCI imaging markers and biomarkers.Ethics and dissemination This study protocol has been approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. The findings will be disseminated in peer-reviewed journals and academic conferences.

Objective: Molidustat is a novel agent investigated for the treatment of anemia in both dialysisdependent (DD) and non-dialysis-dependent (NDD) patients. Its efficacy and safety are still unclear. Methods: We searched five databases to identify randomized controlled trials comparing molidustat to erythropoiesis-stimulating agents (ESAs) or placebo in patients with anemia. Results: Six studies containing 2025 eligible participants were identified. For NDD patients, the change in Hb levels from baseline (ΔHb) was significantly higher for molidustat than for placebo [mean difference (MD) = 1.47 (95 % CI: 1.18 to 1.75), P

High-speed trains (HSTs) transiting subgrade-cutting transition sections in crosswinds have become a common operating scenario. This paper utilizes the Improved Delayed Detached Eddy Simulation (IDDES) turbulence model, considers air compressibility, and establishes a three-dimensional coupled train-subgrade-wind dynamics model. The aerodynamic load (AL) variation rules of trains and discrepancies in the flow field mechanisms when HSTs transit various types of subgrade-cutting transition sections [half cutting and half flat (HCHF), double side cutting (DC), and half cutting and half embankment (HCHE)] under crosswind conditions are revealed using this model. The results indicate the following. (1) The aerodynamic performance deteriorates when trains transit three subgrade-cutting transition sections under crosswinds. (2) As trains enter the transition section from a flat approach, the head car’s AL power spectrum density (PSD) is the largest when operating in the DC case. (3) After the train drives into the subsequent operating scenario, the average of the AL in the DC case is the lowest. (4) In the DC case, a slope of 1:0.75 should be taken as the basis for the design of the corresponding cutting parameters. (5) After the train enters the cutting, the winding flow speed and number of vortex structures surrounding the trains increase significantly.

Summary: Background: Clinical appearance and high-frequency ultrasound (HFUS) are indispensable for diagnosing skin diseases by providing internal and external information. However, their complex combination brings challenges for primary care physicians and dermatologists. Thus, we developed a deep multimodal fusion network (DMFN) model combining analysis of clinical close-up and HFUS images for binary and multiclass classification in skin diseases. Methods: Between Jan 10, 2017, and Dec 31, 2020, the DMFN model was trained and validated using 1269 close-ups and 11,852 HFUS images from 1351 skin lesions. The monomodal convolutional neural network (CNN) model was trained and validated with the same close-up images for comparison. Subsequently, we did a prospective and multicenter study in China. Both CNN models were tested prospectively on 422 cases from 4 hospitals and compared with the results from human raters (general practitioners, general dermatologists, and dermatologists specialized in HFUS). The performance of binary classification (benign vs. malignant) and multiclass classification (the specific diagnoses of 17 types of skin diseases) measured by the area under the receiver operating characteristic curve (AUC) were evaluated. This study is registered with www.chictr.org.cn (ChiCTR2300074765). Findings: The performance of the DMFN model (AUC, 0.876) was superior to that of the monomodal CNN model (AUC, 0.697) in the binary classification (P = 0.0063), which was also better than that of the general practitioner (AUC, 0.651, P = 0.0025) and general dermatologists (AUC, 0.838; P = 0.0038). By integrating close-up and HFUS images, the DMFN model attained an almost identical performance in comparison to dermatologists (AUC, 0.876 vs. AUC, 0.891; P = 0.0080). For the multiclass classification, the DMFN model (AUC, 0.707) exhibited superior prediction performance compared with general dermatologists (AUC, 0.514; P = 0.0043) and dermatologists specialized in HFUS (AUC, 0.640; P = 0.0083), respectively. Compared to dermatologists specialized in HFUS, the DMFN model showed better or comparable performance in diagnosing 9 of the 17 skin diseases. Interpretation: The DMFN model combining analysis of clinical close-up and HFUS images exhibited satisfactory performance in the binary and multiclass classification compared with the dermatologists. It may be a valuable tool for general dermatologists and primary care providers. Funding: This work was supported in part by the National Natural Science Foundation of China and the Clinical research project of Shanghai Skin Disease Hospital.

Tenuazonic acid (TeA) and patulin (PAT), as the naturally occurring mycotoxins with various toxic effects, are often detected in environment and food chain, has attracted more and more attention due to their widespread and high contaminations as well as the coexistence, which leads to potential human and animals’ risks. However, their combined toxicity has not been reported yet. In our study, C. elegans was used to evaluate the type of combined toxicity caused by TeA+PAT and its related mechanisms. The results showed that TeA and PAT can induce synergistic toxic effects based on Combination Index (CI) evaluation model (Chou-Talalay method), that is, the body length, brood size as well as the levels of ROS, CAT and ATP were significantly affected in TeA+PAT-treated group compared with those in TeA- or PAT-treated group. Besides, the expressions of oxidative (daf-2, daf-16, cyp-35a2, ctl-1, ctl-3, pmk-1, jnk-1, skn-1) and intestinal (fat-5, pod-2, egl-8, pkc-3, ajm-1, nhx-2) stress-related genes were disrupted, among which daf-16 displayed the most significant alternation. Further study on daf-16 gene defective C. elegans showed that the damages to the mutant nematodes were significantly attenuated. Since daf-2, daf-16, jnk-1 and pmk-1 are evolutionarily conserved, our findings could hint synergistic toxic effects of TeA+PAT on higher organisms.

Objectives: The prevalence of G6PD deficiency has not been reported in Yangjiang, a western city in Guangdong province. This study aims to investigate the molecular characteristics of G6PD deficiency in this region.Methods: Blood samples were collected from adults at a local hospital to screen for G6PD deficiency. The deficient samples were subjected to further analysis using PCR and reverse dot blot to determine the specific G6PD variants.Results: Among the 3314 male subjects, 250 cases of G6PD deficiency were found using the G6PD enzyme quantitative assay, resulting in a prevalence of 7.54% (250/3314) in the Yangjiang region. The prevalence of G6PD deficiency in females was 3.42% (176/5145). Out of the 268 cases of G6PD deficiency tested for G6PD mutations, reverse dot blot identified 20 different G6PD variants. The most common G6PD variant was c.1388G>A (81/268), followed by c.1376G>T (48/268), c.95A>G (32/268), c.1024C>T (9/268), c.392G>T (7/268), and c.871G>A/c.1311C>T (6/268). It was observed that c.871G>A was always linked to the polymorphism of c.1311C>T in this population.Conclusion: This investigation into G6PD deficiency in this area is expected to significantly improve our understanding of the prevalence and molecular characterization of this condition.

Cerebral ischaemiareperfusion injury is an important pathological process in nervous system diseases during which neurons undergo oxygenglucose deprivation and reoxygenation (OGD/R) injury. No study has used epitranscriptomics to explore the characteristics and mechanism of injury. N6methyladenosine (m6A) is the most abundant epitranscriptomic RNA modification. However, little is known about m6A modifications in neurons, especially during OGD/R. m6A RNA immunoprecipitation sequencing (MeRIPseq) and RNA-sequencing data for normal and OGD/R-treated neurons were analysed by bioinformatics. MeRIP quantitative real-time polymerase chain reaction was used to determine the m6A modification levels on specific RNAs. We report the m6A modification profiles of the mRNA and circRNA transcriptomes of normal and OGD/R-treated neurons. Expression analysis revealed that the m6A levels did not affect m6A mRNA or m6A circRNA expression. We found crosstalk between m6A mRNAs and m6A circRNAs and identified three patterns of m6A circRNA production in neurons; thus, distinct OGD/R treatments induced the same genes to generate different m6A circRNAs. Additionally, m6A circRNA biogenesis during distinct OGD/R processes was found to be time specific. These results expand our understanding of m6A modifications in normal and OGD/R-treated neurons, providing a reference to explore epigenetic mechanisms and potential treatments for OGD/R-related diseases.

Objective: Peroxiredoxin-3 (Prx-3) is widely acknowledged as an antioxidant that protects against mitochondrialreactive oxygen species. Nonetheless, its role in cardiac fibrosis has not been elucidated. We aim to explore the roleand mechanism of Prx-3 in cardiac fibrosis.Materials and Methods: In this experimental study, mice received subcutaneous injections of isoproterenol (ISO) for 14consecutive days (10 mg/kg/d for three days, followed by 5 mg/kg/d for 11 days) to establish a cardiac fibrosis model. Themice were subsequently injected with adenovirus-Prx-3 (ad-Prx-3) to enable Prx-3 overexpression. Echocardiographywas used to evaluate cardiac function. Mice heart fibroblasts were isolated and stimulated with transforming growthfactor β1 (TGFβ1) to induce fibrosis in vitro. Cells were also transfected with ad-Prx-3 for overexpression of Prx-3.Results: Echocardiographic diameters and fibrosis markers indicated that Prx-3 could inhibit ISO-induced cardiacdysfunction and fibrosis. Fibroblasts with Prx-3 overexpression exhibited reduced activation, proliferation, and collagentranscription. We found that Prx-3 reduced the expression of NADPH oxidase 4 (NOX4) and reduced P38 levels. Aftertreatment with a P38 inhibitor, the Prx-3 overexpression-induced anti-fibrosis effect was mitigated.Conclusion: Prx-3 could protect against ISO-induced cardiac fibrosis by inhibiting the NOX4-P38 pathway.

Abstract N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5’ and 3’ untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.